Evaluation of Therapy Management and Patient Compliance in Postmenopausal Patients with Hormone Receptor-positive Breast Cancer Receiving Letrozole Treatment: The EvaluateTM Study

PubMed Central

Fasching, P. A.; Fehm, T.; Kellner, S.; de Waal, J.; Rezai, M.; Baier, B.; Baake, G.; Kolberg, H.-C.; Guggenberger, M.; Warm, M.; Harbeck, N.; Würstlein, R.; Deuker, J.-U.; Dall, P.; Richter, B.; Wachsmann, G.; Brucker, C.; Siebers, J. W.; Fersis, N.; Kuhn, T.; Wolf, C.; Vollert, H.-W.; Breitbach, G.-P.; Janni, W.; Landthaler, R.; Kohls, A.; Rezek, D.; Noesslet, T.; Fischer, G.; Henschen, S.; Praetz, T.; Heyl, V.; Kühn, T.; Krauß, T.; Thomssen, C.; Kümmel, S.; Hohn, A.; Tesch, H.; Mundhenke, C.; Hein, A.; Rauh, C.; Bayer, C. M.; Jacob, A.; Schmidt, K.; Belleville, E.; Hadji, P.; Wallwiener, D.; Grischke, E.-M.; Beckmann, M. W.; Brucker, S. Y.

2014-01-01

Introduction: The EvaluateTM study (Evaluation of therapy management and patient compliance in postmenopausal hormone receptor-positive breast cancer patients receiving letrozole treatment) is a prospective, non-interventional study for the assessment of therapy management and compliance in the routine care of postmenopausal women with invasive hormone receptor-positive breast cancer receiving letrozole. The parameters for inclusion in the study are presented and discussed here. Material and Methods: Between January 2008 and December 2009 a total of 5045 patients in 310 study centers were recruited to the EvaluateTM study. Inclusion criteria were hormone receptor-positive breast cancer and adjuvant treatment or metastasis. 373 patients were excluded from the analysis for various reasons. Results: A total of 4420 patients receiving adjuvant treatment and 252 patients with metastasis receiving palliative treatment were included in the study. For 4181 patients receiving adjuvant treatment, treatment with the aromatase inhibitor letrozole commenced immediately after surgery (upfront). Two hundred patients had initially received tamoxifen and started aromatase inhibitor treatment with letrozole at 1–5 years after diagnosis (switch), und 39 patients only commenced letrozole treatment 5–10 years after diagnosis (extended endocrine therapy). Patient and tumor characteristics were within expected ranges, as were comorbidities and concurrent medication. Conclusion: The data from the EvaluateTM study will offer a good overview of therapy management in the routine care of postmenopausal women with hormone receptor-positive breast cancer. Planned analyses will look at therapy compliance and patient satisfaction with how information is conveyed and the contents of the conveyed information. PMID:25568468

Rethinking the laryngopharyngeal reflux treatment algorithm: Evaluating an alternate empiric dosing regimen and considering up-front, pH-impedance, and manometry testing to minimize cost in treating suspect laryngopharyngeal reflux disease.

PubMed

Carroll, Thomas L; Werner, Astrid; Nahikian, Kael; Dezube, Aaron; Roth, Douglas F

2017-10-01

Empiric proton pump inhibitor (PPI) trials for laryngopharyngeal reflux (LPR) are common. A majority of the patients respond to acid suppression. This work intends to evaluate once-daily, 40 mg omeprazole and once-nightly, 300 mg ranitidine (QD/QHS) dosing as an alternative regimen, and use this study's cohort to evaluate empiric regimens prescribed for LPR as compared to up-front testing with pH impedance multichannel intraluminal impedance (MII) with dual pH probes and high-resolution manometry (HRM) for potential cost minimization. Retrospective cohort review and cost minimization study. A chart review identified patients diagnosed with LPR. All subjects were treated sequentially and outcomes recorded. Initial QD/QHS dosing increased after 3 months to BID if no improvement and ultimately prescribed MII and HRM if they failed BID dosing. Decision tree diagrams were constructed to determine costs of two empiric regimens and up-front MII and HRM. Ninety-seven subjects met the criteria. Responders and nonresponders to empiric therapy were identified. Seventy-two subjects (74%) responded. Forty-eight (67% of responders and 49% of all) improved with QD/QHS dosing. Forty-nine (51%) subjects escalated to BID dosing. Twenty-four subjects (33% of responders and 25% of all) improved on BID therapy. Twenty-five subjects (26%) did not respond to acid suppression. Average weighted cost was $1,897.00 per patient for up-front testing, $3,033.00 for initial BID, and $3,366.00 for initial QD/QHS. An alternate QD/QHS regimen improved the majority who presented with presumed LPR. Cost estimates demonstrate that the QD/QHS regimen was more expensive than the initial BID high-dose PPI for 6 months. Overall per-patient cost appears less with up-front MII and HRM. 4. Laryngoscope, 127:S1-S13, 2017. © 2017 The American Laryngological, Rhinological and Otological Society, Inc.

Predictors of neurologic and nonneurologic death in patients with brain metastasis initially treated with upfront stereotactic radiosurgery without whole-brain radiation therapy

PubMed Central

Johnson, Adam G.; Ruiz, Jimmy; Isom, Scott; Lucas, John T.; Hinson, William H.; Watabe, Kounosuke; Laxton, Adrian W.; Tatter, Stephen B.; Chan, Michael D.

2017-01-01

Abstract Background. In this study we attempted to discern the factors predictive of neurologic death in patients with brain metastasis treated with upfront stereotactic radiosurgery (SRS) without whole brain radiation therapy (WBRT) while accounting for the competing risk of nonneurologic death. Methods. We performed a retrospective single-institution analysis of patients with brain metastasis treated with upfront SRS without WBRT. Competing risks analysis was performed to estimate the subdistribution hazard ratios (HRs) for neurologic and nonneurologic death for predictor variables of interest. Results. Of 738 patients treated with upfront SRS alone, neurologic death occurred in 226 (30.6%), while nonneurologic death occurred in 309 (41.9%). Multivariate competing risks analysis identified an increased hazard of neurologic death associated with diagnosis-specific graded prognostic assessment (DS-GPA) ≤ 2 (P = .005), melanoma histology (P = .009), and increased number of brain metastases (P<.001), while there was a decreased hazard associated with higher SRS dose (P = .004). Targeted agents were associated with a decreased HR of neurologic death in the first 1.5 years (P = .04) but not afterwards. An increased hazard of nonneurologic death was seen with increasing age (P =.03), nonmelanoma histology (P<.001), presence of extracranial disease (P<.001), and progressive systemic disease (P =.004). Conclusions. Melanoma, DS-GPA, number of brain metastases, and SRS dose are predictive of neurologic death, while age, nonmelanoma histology, and more advanced systemic disease are predictive of nonneurologic death. Targeted agents appear to delay neurologic death. PMID:27571883

Evaluation of non-genomic, clinical risk and survival results in endocrine-sensitive, HER-2 negative, node negative breast cancer.

PubMed

Baena Cañada, José M; Gámez Casado, Salvador; Rodríguez Pérez, Lourdes; Quílez Cutillas, Alicia; Cortés Carmona, Cristina; Rosado Varela, Petra; Estalella Mendoza, Sara; Ramírez Daffós, Patricia; Benítez Rodríguez, Encarnación

2018-02-28

In endocrine-sensitive, HER-2 negative, node negative breast cancer, the presence of a low genomic risk allows treatment with adjuvant endocrine therapy alone, obtaining excellent survival rates. The justification for this study is to show that excellent survival rates are also obtained by treating with adjuvant hormone therapy alone, based on clinical risk assessment. A descriptive, observational and retrospective study was performed between 2006 and 2016 with endocrine-sensitive, HER-2 negative, node negative breast cancer, greater than 1cm or between 0.6 and 1cm with unfavourable features. Retrospective review of health records. Mortality data of the National Registry of Deaths. A total of 203 patients were evaluable for survival. One hundred and twenty-three (60.50%) were treated with adjuvant endocrine therapy alone, 77 (37.90%) with chemotherapy and endocrine therapy, one (0.50%) with chemotherapy alone and 2 (1%) were not treated. The overall survival rate at 5 years was 97% (95% confidence interval [CI] 94-100). Distant recurrence-free interval was 94% (95% CI 90-98). In the subgroup of patients treated with endocrine therapy alone, overall survival and distant recurrence-free interval rates at 5 years were 98% (95% CI 95-100) and 97% (95% CI 93-100), respectively. Patients with endocrine-sensitive, HER-2-negative, node negative breast cancer treated with endocrine therapy alone according to their clinical risk have similar survival outcomes as those treated with endocrine therapy according to their genomic risk. Copyright © 2018 Elsevier España, S.L.U. All rights reserved.

Predictors of neurologic and nonneurologic death in patients with brain metastasis initially treated with upfront stereotactic radiosurgery without whole-brain radiation therapy.

PubMed

McTyre, Emory R; Johnson, Adam G; Ruiz, Jimmy; Isom, Scott; Lucas, John T; Hinson, William H; Watabe, Kounosuke; Laxton, Adrian W; Tatter, Stephen B; Chan, Michael D

2017-04-01

In this study we attempted to discern the factors predictive of neurologic death in patients with brain metastasis treated with upfront stereotactic radiosurgery (SRS) without whole brain radiation therapy (WBRT) while accounting for the competing risk of nonneurologic death. We performed a retrospective single-institution analysis of patients with brain metastasis treated with upfront SRS without WBRT. Competing risks analysis was performed to estimate the subdistribution hazard ratios (HRs) for neurologic and nonneurologic death for predictor variables of interest. Of 738 patients treated with upfront SRS alone, neurologic death occurred in 226 (30.6%), while nonneurologic death occurred in 309 (41.9%). Multivariate competing risks analysis identified an increased hazard of neurologic death associated with diagnosis-specific graded prognostic assessment (DS-GPA) ≤ 2 (P = .005), melanoma histology (P = .009), and increased number of brain metastases (P<.001), while there was a decreased hazard associated with higher SRS dose (P = .004). Targeted agents were associated with a decreased HR of neurologic death in the first 1.5 years (P = .04) but not afterwards. An increased hazard of nonneurologic death was seen with increasing age (P =.03), nonmelanoma histology (P<.001), presence of extracranial disease (P<.001), and progressive systemic disease (P =.004). Melanoma, DS-GPA, number of brain metastases, and SRS dose are predictive of neurologic death, while age, nonmelanoma histology, and more advanced systemic disease are predictive of nonneurologic death. Targeted agents appear to delay neurologic death. © The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Barriers to and facilitative processes of endocrine therapy adherence among women with breast cancer.

PubMed

Bright, Emma E; Petrie, Keith J; Partridge, Ann H; Stanton, Annette L

2016-07-01

The treatment of chronic illness, and the prevention of disease progression and recurrence, often involve long-term adherence to prescription medications in breast cancer. Despite the survival benefit of endocrine therapies, nonadherence remains high. In this study, we examined barriers to and facilitators of endocrine therapy adherence among women with breast cancer (n = 1371). Participants currently taking tamoxifen or aromatase inhibitors were recruited from Dr. Susan Love Research Foundation's Army of Women(®) Registry. Participants responded online to open-ended and close-ended questions about thoughts, feelings, and behaviors relevant to endocrine therapy. Two weeks later, women were invited to complete a second online questionnaire regarding current endocrine therapy adherence. Approximately one-third (36 %) of participants reported the presence of factors that make endocrine therapy difficult; reporting any barrier to medication adherence was significantly associated with nonadherence (P < 0.001). In addition, 31 % of women used one or more strategies to maintain their motivation to adhere and the use of cognitive self-talk (e.g., thoughts regarding endocrine therapy efficacy) was related to higher adherence. Hierarchical linear regressions revealed a significant behavioral barrier × behavioral facilitator interaction (P < 0.05); participants who endorsed a behavioral barrier in the absence of a behavioral facilitator reported the lowest adherence. Findings suggest that a sizeable minority of women face barriers to taking endocrine therapy, which are associated with nonadherence.

Navigation through inter- and intratumoral heterogeneity of endocrine resistance mechanisms in breast cancer: A potential role for Liquid Biopsies?

PubMed

Reinhardt, Florian; Franken, André; Fehm, Tanja; Neubauer, Hans

2017-11-01

The majority of breast cancers are hormone receptor positive due to the expression of the estrogen and/or progesterone receptors. Endocrine therapy is a major treatment option for all disease stages of hormone receptor-positive breast cancer and improves overall survival. However, endocrine therapy is limited by de novo and acquired resistance. Several factors have been proposed for endocrine therapy failures, which include molecular alterations in the estrogen receptor pathway, altered expression of cell-cycle regulators, autophagy, and epithelial-to-mesenchymal transition as a consequence of tumor progression and selection pressure. It is essential to reveal and monitor intra- and intertumoral alterations in breast cancer to allow optimal therapy outcome. Endocrine therapy navigation by molecular profiling of tissue biopsies is the current gold standard but limited in many reasons. "Liquid biopsies" such as circulating-tumor cells and circulating-tumor DNA offer hope to fill that gap in allowing non-invasive serial assessment of biomarkers predicting success of endocrine therapy regimen. In this context, this review will provide an overview on inter- and intratumoral heterogeneity of endocrine resistance mechanisms and discuss the potential role of "liquid biopsies" as navigators to personalize treatment methods and prevent endocrine treatment resistance in breast cancer.

Gait or Walking Problems

MedlinePlus

... be frank and upfront with your PT about cost, payment plans, and the benefits you can expect from therapy. Weakness Muscle weakness ... medical equipment) may be available through private or public insurance, community ... benefits if you have done military service. Reimbursement programs ...

Long term effects of extended adjuvant endocrine therapy on quality of life in breast cancer patients.

PubMed

Kool, M; Fontein, D B Y; Meershoek-Klein Kranenbarg, E; Nortier, J W R; Rutgers, E J T; Marang-van de Mheen, P J; van de Velde, C J H

2015-06-01

The standard treatment for hormone-receptor positive, postmenopausal early breast cancer patients is 5 years of adjuvant endocrine therapy. Previous studies demonstrate that prolonging adjuvant endocrine therapy may improve disease-free survival. However, endocrine therapy is known for its adverse events, which may negatively affect Quality of Life (QoL). The aim of this study is to assess the impact of extended adjuvant endocrine therapy on long-term QoL outcomes. 471 patients selected from the IDEAL trial were invited to complete a questionnaire 1-1.5 years after starting with extended therapy. The questionnaire consisted of the EORTC QLQ-C30 and QLQ-BR23 questionnaires. Mean QoL outcomes were compared with EORTC reference values for stage I and II breast cancer patients and the general population. Furthermore, QoL outcomes were compared between different treatment regimens. A difference of eight points was considered clinically relevant. IDEAL patients receiving extended adjuvant endocrine therapy have significantly and clinically relevant better global QoL compared with reference values for stage I and II breast cancer patients (79.6 versus 64.6; p < 0.01) and the general population (79.6 versus 71.2; p < 0.01). Similar results were found for emotional function, pain, appetite loss, diarrhea and financial problems. Between treatment regimens prior to extended adjuvant endocrine therapy, differences were only found on specific QoL domains (e.g. arm symptoms). Breast cancer patients on extended adjuvant endocrine therapy have significantly and clinically relevant better global QoL compared with other stage I-II breast cancer patients and the general population, 6-8.5 years after diagnosis. Copyright © 2015 Elsevier Ltd. All rights reserved.

Use and Effectiveness of Adjuvant Endocrine Therapy for Hormone Receptor-Positive Breast Cancer in Men.

PubMed

Venigalla, Sriram; Carmona, Ruben; Guttmann, David M; Jain, Varsha; Freedman, Gary M; Clark, Amy S; Shabason, Jacob E

2018-05-24

Although adjuvant endocrine therapy confers a survival benefit among females with hormone receptor (HR)-positive breast cancer, the effectiveness of this treatment among males with HR-positive breast cancer has not been rigorously investigated. To investigate trends, patterns of use, and effectiveness of adjuvant endocrine therapy among men with HR-positive breast cancer. This retrospective cohort study identified patients in the National Cancer Database with breast cancer who had received treatment from 2004 through 2014. Inclusion criteria for the primary study cohort were males at least 18 years old with nonmetastatic HR-positive invasive breast cancer who underwent surgery with or without adjuvant endocrine therapy. A cohort of female patients was also identified using the same inclusion criteria for comparative analyses by sex. Data analysis was conducted from October 1, 2017, to December 15, 2017. Receipt of adjuvant endocrine therapy. Patterns of adjuvant endocrine therapy use were assessed using multivariable logistic regression analyses. Association between adjuvant endocrine therapy use and overall survival was assessed using propensity score-weighted multivariable Cox regression models. The primary study cohort comprised 10 173 men with HR-positive breast cancer (mean [interquartile range] age, 66 [57-75] years). The comparative cohort comprised 961 676 women with HR-positive breast cancer (mean [interquartile range] age, 62 [52-72] years). The median follow-up for the male cohort was 49.6 months (range, 0.1-142.5 months). Men presented more frequently than women with HR-positive disease (94.0% vs 84.3%, P < .001). However, eligible men were less likely than women to receive adjuvant endocrine therapy (67.3% vs 79.0%; OR, 0.61; 95% CI, 0.58-0.63; P < .001). Treatment at academic facilities (odds ratio, 1.13; 95% CI, 1.02-1.25; P = .02) and receipt of adjuvant radiotherapy (odds ratio, 2.83; 95% CI, 2.55-3.15; P < .001) or chemotherapy (odds ratio, 1.20; 95% CI, 1.07-1.34; P < .001) were statistically significantly associated with adjuvant endocrine therapy use in men. A propensity score-weighted analysis indicated that relative to no use, adjuvant endocrine therapy use in men was associated with improved overall survival (hazard ratio, 0.70; 95% CI, 0.63-0.77; P < .001). There is a sex disparate underuse of adjuvant endocrine therapy among men with HR-positive breast cancer despite the use of this treatment being associated with improved overall survival. Further research and interventions may be warranted to bridge gaps in care in this population.

[Histological effects of short term endocrine therapy on prostatic cancer].

PubMed

Irisawa, C; Yoshimura, Y; Yokota, T; Yamaguchi, O; Kondou, Y; Hamasaki, T; Yamad, Y; Kurosu, S; Chiba, R

1996-07-01

The objective of this study is to investigate the pathological changes which occurred in prostatic cancer shortly after the commencement of endocrine therapy. Fourty-three patients underwent radical prostatectomy immediately after the short term endocrine therapy (treatment period was within one month) and the histological pictures of operative specimens were compared to those obtained from the pretreatment biopsy specimens. Degenerative changes of cancer cells, such as nuclear and cytoplasmic vacuole, collapse of the cytoplasm and the appearance of naked hyperchromatic nucleus were noticed after the short term endocrine therapy. Especially in the cases which were histologically evaluated to be poorly differentiated in the biopsy specimens, not only degenerative changes but also destruction of cancer nests caused by cell death were observed. The histological effects affected by short term endocrine treatment had no relation to the prognosis, but in the cases of stage D2, the pathological grade judged by post-therapeutic specimens were found to be useful for the prediction of prognosis. Endocrine therapy induces remarkable pathological changes in prostatic cancer within a very short time after beginning treatment.

[Synergistic effect of cell kinetics-directed chemo-endocrine therapy on experimental mammary tumors].

PubMed

Ueki, H

1987-11-01

We tried to demonstrate that the cell kinetics-directed chemoendocrine therapy is more effective on hormone dependent breast cancer than empirical combination of the endocrine therapy and chemotherapy. Cell kinetics of each tumor was measured by flow cytometric analysis. Estrogen dependent human breast cancer cell line MCF-7 was used in vitro. In vivo, androgen dependent SC-115 carcinoma was transplanted to DDS mice. In vitro, tamoxifen was administered as the endocrine therapy. In vivo, we carried out testectomy on DDS mice. Effect of the endocrine therapy on the cell kinetics of the tumor was thought to be G1-S depression. High density 5FU was administered as the chemotherapeutic agents, whose content was 1 microgram/ml in vitro and 40 mg/kg in vivo. 5FU brought temporary decrease of cells in S phase. Only anteceding 5FU administration had synergistic effect in combination of 5FU and the endocrine therapy. 5FU was convinced to act more effectively on cells in S phase, so it was shown that cell kinetics-directed schedule was superior to the empirical treatment schedule in chemoendocrine therapy.

Omitting radiation therapy after lumpectomy for pure DCIS does not reduce the risk of salvage mastectomy.

PubMed

Rakovitch, Eileen; Nofech-Mozes, Sharon; Hanna, Wedad; Sutradhar, Rinku; Gu, Sumei; Fong, Cindy; Tuck, Alan; Youngson, Bruce; Miller, Naomi; Done, Susan J; Chang, Martin C; Sengupta, Sandip; Elavathil, Leela; Jani, Prashant A; Bonin, Michel; Lalani, Nafisha; Paszat, Lawrence

2018-02-01

Radiation therapy (RT) after breast-conserving surgery (BCS) for Ductal Carcinoma in Situ (DCIS) halves the risk of local recurrence (LR). The omission of RT is often supported by the paradigm that patients who develop LR can be salvaged with further breast-conserving therapy leading to higher rates of breast preservation and improved quality of life. However, population-based, long-term rates of breast preservation in women treated by upfront BCS ± RT are unknown. Women diagnosed with pure DCIS from 1994 to 2003 treated with BCS ± RT in Ontario were identified. Median follow-up is 12 years. The development and treatment of LR and contralateral breast cancers were determined by administrative databases with validation. The 10-year mastectomy-free survival was calculated using the Kaplan-Meier method. The impact of RT on breast preservation was determined by propensity-adjusted cox proportional hazards model. The cohort includes 3303 women with DCIS; 1649 (50%) underwent BCS alone, 1654 (50%) underwent BCS + RT. Women treated by BCS alone were more likely to develop a LR compared to those treated by upfront BCS + RT (20.8% versus 15.5%, p < 0.001). Mastectomy was used to treat LR in 57.4% (197/343) of women who recurred after BCS alone and 67.6% (174/257) of those who recurred after BCS + RT. Women treated with upfront BCS + RT had higher rates of bilateral breast preservation at 10 years compared to those treated by BCS alone (87.3% vs.82.7%, p = 0.0096). Local Recurrence after BCS alone does not favor breast preservation. Copyright © 2017 Elsevier Ltd. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huang Meijuan; Jiang Yu; State Key Laboratory of Biotherapy, West China Hospital, Medical School, Sichuan University, Chengdu

Purpose: To investigate the role of early or up-front radiotherapy (RT), the optimal RT dose required to achieve appropriate treatment outcome and prognostic factors for patients with localized extranodal NK/T-cell lymphoma, nasal-type, in the upper aerodigestive tract. Methods and Materials: Eighty-two patients were reviewed. Eight patients were treated with chemotherapy (CT) alone, 9 patients received RT alone, and 65 patients were given combined modality treatment of CT and RT (CMT). Of those 74 patients receiving RT, 31 patients were given up-front RT, whereas CT was the initial therapy for 43 patients and 41 of those 43 patients received early RT.more » Results: Five-year overall survival (OS) and disease-free survival (DFS) were 52.3% and 39.2%, respectively. RT was the only independent prognostic factor for both OS and DFS at both the univariate and multivariate level. The 5-year OS and DFS were better in patients receiving {>=}54 Gy of RT as compared with that of <54 Gy (5-year OS 75.5% vs. 46.1%, p = 0.019; 5-year DFS 60.3% vs. 33.4%, p = 0.004). Up-front RT presented better survival in Stage I patients when compared with that of initial CT followed by early RT (5-year OS 90.0% vs. 48.9%, p = 0.012; 5-year DFS 78.7% vs. 39.9%, p = 0.021). Conclusion: Early or up-front RT had an essential role in improved OS and DFS in patients with localized extranodal NK/T-cell lymphoma, nasal-type, in the upper aerodigestive tract. The recommended tumor dose was at least 54 Gy. Up-front RT may yield more benefits on survival in patients with Stage I disease.« less

Endocrine and Metabolic Aspects of Tuberculosis

PubMed Central

Vinnard, Christopher; Blumberg, Emily A.

2017-01-01

Endocrine and metabolic derangements are infrequent in patients with tuberculosis, but they are important when they occur. The basis for these abnormalities is complex. While Mycobacterium tuberculosis has been described to infect virtually every endocrine gland, the incidence of gland involvement is low, especially in the era of effective antituberculosis therapy. Furthermore, endocrine and metabolic abnormalities do not always reflect direct infection of the gland but may result from physiological response or as a consequence of therapy. Metabolic disease may also predispose patients to the development of active tuberculosis, particularly in the case of diabetes mellitus. While hormonal therapy may be necessary in some instances, frequently these endocrine complications do not require specific interventions other than antituberculous therapy itself. With the exception of diabetes mellitus, which will be covered elsewhere, this chapter reviews the endocrinologic and metabolic issues related to tuberculosis. PMID:28233510

Upfront haploidentical transplant for acquired severe aplastic anemia: registry-based comparison with matched related transplant.

PubMed

Xu, Lan-Ping; Jin, Song; Wang, Shun-Qing; Xia, Ling-Hui; Bai, Hai; Gao, Su-Jun; Liu, Qi-Fa; Wang, Jian-Min; Wang, Xin; Jiang, Ming; Zhang, Xi; Wu, De-Pei; Huang, Xiao-Jun

2017-01-21

Haploidentical donor (HID) hematopoietic stem cell transplantation (HSCT) is an alternative treatment method for severe aplastic anemia (SAA) patients lacking suitable identical donors and those who are refractory to immunosuppressive therapy (IST). The current study evaluated the feasibility of upfront haploidentical HSCT in SAA patients. We conducted a multicenter study based on a registry database. One hundred fifty-eight SAA patients who underwent upfront transplantation between June 2012 and September 2015 were enrolled. Eighty-nine patients had haploidentical donors (HIDs), and 69 had matched related donors (MRDs) for HSCT. The median times for myeloid engraftment in the HID and MRD cohorts were 12 (range, 9-20) and 11 (range, 8-19) days, with a cumulative incidence of 97.8 and 97.1% (P = 0.528), respectively. HID recipients had an increased cumulative incidence of grades II-IV acute graft-versus-host disease (aGVHD) (30.3 vs. 1.5%, P < 0.001), grades III-IV aGVHD (10.1 vs. 1.5%, P = 0.026), and chronic GVHD (cGVHD) (30.6 vs. 4.4%, P < 0.001) at 1 year but similar extensive cGVHD (3.4 vs. 0%, P = 0.426). The three-year estimated overall survival (OS) rates were 86.1 and 91.3% (P = 0.358), while the three-year estimated failure-free survival (FFS) rates were 85.0 and 89.8% (P = 0.413) in the HID and MRD cohorts, respectively. In multivariate analysis, survival outcome for the entire population was significantly adversely associated with increased transfusions and poor performance status pre-SCT. We did not observe differences in primary engraftment and survival outcomes by donor type. Haploidentical SCT as upfront therapy was an effective and safe option for SAA patients, with favorable outcomes in experienced centers.

Impact of autologous and allogeneic stem cell transplantation in peripheral T-cell lymphomas.

PubMed

Reimer, Peter

2010-01-01

Peripheral T/NK-cell lymphomas (PTCLs) are rare malignancies characterized by poor prognosis. So far, no standard therapy has been established, due to the lack of randomised studies. High-dose therapy and autologous stem cell transplantation (HDT-autoSCT) have shown good feasibility with low toxicity in retrospective studies. In relapsing and refractory PTCL several comparison analyses suggest similar efficacy for PTCL when compared with aggressive B-cell lymphoma. In the upfront setting, prospective data show promising results with a long-lasting overall survival in a relevant subset of patients. Achieving a complete remission at transplantation seems to be the most important prognostic factor. Allogeneic stem cell transplantation (alloSCT) has been investigated only as salvage treatment. Especially when using reduced intensity conditioning regimen, eligible patients seem to benefit from this approach. To define the role for upfront stem cell transplantation a randomised trial by the German High-Grade Non-Hodgkin Lymphoma Study Group comparing HDT-autoSCT and alloSCT will be initiated this year.

Relevant factors for the optimal duration of extended endocrine therapy in early breast cancer.

PubMed

Blok, Erik J; Kroep, Judith R; Meershoek-Klein Kranenbarg, Elma; Duijm-de Carpentier, Marjolijn; Putter, Hein; Liefers, Gerrit-Jan; Nortier, Johan W R; Rutgers, Emiel J Th; Seynaeve, Caroline M; van de Velde, Cornelis J H

2018-04-01

For postmenopausal patients with hormone receptor-positive early breast cancer, the optimal subgroup and duration of extended endocrine therapy is not clear yet. The aim of this study using the IDEAL patient cohort was to identify a subgroup for which longer (5 years) extended therapy is beneficial over shorter (2.5 years) extended endocrine therapy. In the IDEAL trial, 1824 patients who completed 5 years of adjuvant endocrine therapy (either 5 years of tamoxifen (12%), 5 years of an AI (29%), or a sequential strategy of both (59%)) were randomized between either 2.5 or 5 years of extended letrozole. For each prior therapy subgroup, the value of longer therapy was assessed for both node-negative and node-positive patients using Kaplan Meier and Cox regression survival analyses. In node-positive patients, there was a significant benefit of 5 years (over 2.5 years) of extended therapy (disease-free survival (DFS) HR 0.67, p = 0.03, 95% CI 0.47-0.96). This effect was only observed in patients who were treated initially with a sequential scheme (DFS HR 0.60, p = 0.03, 95% CI 0.38-0.95). In all other subgroups, there was no significant benefit of longer extended therapy. Similar results were found in patients who were randomized for their initial adjuvant therapy in the TEAM trial (DFS HR 0.37, p = 0.07, 95% CI 0.13-1.06), although this additional analysis was underpowered for definite conclusions. This study suggests that node-positive patients could benefit from longer extended endocrine therapy, although this effect appears isolated to patients treated with sequential endocrine therapy during the first 5 years and needs validation and long-term follow-up.

Annuity payments can increase patient access to innovative cell and gene therapies under England’s net budget impact test

PubMed Central

Jørgensen, Jesper; Kefalas, Panos

2017-01-01

ABSTRACT Background: Cell and gene therapies have the potential to provide therapeutic breakthroughs, but the high costs of researching, developing, manufacturing and delivering them translate into prices that may challenge healthcare budgets. Various measures exist that aim to address the affordability challenge, including reducing price, limiting patient numbers and/or linking remuneration to product performance. Objective: To explore how the net budget impact test recently introduced in England can affect patient access to high-value, one-off cell and gene therapies, and how managed entry agreements can improve access. Methods: We use a hypothetical example where a new high-value, one-off therapy launches in an indication where it displaces a relatively low cost chronic treatment. We calculate the number of patients that can be treated without exceeding the £20 million net budget impact threshold, and compare results for scenarios where a full upfront payment is used, and where annuity-based payments are used. Results: Charging a full upfront payment at the time of treatment can lead to suboptimal patient access. Conclusion: Annuity-based payments in combination with an outcomes-based remuneration scheme reduce consequences of decision uncertainty and can increase patient access, without exceeding the net budget impact test. PMID:28839525

The role of whole brain radiation therapy in the management of melanoma brain metastases

PubMed Central

2014-01-01

Background Brain metastases are common in patients with melanoma, and optimal management is not well defined. As melanoma has traditionally been thought of as “radioresistant,” the role of whole brain radiation therapy (WBRT) in particular is unclear. We conducted this retrospective study to identify prognostic factors for patients treated with stereotactic radiosurgery (SRS) for melanoma brain metastases and to investigate the role of additional up-front treatment with whole brain radiation therapy (WBRT). Methods We reviewed records of 147 patients who received SRS as part of initial management of their melanoma brain metastases from January 2000 through June 2010. Overall survival (OS) and time to distant intracranial progression were calculated using the Kaplan-Meier method. Prognostic factors were evaluated using the Cox proportional hazards model. Results WBRT was employed with SRS in 27% of patients and as salvage in an additional 22%. Age at SRS > 60 years (hazard ratio [HR] 0.64, p = 0.05), multiple brain metastases (HR 1.90, p = 0.008), and omission of up-front WBRT (HR 2.24, p = 0.005) were associated with distant intracranial progression on multivariate analysis. Extensive extracranial metastases (HR 1.86, p = 0.0006), Karnofsky Performance Status (KPS) ≤ 80% (HR 1.58, p = 0.01), and multiple brain metastases (HR 1.40, p = 0.06) were associated with worse OS on univariate analysis. Extensive extracranial metastases (HR 1.78, p = 0.001) and KPS (HR 1.52, p = 0.02) remained significantly associated with OS on multivariate analysis. In patients with absent or stable extracranial disease, multiple brain metastases were associated with worse OS (multivariate HR 5.89, p = 0.004), and there was a trend toward an association with worse OS when up-front WBRT was omitted (multivariate HR 2.56, p = 0.08). Conclusions Multiple brain metastases and omission of up-front WBRT (particularly in combination) are associated with distant intracranial progression. Improvement in intracranial disease control may be especially important in the subset of patients with absent or stable extracranial disease, where the competing risk of death from extracranial disease is low. These results are hypothesis generating and require confirmation from ongoing randomized trials. PMID:24954062

Comparative effectiveness of everolimus-based therapy versus endocrine monotherapy among postmenopausal women with HR+/HER2- metastatic breast cancer: a retrospective chart review in community oncology practices in the US.

PubMed

Xie, Jipan; Hao, Yanni; Li, Nanxin; Lin, Peggy L; Ohashi, Erika; Koo, Valerie; Signorovitch, James E; Wu, Eric Q; Yardley, Denise A

2015-06-01

Everolimus-based therapy and endocrine monotherapy are used among postmenopausal women with hormone receptor-positive human epidermal growth factor receptor-2 negative (HR+/HER2-) metastatic breast cancer (mBC) whose disease progressed or recurred on a non-steroidal aromatase inhibitor (NSAI). However, limited evidence exists regarding the real-world comparative effectiveness of these agents. This retrospective chart review examined postmenopausal HR+/HER2- mBC patients in community-based oncology practices who received everolimus-based therapy or endocrine monotherapy (index therapy) as any line of therapy for mBC between 1 July 2012 and 15 April 2013 after NSAI failure. Time on treatment (TOT), progression-free survival (PFS), and time to chemotherapy (TTC) from index therapy initiation were compared using Kaplan-Meier analyses and Cox proportional hazards models adjusting for baseline characteristics. A total of 243 and 270 patients received everolimus-based therapy or endocrine monotherapy in a quota-based sample. Patients treated with everolimus-based therapy had a higher proportion of visceral metastases, high tumor burden, and use of prior chemotherapies for mBC. After adjusting for baseline characteristics, everolimus-based therapy was associated with significantly longer TOT (HR = 0.67, 95% CI: 0.51-0.87) and PFS (HR = 0.75, 95% CI: 0.57-0.98) than endocrine monotherapy. No significant difference was found between everolimus-based therapy and endocrine monotherapy in TTC (HR = 0.81, 95% CI: 0.52-1.27). Results stratified by line of therapy were generally consistent with the overall results. Limitations include recall and information bias with potentially absent or erroneous chart data, unobserved factors due to non-randomization, inability to measure outcome assessments paired with measuring outcomes prior to exposures, and potential patient selection bias associated with chart review. Among a nationwide sample of postmenopausal HR+/HER2- mBC patients treated in community oncology settings, treatment with everolimus-based therapy was associated with significantly longer TOT and PFS compared to endocrine monotherapy.

Outcome of aplastic anaemia in children. A study by the severe aplastic anaemia and paediatric disease working parties of the European group blood and bone marrow transplant.

PubMed

Dufour, Carlo; Pillon, Marta; Sociè, Gerard; Rovò, Alicia; Carraro, Elisa; Bacigalupo, Andrea; Oneto, Rosi; Passweg, Jakob; Risitano, Antonio; Tichelli, Andrè; Peffault de Latour, Regis; Schrezenmeier, Hubert; Hocshmann, Britta; Peters, Christina; Kulasekararaj, Austin; Van Biezen, Anja; Samarasinghe, Sujith; Hussein, Ayad Ahmed; Ayas, Mouhab; Aljurf, Mahmoud; Marsh, Judith

2015-05-01

This study analysed the outcome of 563 Aplastic Anaemia (AA) children aged 0-12 years reported to the Severe Aplastic Anaemia Working Party database of the European Society for Blood and Marrow Transplantation, according to treatment received. Overall survival (OS) after upfront human leucocyte antigen-matched family donor (MFD) haematopoietic stem cell transplantation (HSCT) or immunosuppressive treatment (IST) was 91% vs. 87% (P 0·18). Event-free survival (EFS) after upfront MFD HSCT or IST was 87% vs. 33% (P 0·001). Ninety-one of 167 patients (55%) failed front-line IST and underwent rescue HSCT. The OS of this rescue group was 83% compared with 91% for upfront MFD HSCT patients and 97% for those who did not fail IST up-front (P 0·017). Rejection was 2% for MFD HSCT and HSCT post-IST failure (P 0·73). Acute graft-versus-host disease (GVHD) grade II-IV was 8% in MFD graft vs. 25% for HSCT post-IST failure (P < 0·0001). Chronic GVHD was 6% in MFD HSCT vs. 20% in HSCT post-IST failure (P < 0·0001). MFD HSCT is an excellent therapy for children with AA. IST has a high failure rate, but remains a reasonable first-line choice if MFD HSCT is not available because high OS enables access to HSCT, which is a very good rescue option. © 2015 John Wiley & Sons Ltd.

Refining Post-Surgical Therapy for Women with Lymph Node-Positive Breast Cancer

Cancer.gov

In this trial, women with HER2-negative, HR-positive breast cancer and 1-3 positive lymph nodes with recurrence scores of 25 or lower will be randomized to undergo adjuvant chemotherapy before starting endocrine therapy or to begin endocrine therapy.

The interaction between ER and NFκB in resistance to endocrine therapy

PubMed Central

2012-01-01

Endocrine therapy is a commonly used treatment for estrogen receptor (ER)-positive breast cancer. Although endocrine therapy has a favorable outcome in many patients, development of resistance is common. Recent studies have shown that NFκB, a transcription factor regulating a wide variety of cellular processes, might play a role in the development of endocrine resistance. The precise interaction between ER and NFκB and how this contributes to the attenuated responsiveness of ER-positive breast cancer cells to hormonal treatment remains unclear. This review provides an overview of the mechanisms of action for both transcription factors and focuses on the current knowledge explaining how ER and NFκB affect each other's activity and how this cross-talk might contribute to the development of an endocrine resistance phenotype in breast cancer cells. PMID:22963717

International network on endocrine complications in thalassaemia (I-CET): an opportunity to grow.

PubMed

De Sanctis, V; Soliman, A T; Angastiniotis, M; Eleftheriou, A; Kattamis, Ch; Karimi, M; El Kholy, M; Elsedfy, H; Yassin, Mohd Abdel Daem Mohd; El Awwa, A; Stoeva, I; Skordis, N; Raiola, G; Fiscina, B

2012-04-01

Most of the endocrine complications in thalassaemia are attributable to iron overload which may be the result of economic circumstances (expense of the chelation therapy), late onset of chelation therapy or poor compliance with the iron chelation therapy. The major difficulties reported by hematologists or pediatric endocrinologists experienced in thalassaemias or thalassaemia syndromes in following growth disorders and endocrine complications were: lack of familiarity with medical treatment of endocrine complications (40%), interpretation of endocrine tests (30%), costs (65%), absence of paediatric endocrinologist for consultation on growth disorders and endocrine complications (27%), facilities (27%), other (e.g. lack of collaboration and on-time consultation between thalassaemic Centers supervised by hematologists and endocrinologists) (17%). Because any progress we make in research into growth disorders and endocrine complications in thalassaemia should be passed on to all those suffering from it, guaranteeing them the same therapeutic benefits and the same quality of life, on the 8th of May, 2009 in Ferrara (Italy), the International Network on Endocrine Complications in Thalassemia (I-CET) was founded. The I-CET group is planning to conduct, in Ferrara in May 2012, a workshop, "MRI and Endocrine Complications in Thalassaemia", and in Doha (Qatar) in September 2012, a 3-day intensive course entitled, "Growth disorders and Endocrine Complications in Thalassaemia", to provide interested pediatricians, physicians and hematologists from all over the world with an in-depth approach to the diagnosis and management of growth and endocrine disorders in thalassaemic patients.

The risk of immune-related endocrine disorders associated with anti-PD-1 inhibitors therapy for solid tumors: A systematic review and meta-analysis.

PubMed

Su, Qiang; Zhang, Xiao-Chen; Wang, Di-Ya; Zhang, Huai-Rong; Zhu, Cheng; Hou, Yan-Li; Liu, Jun-Li; Gao, Zu-Hua

2018-06-01

We performed a systematic review and meta-analysis to evaluate the risk of immune-related endocrine disorders associated with PD-1 inhibitors therapy for solid tumors. An Embase and PubMed search through December 6, 2017, using the following keywords was performed: immune-related endocrine disorders, and PD-1 inhibitors, etc. The data were analyzed using R 3.4.3 (R Project) and the metafor package. Patients treated with chemotherapy alone were used as control for the purpose of comparison. A total of 12 clinical trials including 5577 patients were found eligible for the meta-analysis. Compared with chemotherapy, the risk ratios of all-grade endocrine disorders are 13.89, (95% CI: 5.35-36.05, p < 0.001) for nivolumab therapy, and 9.85, (95% CI: 5.65-17.17, p < 0.001) for pembrolizumab therapy. The risk of all-grade hypothyroidism and hyperthyroidism incidence was increased for nivolumab therapy (hypothyroidism: RR 10.07, 95% CI: 3.37-30.11, p < 0.001; hyperthyroidism: RR 4.29, 95% CI: 1.13-16.30, p = 0.034) and for pembrolizumab therapy (hypothyroidism: RR 7.73, 95% CI: 3.86-15.49, p < 0.001; hyperthyroidism: RR 5.09, 95% CI: 2.36-10.97, p < 0.001). There was a significant increase in the risk of grade 1-5 endocrine disorders incidence for ipilimumab-nivolumab combination therapy (versus ipilimumab, RR 3.20, 95% CI: 2.08-4.91, p < 0.001; versus nivolumab, RR 2.54, 95% CI: 1.70-3.80, p < 0.001). Both nivolumab and pembrolizumab therapy could result in a higher risk of all-grade immune-related endocrine disorders than chemotherapy. Nivolumab and ipilimumab combination therapy could result in an even higher risk of all-grade immune-related endocrine disorders than ipilimumab or nivolumab alone. Awareness of these side effects could guide clinicians to better manage the patients treated with anti-PD-1 inhibitors therapy for solid tumors. Copyright © 2018 Elsevier B.V. All rights reserved.

Emerging application of genomics-guided therapeutics in personalized lung cancer treatment.

PubMed

Zaman, Aubhishek; Bivona, Trever G

2018-05-01

In lung cancer, genomics-driven comprehensive molecular profiling has identified novel chemically and immunologically addressable vulnerabilities, resulting in an increasing application of precision medicine by targeted inactivation of tumor oncogenes and immunogenic activation of host anti-tumor surveillance as modes of treatment. However, initially profound response of these targeted therapies is followed by relapse due to therapy-resistant residual disease states. Although distinct mechanisms and frameworks for therapy resistance have been proposed, accounting for and upfront prediction of resistance trajectories has been challenging. In this review, we discuss in both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), the current standing, and challenges associated with genomics-guided strategies for personalized therapy against both oncogenic alterations as well as post-therapy resistance mechanisms. In NSCLC, we catalog the targeted therapy approaches against most notable oncogenic alterations such as epidermal growth factor receptor (EGFR), serine/threonine-protein kinase b-raf (BRAF), Kirsten rat sarcoma viral proto-oncogene (KRAS), anaplastic lymphoma kinase (ALK), ROS1 proto-oncogene receptor tyrosine kinase (ROS1). For SCLC, currently highly recalcitrant to targeted therapy, we enumerate a range of exciting and maturing precision medicine approaches. Furthermore, we discuss a number of immunotherapy approaches, in combination or alone, that are being actively pursued clinically in lung cancer. This review not only highlights common mechanistic themes underpinning different classes of resistance and discusses tumor heterogeneity as a source of residual disease, but also discusses potential ways to overcome these barriers. We emphasize how an extensive understanding of these themes can predict and improve therapeutic strategies, such as through poly-therapy approaches, to forestall tumor evolution upfront.

Adherence to adjuvant endocrine therapy: is it a factor for ethnic differences in breast cancer outcomes in New Zealand?

PubMed

Seneviratne, Sanjeewa; Campbell, Ian; Scott, Nina; Kuper-Hommel, Marion; Kim, Boa; Pillai, Avinesh; Lawrenson, Ross

2015-02-01

Despite the benefits of adjuvant endocrine therapy for hormone receptor positive breast cancer, many women are non-adherent or discontinue endocrine treatment early. We studied differences in adherence to adjuvant endocrine therapy by ethnicity in a cohort of New Zealand women with breast cancer and its impact on breast cancer outcomes. We analysed data on women (n = 1149) with newly diagnosed hormone receptor positive, non-metastatic, invasive breast cancer who were treated with adjuvant endocrine therapy in the Waikato during 2005-2011. Linked data from the Waikato Breast Cancer Registry and National Pharmaceutical Database were examined to identify differences by ethnicity in adherence to adjuvant endocrine therapy and the effect of sub-optimal adherence on cancer recurrence and mortality. Overall, a high level of adherence of ≥80% was observed among 70.4% of women, which declined from 76.8% to 59.3% from the first to fifth year of treatment. Māori women were significantly more likely to be sub-optimally adherent (<80%) compared with European women (crude rate 37% vs. 28%, p = 0.005, adjusted OR = 1.51, 95% CI 1.04-2.17). Sub-optimal adherence was associated with a significantly higher risk of breast cancer mortality (HR = 1.77, 95% CI 1.05-2.99) and recurrence (HR = 2.14, 95% CI 1.46-3.14). Sub-optimal adherence to adjuvant endocrine therapy was a likely contributor for breast cancer mortality inequity between Māori and European women, and highlights the need for future research to identify effective ways to increase adherence in Māori women. Copyright © 2014 Elsevier Ltd. All rights reserved.

[Arterial hypertension secondary to endocrine disorders].

PubMed

Minder, Anna; Zulewski, Henryk

2015-06-01

Endocrine hypertension offers a potentially curative therapy if the underlying cause is identified and treated accordingly. In contrast to the high prevalence of arterial hypertension especially in the elderly, the classical endocrine causes remain a rare entity. Among patients with arterial hypertension the prevalence of Cushing's syndrome or pheochromocytoma is less than 1%. Primary hyperaldosteronism is more frequent with a reported prevalence of up to 9%. In order to avoid unnecessary, costly and potentially harmful evaluations and therapies due to the limited sensitivity and specificity of the critical endocrine tests it is mandatory to limit the exploration for endocrine causes to preselected patients with high pretest probability for an endocrine disorder. Younger age at manifestation of arterial hypertension or drug resistant hypertension together with other clinical signs of an endocrine disorder should raise the suspicion and prompt the appropriate evaluation.

A randomized trial of adjuvant endocrine therapy, chemotherapy, and chemoendocrine therapy for operable breast cancer stratified by estrogen receptors.

PubMed

Nomura, Y; Tashiro, H; Hisamatsu, K; Shinozuka, K

1988-06-01

Based on estrogen receptor (ER) status and menopausal status, operable breast cancer (International Union Against Cancer [UICC] Stage I, II, and III) patients were randomized for adjuvant endocrine therapy, chemotherapy, and chemoendocrine therapy, and the effects on the disease-free survival (DFS) and overall survival (OS) were compared. Adjuvant endocrine therapy was composed of tamoxifen (TAM) 20 mg/day orally for 2 years in postmenopausal patients. In premenopausal patients, oophorectomy (OVEX) was done before TAM administration. In the chemotherapy arm, the patients were given 0.06 mg/kg of body weight of mitomycin C (MMC) intravenously (IV) and then an oral administration of cyclophosphamide (CPA) 100 mg/body orally in an administration of a 3-month period and a 3-month intermission. This 6-month schedule was repeated four times in 2 years. As the chemoendocrine therapy arm, TAM with MMC + CPA chemotherapy was added. The patients were randomized according to ER and menopausal status. Estrogen receptor-positive (ER+) cancer patients were randomized to three arms: TAM +/- OVEX, MMC + CPA, or MMC + CPA + TAM. For estrogen receptor-negative (ER-) patients, there were two arms: MMC + CPA, or MMC + TAM. The study started in September 1978, and 692 patients entered until the end of 1984 were evaluated. The median follow-up was about 46 months. Totally, a 9.8% rate (68/692) of recurrence was noted, a 7.5% rate (52/692) of mortality. There were no significant differences in DFS or OS among the treatment arms in ER+ or ER- patients. There was significant differences in adverse effects such as bone marrow suppression, gastrointestinal disturbances, cystitis, hair loss between endocrine therapy and chemotherapy or chemoendocrine therapy groups. In this preliminary study, it was concluded that because of less adverse effects of endocrine therapy, it seems rational to select the operable breast cancer patients by the presence or absence of ER, namely, endocrine therapy for ER+ and chemotherapy for ER- cancer patients.

Evolving Hematopoietic Stem Cell Transplantation Strategies in Severe Aplastic Anemia

PubMed Central

Dietz, Andrew C.; Lucchini, Giovanna; Samarasinghe, Sujith; Pulsipher, Michael A.

2016-01-01

Purpose of Review Significant improvements in unrelated donor hematopoietic stem cell transplantation (HSCT) in recent years has solidified its therapeutic role in severe aplastic anemia (SAA) and led to evolution of treatment algorithms, particularly for children. Recent Findings Advances in understanding genetics of inherited bone marrow failure syndromes (IBMFS) have allowed more confidence in accurately diagnosing SAA and avoiding treatments that could be dangerous and ineffective in individuals with IBMFS, which can be diagnosed in 10–20% of children presenting with a picture of SAA. Additionally long-term survival after matched sibling donor (MSD) and matched unrelated donor (MUD) HSCT now exceed 90% in children. Late effects after HSCT for SAA are minimal with current strategies and compare favorably to late effects after up-front immunosuppressive therapy (IST), except for patients with chronic graft versus host disease (GVHD). Summary 1) Careful assessment for signs or symptoms of IBMFS along with genetic screening for these disorders is of major importance. 2) MSD HSCT is already considered standard of care for up-front therapy and some groups are evaluating MUD HSCT as primary therapy. 3) Ongoing studies will continue to challenge treatment algorithms and may lead to an even more expanded role for HSCT in SAA. PMID:26626557

Brain Metastasis Velocity: A Novel Prognostic Metric Predictive of Overall Survival and Freedom From Whole-Brain Radiation Therapy After Distant Brain Failure Following Upfront Radiosurgery Alone

DOE Office of Scientific and Technical Information (OSTI.GOV)

Farris, Michael, E-mail: mfarris@wakehealth.edu; McTyre, Emory R.; Cramer, Christina K.

Purpose: Prior statistical models attempted to identify risk factors for time to distant brain failure (DBF) or time to salvage whole-brain radiation therapy (WBRT) to predict the benefit of early WBRT versus stereotactic radiosurgery (SRS) alone. We introduce a novel clinical metric, brain metastasis velocity (BMV), for predicting clinical outcomes after initial DBF following upfront SRS alone. Methods and Materials: BMV was defined as the cumulative number of new brain metastases that developed over time since first SRS in years. Patients were classified by BMV into low-, intermediate-, and high-risk groups, consisting of <4, 4 to 13, and >13 newmore » metastases per year, respectively. Histology, number of metastases at the time of first SRS, and systemic disease status were assessed for effect on BMV. Results: Of 737 patients treated at our institution with upfront SRS without WBRT, 286 had ≥1 DBF event. A lower BMV predicted for improved overall survival (OS) following initial DBF (log-rank P<.0001). Median OS for the low, intermediate, and high BMV groups was 12.4 months (95% confidence interval [CI], 10.4-16.9 months), 8.2 months (95% CI, 5.0-9.7 months), and 4.3 months (95% CI, 2.6-6.7 months), respectively. Multivariate analysis showed that BMV remained the dominant predictor of OS, with a hazard ratio of 2.75 for the high BMV group (95% CI, 1.94-3.89; P<.0001) and a hazard ratio of 1.65 for the intermediate BMV group (95% CI, 1.18-2.30; P<.004). A lower BMV was associated with decreased rates of salvage WBRT (P=.02) and neurologic death (P=.008). Factors predictive for a higher BMV included ≥2 initial brain metastases (P=.004) and melanoma histology (P=.008). Conclusions: BMV is a novel metric associated with OS, neurologic death, and need for salvage WBRT after initial DBF following upfront SRS alone.« less

Practice Patterns and Outcomes for Pemetrexed Plus Platinum Doublet as Neoadjuvant Chemotherapy in Adenocarcinomas of Lung: Looking Beyond the Usual Paradigm.

PubMed

Noronha, V; Zanwar, S; Joshi, A; Patil, V M; Mahajan, A; Janu, A; Agarwal, J P; Bhargava, P; Kapoor, A; Prabhash, K

2018-01-01

Neoadjuvant chemotherapy (NACT) is the standard of care in non-small cell lung cancers (NSCLC) with locally advanced N2 disease. There is a scarcity of data for the pemetrexed-platinum regimen as NACT. Also, apart from N2 disease, the role of NACT in locally advanced NSCLCs for tumour downstaging is unclear. Non-metastatic adenocarcinomas of lung treated with pemetrexed-platinum-based NACT were analysed. The patients with locoregionally advanced N2 disease and those who were borderline candidates for upfront definitive treatment were planned for NACT after discussion in a multidisciplinary clinic. In total, four cycles of 3-weekly pemetrexed and platinum were delivered in the combined neoadjuvant and adjuvant setting. A response assessment was carried out using RECIST criteria. Progression-free (PFS) and overall survival were calculated using the Kaplan-Meier method. Of 114 patients, 96 evaluable patients received NACT with pemetrexed-platinum. The most common indication for NACT was N2 disease at baseline (46.8%). The objective response rate was 36.4% (95% confidence interval 22-52%), including two complete and 32 partial responses, whereas 12.5% of patients had progressive disease on NACT. The median PFS was 14 months (95% confidence interval 10.7-17.3) and the median overall survival was 22 months (95% confidence interval 15.6-28.4) at a median follow-up of 16 months. There was a significant improvement in the overall survival of patients undergoing definitive therapy versus no definitive therapy (median overall survival 25 months [95% confidence interval 19.6-30.4] versus 12 months [95% confidence interval 3.2-20.7], respectively; P = 0.015, hazard ratio 0.56 [95% confidence interval 0.3-0.9]). Among patients who could not undergo definitive chemoradiation upfront due to dosimetric constraints (n = 34), 24 (70.6%) patients finally underwent definitive therapy after NACT. Pemetrexed-platinum-based NACT seems to be an effective option and many borderline cases, where upfront definitive therapy is not feasible, may become amenable to the same after incorporation of NACT. Copyright © 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Palbociclib (PD0332991)-a Selective and Potent Cyclin-Dependent Kinase Inhibitor: A Review of Pharmacodynamics and Clinical Development.

PubMed

Clark, Amy S; Karasic, Thomas B; DeMichele, Angela; Vaughn, David J; O'Hara, Mark; Perini, Rodolfo; Zhang, Paul; Lal, Priti; Feldman, Michael; Gallagher, Maryann; O'Dwyer, Peter J

2016-02-01

Palbociclib (PD0332991) is a newly developed drug that received breakthrough designation and recent US Food and Drug Administration approval in combination with endocrine therapy in the treatment of hormone receptor positive, ERBB2-negative (formerly HER2 or HER2/neu) breast cancer in the first-line metastatic setting. Herein we describe the preclinical and translational data and early- and late-phase clinical trials in which palbociclib has been investigated in a broad array of tumor types. We discuss the pharmacodynamics, pharmacokinetics, toxic effects, and clinical response rates. On March 1, 2015, we conducted a review of the literature describing the development of palbociclib. We used the PubMed search terms "PD0332991," "palbociclib," and "CDK4/6 inhibitor" to find all published articles of interest, without limitation as to publication date. Palbociclib is a potent and specific oral cyclin-dependent kinase (CDK) 4/6 inhibitor that has strong preclinical data to support its activity in retinoblastoma protein-expressing tumors. Phase 1 trials have demonstrated safety, and phase 2 trials have shown single-agent activity in mantle-cell lymphoma, breast cancer, liposarcoma, and teratoma with reversible neutropenia as the main toxic effect. Addition of palbociclib to endocrine therapy improves progression-free survival in endocrine therapy-naïve and endocrine therapy-resistant metastatic settings. Palbociclib is well tolerated and has therapeutic potential for multiple cancers, including breast cancer, where its efficacy has been demonstrated alone and in combination with endocrine therapy. Additional combinations of palbociclib with endocrine therapy, chemotherapy, and targeted therapy have potential in various tumors, and phase 3 trials are under way.

Impact of Therapy Sequence with Alkylating Agents and MGMT Status in Patients with Advanced Neuroendocrine Tumors.

PubMed

Krug, Sebastian; Boch, Michael; Rexin, Peter; Gress, Thomas M; Michl, Patrick; Rinke, Anja

2017-05-01

Alkylating chemotherapeutics with either a streptozotocin-(STZ) or temozolomide-(TEM) backbone are routinely used in patients with progressive and unresectable pancreatic neuroendocrine tumors (PNET). In addition, dacarbazine (DTIC) was described as an alternative alkylating therapy option for PNETs. The optimal treatment sequence with alkylating compounds and a potential use of O6-methylguanine-DNA methyltransferase (MGMT) level as predictive biomarker have not yet been sufficiently elucidated. The aim of our study was the evaluation of therapy sequence with either STZ-based treatment followed by DTIC (group A) or the inverse schedule with upfront DTIC (group B) and to correlate MGMT status with clinicopathological characteristics and response to therapy. We retrospectively analyzed 28 patients with neuroendocrine tumors (NET) who were treated with STZ-based therapy and DTIC. Additionally, in a second group MGMT immunohistochemistry was performed from primary and metastatic tumor sites. For statistical evaluation Kaplan-Meier analysis, Cox regression methods and Fisher's exact test were used. There was no difference of objective response and disease control between either STZ-based therapy followed by DTIC treatment (group A) after progression or the reverse sequence (group B). Median time to progression (TTP) was estimated to be 21 months in both arms. First-line STZ-based chemotherapy was not superior to first-line DTIC treatment (16 vs. 13 months; p=0.8). MGMT status did not correlate with clinicopathological characteristics or response to therapy with these alkylating agents. Upfront chemotherapy with either STZ-based treatment or DTIC monotherapy showed similar efficacy and median TTP rates. In this study, MGMT protein expression assessed by immunohistochemistry did not play an important role as a predictive marker for alkylating agents. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Mapping the Decision-Making Process for Adjuvant Endocrine Therapy for Breast Cancer: The Role of Decisional Resolve.

PubMed

Beryl, Louise L; Rendle, Katharine A S; Halley, Meghan C; Gillespie, Katherine A; May, Suepattra G; Glover, Jennifer; Yu, Peter; Chattopadhyay, Runi; Frosch, Dominick L

2017-01-01

Studies show adjuvant endocrine therapy increases survival and decreases risk of breast cancer recurrence for hormone receptor-positive tumors. Yet studies also suggest that adherence rates among women taking this therapy may be as low as 50% owing largely to adverse side effects. Despite these rates, research on longitudinal patient decision making regarding this therapy is scant. We sought to map the decision-making process for women considering and initiating adjuvant endocrine therapy, paying particular attention to patterns of uncertainty and decisional change over time. A longitudinal series of semistructured interviews conducted at a multispecialty health care organization in Northern California with 35 newly diagnosed patients eligible for adjuvant endocrine therapy were analyzed. Analysis led to the identification and indexing of 3 new decision-making constructs-decisional phase, decisional direction, and decisional resolve-which were then organized using a visual matrix and examined for patterns characterizing the decision-making process. Our data reveal that most patients do not make a single, discrete decision to take or not take hormone therapy but rather traverse multiple decisional states, characterized by 1) phase, 2) direction, and 3) strength of resolve. Our analysis tracks these decisional states longitudinally using a grayscale-coded matrix. Our data show that decisional resolve wavers not just when considering therapy, as the existing concept of decisional conflict suggests, but even after initiating it, which may signal future decisions to forgo therapy. Adjuvant endocrine therapy, like other chronic care decisions, has a longer decision-making process and implementation period. Thus, theoretical, empirical, and clinical approaches should consider further exploring the new concept and measurement of decisional resolve, as it may help to improve subsequent medication adherence. © The Author(s) 2016.

Overcoming Endocrine Resistance by Targeting ER/FoxA1/IL-8 Axis

DTIC Science & Technology

2015-10-01

residual disease after 6-month neoadjuvant endocrine therapy 45 . Recent studies unveiled gain-of- function mutations in ESR1 , the gene encoding ER...described previously 61 . SYBR dye (Life Technologies) was used in real- time PCR and the target primer sequences are as follows: ESR1 forward...Breast Cancer Symposium (ed^(eds). Cancer Res (2013). 46. Li S, et al. Endocrine-therapy-resistant ESR1 variants revealed by genomic characterization of

Erlotinib versus Radiation Therapy for Brain Metastases in Patients with EGFR-Mutant Lung Adenocarcinoma

PubMed Central

Gerber, Naamit K.; Yamada, Yoshiya; Rimner, Andreas; Shi, Weiji; Riely, Gregory J.; Beal, Kathryn; Yu, Helena A.; Chan, Timothy A.; Zhang, Zhigang; Wu, Abraham J.

2017-01-01

Purpose/Objectives Radiation therapy (RT) is the principal modality in the treatment of patients with brain metastases (BM). However, given the activity of EGFR tyrosine kinase inhibitors in the central nervous system (CNS), it is uncertain whether upfront brain RT is necessary for patients with EGFR-mutant lung adenocarcinoma with BM. Methods and Materials Patients with EGFR-mutant lung adenocarcinoma and newly diagnosed BM were identified. Results 222 patients were identified. Exclusion criteria included prior erlotinib use, presence of a de novo erlotinib resistance mutation, or incomplete data. Of the remaining 110 patients, 63 were treated with erlotinib, 32 with whole-brain RT (WBRT), and 15 with stereotactic radiosurgery (SRS). Median OS for the whole cohort was 33 months. There was no significant difference in OS between the WBRT and erlotinib groups (median 35 vs. 26 months, p = .62), while patients treated with SRS had a longer OS compared with the erlotinib group (median, 64 months, p = .004). Median time to ICP was 17 months. There was a longer time to ICP in patients who received WBRT vs. erlotinib upfront (median 24 vs. 16 months, p = .04). Patients in the erlotinib or SRS group were more likely to fail intracranially as a component of first failure, while WBRT patients were more likely to fail outside the brain (p = .004). Conclusions The survival of patients with EGFR-mutant adenocarcinoma with BM is notably long, whether they receive upfront erlotinib or brain RT. We observed longer intracranial control with WBRT, even though the WBRT patients had a higher burden of intracranial disease. Despite the equivalent survival between the WBRT and erlotinib group, this study underscores the role of WBRT in producing durable intracranial control in comparison to a targeted biologic agent with known CNS activity. PMID:24679729

Use of autologous hematopoietic cell transplantation as initial therapy in multiple myeloma and the impact of socio-geo-demographic factors in the era of novel agents.

PubMed

Al-Hamadani, Mohammed; Hashmi, Shahrukh K; Go, Ronald S

2014-08-01

Very effective combination chemotherapy using novel agents has become available in multiple myeloma (MM). Its impact on the use of high-dose chemotherapy and autologous hematopoietic stem cell transplantation (AHCT) as part of initial therapy is unknown. Using the National Cancer Data Base, we studied the rate of upfront AHCT use among 137,409 newly diagnosed MM patients from 1998 to 2010 in the United States and determined whether disparity exists among various sociodemographic as well as geographic subgroups. Overall, 12,378 (9.0%) patients received AHCT as part of initial treatment. The use of upfront AHCT increased steadily from 5.2% in 1998 to 12.1% in 2010 (trend test, P < 0.001), with no sign of plateau. This was seen across all socio-geo-demographic subgroups except among patients treated in the Northeast where the rate fell from 8.7% in 1998 to 6.6% in 2010. In multivariable analysis, patients with the following characteristics were the least likely to receive AHCT (odds ratio): year of diagnosis from 1998 to 2003 before the era of novel agents (0.67), older age (0.35), Black race (0.58), Hispanic ethnicity (0.78), low level of education or annual household income (0.55), residence in a metro area (0.66), no or unknown medical insurance (0.30), treatment at a community cancer center (0.16), and treatment facility located in the Northeast region (0.54). Even after the introduction of novel agents, the rate of upfront AHCT in MM continues to increase annually. Significant disparities exist dependent on demographic, social, and geographic factors. © 2014 Wiley Periodicals, Inc.

Assessment and management of bone health in women with oestrogen receptor-positive breast cancer receiving endocrine therapy: Position statement of the Endocrine Society of Australia, the Australian and New Zealand Bone & Mineral Society, the Australasian Menopause Society and the Clinical Oncology Society of Australia.

PubMed

Grossmann, Mathis; Ramchand, Sabashini; Milat, Frances; Vincent, Amanda; Lim, Elgene; Kotowicz, Mark A; Hicks, Jill; Teede, Helena

2018-05-09

To formulate clinical consensus recommendations on bone health assessment and management of women with oestrogen receptor-positive early breast cancer receiving endocrine therapy. Representatives appointed by relevant Australian Medical Societies used a systematic approach for adaptation of guidelines (ADAPTE) to derive an evidence-informed position statement addressing five key questions. Women receiving adjuvant aromatase inhibitors and the subset of premenopausal woman on tamoxifen have accelerated bone loss and increased fracture risk. Both bisphosphonates and denosumab prevent bone loss, additionally denosumab has proven anti-fracture benefit. Women considering endocrine therapy need fracture risk assessment, including clinical risk factors, biochemistry and bone mineral density (BMD) measurement, with monitoring based on risk factors. Weight-bearing exercise, vitamin D and calcium sufficiency is recommended routinely. Antiresorptive treatment should be considered in women with prevalent or incident clinical or morphometric fractures, a T-score (or Z-scores in women <50 years) of <-2.0 at any site, or if annual bone loss is ≥5%, considering baseline BMD and other fracture risk factors. Duration of antiresorptive treatment can be individualised based on absolute fracture risk. Relative to their skeletal benefits, risks of adverse events with antiresorptive treatments are low. Skeletal health should be considered in the decision-making process regarding choice and duration of endocrine therapy. Before and during endocrine therapy, skeletal health should be assessed regularly, optimised by nonpharmacological intervention and where indicated antiresorptive treatment, in an individualised, multidisciplinary approach. Clinical trials are needed to better delineate long-term fracture risks of adjuvant endocrine therapy, and to determine the efficacy of interventions designed to minimise these risks. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Residual Prostate Cancer in Patients Treated With Endocrine Therapy With or Without Radical Radiotherapy: A Side Study of the SPCG-7 Randomized Trial

DOE Office of Scientific and Technical Information (OSTI.GOV)

Solberg, Arne, E-mail: arne.solberg@stolav.n; Haugen, Olav A.; Department of Pathology and Medical Genetics, St. Olav's Hospital, Trondheim University Hospital, Trondheim

2011-05-01

Purpose: The Scandinavian Prostate Cancer Group-7 randomized trial demonstrated a survival benefit of combined endocrine therapy and external-beam radiotherapy over endocrine therapy alone in patients with high-risk prostate cancer. In a subset of the study population, the incidence and clinical implications of residual prostate cancer in posttreatment prostate biopsy specimens was evaluated. Methods and Materials: Biopsy specimens were obtained from 120 of 875 men in the Scandinavian Prostate Cancer Group-7 study. Results: Biopsies were performed at median of 45 months follow-up. In 63 patients receiving endocrine treatment only and 57 patients receiving combined treatment, residual cancer was found in 66%more » (n = 41) and 22% (n = 12), respectively (p < 0.0001). The vast majority of residual tumors were poorly differentiated (Gleason score {>=}8). Endocrine therapy alone was predictive of residual prostate cancer: odds ratio 7.49 (3.18-17.7), p < 0.0001. In patients with positive vs. negative biopsy the incidences of clinical events were as follows: biochemical recurrence 74% vs. 27% (p < 0.0001), local progression 26% vs. 4.7% (p = 0.002), distant recurrence 17% vs. 9.4% (p = 0.27), clinical recurrence 36% vs. 13% (p = 0.006), cancer-specific death 19% vs. 9.7% (p = 0.025). In multivariable analysis, biochemical recurrence was significantly associated with residual cancer: hazard ratio 2.69 (1.45-4.99), p = 0.002, and endocrine therapy alone hazard ratio 3.45 (1.80-6.62), p < 0.0001. Conclusions: Radiotherapy combined with hormones improved local tumor control in comparison with endocrine therapy alone. Residual prostate cancer was significantly associated with serum prostate-specific antigen recurrence, local tumor progression, clinical recurrence, and cancer-specific death in univariable analysis. Residual cancer was predictive of prostate-specific antigen recurrence in multivariable analysis.« less

Loss of MutL Disrupts CHK2-Dependent Cell-Cycle Control through CDK4/6 to Promote Intrinsic Endocrine Therapy Resistance in Primary Breast Cancer.

PubMed

Haricharan, Svasti; Punturi, Nindo; Singh, Purba; Holloway, Kimberly R; Anurag, Meenakshi; Schmelz, Jacob; Schmidt, Cheryl; Lei, Jonathan T; Suman, Vera; Hunt, Kelly; Olson, John A; Hoog, Jeremy; Li, Shunqiang; Huang, Shixia; Edwards, Dean P; Kavuri, Shyam M; Bainbridge, Matthew N; Ma, Cynthia X; Ellis, Matthew J

2017-10-01

Significant endocrine therapy-resistant tumor proliferation is present in ≥20% of estrogen receptor-positive (ER + ) primary breast cancers and is associated with disease recurrence and death. Here, we uncover a link between intrinsic endocrine therapy resistance and dysregulation of the MutL mismatch repair (MMR) complex ( MLH1/3 , PMS1/2 ), and demonstrate a direct role for MutL complex loss in resistance to all classes of endocrine therapy. We find that MutL deficiency in ER + breast cancer abrogates CHK2-mediated inhibition of CDK4, a prerequisite for endocrine therapy responsiveness. Consequently, CDK4/6 inhibitors (CDK4/6i) remain effective in MutL-defective ER + breast cancer cells. These observations are supported by data from a clinical trial where a CDK4/6i was found to strongly inhibit aromatase inhibitor-resistant proliferation of MutL-defective tumors. These data suggest that diagnostic markers of MutL deficiency could be used to direct adjuvant CDK4/6i to a population of patients with breast cancer who exhibit marked resistance to the current standard of care. Significance: MutL deficiency in a subset of ER + primary tumors explains why CDK4/6 inhibition is effective against some de novo endocrine therapy-resistant tumors. Therefore, markers of MutL dysregulation could guide CDK4/6 inhibitor use in the adjuvant setting, where the risk benefit ratio for untargeted therapeutic intervention is narrow. Cancer Discov; 7(10); 1168-83. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 1047 . ©2017 American Association for Cancer Research.

Suppression of Androgen Receptor Transactivation by Akt Kinase

DTIC Science & Technology

2005-01-01

with the potential to be particularly effective. A therapy Endocrine Societcs 84th Annual Meeting, San Francisco, June 19-22,2002, that suppresses the...PI3K/Akt pathway combined with classic p. 526 (abstr.), Endocrine Society Press, Bethesda, MD ablation therapy could reach the maximal effect in 10...10):2409-2423 Printed in U.S.A. Copyright © 2004 by The Endocrine Society do!: 10.1210/me.2004-0117 Regulation of Androgen Receptor Signaling by PTEN

Adjuvant endocrine therapy for premenopausal women with hormone-responsive breast cancer.

PubMed

Mathew, Aju; Davidson, Nancy E

2015-11-01

Multiple strategies for endocrine treatment of premenopausal women with hormone-responsive breast cancer have been assessed and results have been presented over the last two years. These include tamoxifen for 5-10 years (ATLAS and aTTom), tamoxifen for 5 years followed by aromatase inhibitor (AI) for 5 years for women who have become postmenopausal (MA-17); ovarian ablation (OA) by surgery (EBCTCG overview); ovarian function suppression (OFS) by LHRH agonist (LHRH agonist meta-analysis); or combinations of approaches including OFS plus tamoxifen or AI (SOFT, TEXT, ABCSG 12 and E3193). Many of these trials have taken place in the backdrop of (neo)adjuvant chemotherapy which can confound interpretation because such therapy can suppress ovarian function either transiently or permanently. Nonetheless these trials suggest in aggregate that 10 years of tamoxifen are better than 5 years and that a program of extended adjuvant therapy of tamoxifen for 5 years followed by aromatase inhibitor for 5 years is effective for suitable candidates. The SOFT and E3193 trials do not show a major advantage for use of OFS + tamoxifen compared to tamoxifen alone. The joint SOFT/TEXT analysis and ABCGS12 trials both suggest that outcomes can be excellent with the use of combined endocrine therapy alone in properly selected patients but give conflicting results with regard to potential benefits for OFS + AI compared with OFS + tamoxifen. Further work will be needed to ascertain long-term outcomes, identify factors that predict who will benefit from extended adjuvant endocrine therapy, and assess role of OFS by medical or surgical means. It is clear, however, that endocrine therapy is a critical part of the adjuvant regimen for most premenopausal women with hormone-responsive breast cancer, and a subset of these women with luminal A-type tumors can be safely treated with endocrine therapy alone. Copyright © 2015 Elsevier Ltd. All rights reserved.

Treatment options after sorafenib failure in patients with hepatocellular carcinoma

PubMed Central

Dika, Imane El

2017-01-01

Second line therapy after failure of sorafenib continues to be under study. Prognosis of hepatocellular carcinoma is measured in months, with median overall survival reaching 10.7 months with sorafenib. Because of the modest net benefit sorafenib has contributed, and rising incidence of hepatocellular carcinoma in the world, continued efforts are ongoing to look for efficient upfront, second line, or combination therapies. Herein we review the most relevant to date published literature on treatment options beyond sorafenib, reported studies, ongoing investigational efforts, and possibilities for future studies in advanced hepatocellular carcinoma. PMID:29151326

Mechanisms of Resistance to Endocrine Therapy in Breast Cancer: Focus on Signaling Pathways, miRNAs and Genetically Based Resistance

PubMed Central

García-Becerra, Rocío; Santos, Nancy; Díaz, Lorenza; Camacho, Javier

2013-01-01

Breast cancer is the most frequent malignancy diagnosed in women. Approximately 70% of breast tumors express the estrogen receptor (ER). Tamoxifen and aromatase inhibitors (AIs) are the most common and effective therapies for patients with ERα-positive breast cancer. Alone or combined with chemotherapy, tamoxifen significantly reduces disease progression and is associated with more favorable impact on survival in patients. Unfortunately, endocrine resistance occurs, either de novo or acquired during the course of the treatment. The mechanisms that contribute to hormonal resistance include loss or modification in the ERα expression, regulation of signal transduction pathways, altered expression of specific microRNAs, balance of co-regulatory proteins, and genetic polymorphisms involved in tamoxifen metabolic activity. Because of the clinical consequences of endocrine resistance, new treatment strategies are arising to make the cells sensitive to tamoxifen. Here, we will review the current knowledge on mechanisms of endocrine resistance in breast cancer cells. In addition, we will discuss novel therapeutic strategies to overcome such resistance. Undoubtedly, circumventing endocrine resistance should help to improve therapy for the benefit of breast cancer patients. PMID:23344024

Resistance to therapy in estrogen receptor positive and human epidermal growth factor 2 positive breast cancers: progress with latest therapeutic strategies.

PubMed

Lousberg, Laurence; Collignon, Joëlle; Jerusalem, Guy

2016-11-01

In this article, we focus on the subtype of estrogen receptor (ER)-positive, human epidermal growth factor 2 (HER2)-positive breast cancer (BC). Preclinical and clinical data indicate a complex molecular bidirectional crosstalk between the ER and HER2 pathways. This crosstalk probably constitutes one of the key mechanisms of drug resistance in this subclass of BC. Delaying or even reversing drug resistance seems possible by targeting pathways implicated in this crosstalk. High-risk patients currently receive anti-HER2 therapy, chemotherapy and endocrine therapy in the adjuvant setting. In metastatic cases, most patients receive a combination of anti-HER2 therapy and chemotherapy. Only selected patients presenting more indolent disease are candidates for combinations of anti-HER2 therapy and endocrine therapy. However, relative improvements in progression-free survival by chemotherapy-based regimens are usually lower in ER-positive patients than the ER-negative and HER2-positive subgroup. Consequently, new approaches aiming to overcome endocrine therapy resistance by adding targeted therapies to endocrine therapy based regimens are currently explored. In addition, dual blockade of HER2 or the combination of trastuzumab and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOP) inhibitors targeting the downstream pathway are strategies to overcome resistance to trastuzumab. This may lead in the near future to the less frequent use of chemotherapy-based treatment options in ER-positive, HER2-positive BC.

Upfront dilution of ferritin samples to reduce hook effect, improve turnaround time and reduce costs.

PubMed

Wu, Shu Juan; Hayden, Joshua A

2018-02-15

Sandwich immunoassays offer advantages in the clinical laboratory but can yield erroneously low results due to hook (prozone) effect, especially with analytes whose concentrations span several orders of magnitude such as ferritin. This study investigated a new approach to reduce the likelihood of hook effect in ferritin immunoassays by performing upfront, five-fold dilutions of all samples for ferritin analysis. The impact of this change on turnaround time and costs were also investigated. Ferritin concentrations were analysed in routine clinical practice with and without upfront dilutions on Siemens Centaur® XP (Siemens Healthineers, Erlang, Germany) immunoanalysers. In addition, one month of baseline data (1026 results) were collected prior to implementing upfront dilutions and one month of data (1033 results) were collected after implementation. Without upfront dilutions, hook effect was observed in samples with ferritin concentrations as low as 86,028 µg/L. With upfront dilutions, samples with ferritin concentrations as high as 126,050 µg/L yielded values greater than the measurement interval and would have been diluted until an accurate value was obtained. The implementation of upfront dilution of ferritin samples led to a decrease in turnaround time from a median of 2 hours and 3 minutes to 1 hour and 18 minutes (P = 0.002). Implementation of upfront dilutions of all ferritin samples reduced the possibility of hook effect, improved turnaround time and saved the cost of performing additional dilutions.

47 CFR 54.638 - Upfront payments.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 47 Telecommunication 3 2014-10-01 2014-10-01 false Upfront payments. 54.638 Section 54.638 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES (CONTINUED) UNIVERSAL SERVICE Universal Service Support for Health Care Providers Healthcare Connect Fund § 54.638 Upfront...

47 CFR 54.638 - Upfront payments.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 47 Telecommunication 3 2013-10-01 2013-10-01 false Upfront payments. 54.638 Section 54.638 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES (CONTINUED) UNIVERSAL SERVICE Universal Service Support for Health Care Providers Healthcare Connect Fund § 54.638 Upfront...

Outcomes and healthcare utilization in children and young adults with aplastic anemia: A multiinstitutional analysis.

PubMed

Gupta, Ashish; Fu, Pingfu; Hashem, Hasan; Vatsayan, Anant; Shein, Steven; Dalal, Jignesh

2017-12-01

Aplastic anemia is a bone marrow failure syndrome with high mortality affecting children and young adults. Although current treatment guidelines recommend hematopoietic stem cell transplant (HCT) for patients with matched sibling donors, outcomes with alternate donor options have been improving. We analyzed a validated multiinstitutional pediatric cohort using one of the largest pediatric and young adult database, the Pediatric Health Information System, for patients diagnosed with aplastic anemia (AA) from 2006 to 2015. Outcomes with upfront and salvage transplants were analyzed along with healthcare utilization. Among 2,169 patients in the study period, almost 20% underwent HCT, while others received immunosuppressive therapy. In a multivariate model, there was no significant difference in mortality with upfront or salvage transplants (odds ratio [OR] 1.24, 95% confidence interval [CI] 0.6-2.58, P = 0.567), while every platelet transfusion was associated with higher mortality (OR 1.37, 95% CI 1.12-1.67, P = 0.002). Healthcare utilization was significantly higher in salvage transplants requiring frequent hospitalization and transfusion requirements. Treatment mortality and graft failure rates were significantly reduced in the salvage transplant group in recent years (2011-2015 as compared to 2006-2010). As outcomes with HCT continue to improve in severe AA, transplant with good alternate donors should be considered upfront in children and young adults. © 2017 Wiley Periodicals, Inc.

Isohormonal therapy of endocrine autoimmunity.

PubMed

Schloot, N; Eisenbarth, G S

1995-06-01

For most autoimmune disorders, the site (if any) of chronic immunization required for perpetuation of autoimmunity is unknown. However, one possible site is the target organ itself. If this were the case, feedback regulation of target cell activity might influence autoimmunity. Here, Nanette Schloot and George Eisenbarth review several recent studies suggesting that therapies that inhibit hormonal secretion of target endocrine organs, and/or modulate immunity by therapy with the isohormone, are associated with disease suppression.

Decision analytic modeling for the economic analysis of proton radiotherapy for non-small cell lung cancer

PubMed Central

Richard, Patrick J.; Zeng, Jing; Apisarnthanarax, Smith; Rengan, Ramesh; Phillips, Mark H.

2018-01-01

Background Although proton radiation treatments are more costly than photon/X-ray therapy, they may lower overall treatment costs through reducing rates of severe toxicities and the costly management of those toxicities. To study this issue, we created a decision-model comparing proton vs. X-ray radiotherapy for locally advanced non-small cell lung cancer patients. Methods An influence diagram was created to model for radiation delivery, associated 6-month pneumonitis/esophagitis rates, and overall costs (radiation plus toxicity costs). Pneumonitis (age, chemo type, V20, MLD) and esophagitis (V60) predictors were modeled to impact toxicity rates. We performed toxicity-adjusted, rate-adjusted, risk group-adjusted, and radiosensitivity analyses. Results Upfront proton treatment costs exceeded that of photons [$16,730.37 (3DCRT), $23,893.83 (IMRT), $41,061.80 (protons)]. Based upon expected population pneumonitis and esophagitis rates for each modality, protons would be expected to recover $1,065.62 and $1,139.63 of the cost difference compared to 3DCRT or IMRT. For patients treated with IMRT experiencing grade 4 pneumonitis or grade 4 esophagitis, costs exceeded patients treated with protons without this toxicity. 3DCRT patients with grade 4 esophagitis had higher costs than proton patients without this toxicity. For the risk group analysis, high risk patients (age >65, carboplatin/paclitaxel) benefited more from proton therapy. A biomarker may allow patient selection for proton therapy, although the AUC alone is not sufficient to determine if the biomarker is clinically useful. Conclusions The comparison between proton and photon/X-ray radiation therapy for NSCLC needs to consider both the up-front cost of treatment and the possible long term cost of complications. In our analysis, current costs favor X-ray therapy. However, relatively small reductions in the cost of proton therapy may result in a shift to the preference for proton therapy.

[Hormone therapies in pregnancy].

PubMed

Tommaselli, G A; Pellicano, M; Guida, M; Palomba, S; Savarese, F; Nola, B; Ferrara, C; Lapadula, C; Nappi, C

2002-04-01

Maternal endocrine disorders can have detrimental effects on the fetus and the pregnancy can affect the course of a pre-exisiting endocrinopathy or induce the onset of one of these disorders. Therapies for endocrine disorders are not always safe to administer during pregnancy. Before administering any therapy to the mother, the effects on the fetus, the degree of placental trespassing as well as the potential damaging effects must be assessed. An accurate evaluation of the risks/benefits of any drug to be used on the mother is needed, assessing above all a potential theratogenic effect. In this review, the incidence of the main endocrine disorders, their evolution during pregnancy, their effects on mothers and fetuses and new acquisition on the treatment during pregnancy are discussed.

Keeping Up with the Diabetes Technology: 2016 Endocrine Society Guidelines of Insulin Pump Therapy and Continuous Glucose Monitor Management of Diabetes.

PubMed

Galderisi, Alfonso; Schlissel, Elise; Cengiz, Eda

2017-09-23

Decades after the invention of insulin pump, diabetes management has encountered a technology revolution with the introduction of continuous glucose monitoring, sensor-augmented insulin pump therapy and closed-loop/artificial pancreas systems. In this review, we discuss the significance of the 2016 Endocrine Society Guidelines for insulin pump therapy and continuous glucose monitoring and summarize findings from relevant diabetes technology studies that were conducted after the publication of the 2016 Endocrine Society Guidelines. The 2016 Endocrine Society Guidelines have been a great resource for clinicians managing diabetes in this new era of diabetes technology. There is good body of evidence indicating that using diabetes technology systems safely tightens glycemic control while managing both type 1 and type 2 diabetes. The first-generation diabetes technology systems will evolve as we gain more experience and collaboratively work to improve them with an ultimate goal of keeping people with diabetes complication and burden-free until the cure for diabetes becomes a reality.

Bone remodeling and regulating biomarkers in women at the time of breast cancer diagnosis.

PubMed

Yao, Song; Zhang, Yali; Tang, Li; Roh, Janise M; Laurent, Cecile A; Hong, Chi-Chen; Hahn, Theresa; Lo, Joan C; Ambrosone, Christine B; Kushi, Lawrence H; Kwan, Marilyn L

2017-02-01

The majority of breast cancer patients receive endocrine therapy, including aromatase inhibitors known to cause increased bone resorption. Bone-related biomarkers at the time of breast cancer diagnosis may predict future risk of osteoporosis and fracture after endocrine therapy. In a large population of 2,401 female breast cancer patients who later underwent endocrine therapy, we measured two bone remodeling biomarkers, TRAP5b and BAP, and two bone regulating biomarkers, RANKL and OPG, in serum samples collected at the time of breast cancer diagnosis. We analyzed these biomarkers and their ratios with patients' demographic, lifestyle, clinical tumor characteristics, as well as bone health history. The presence of bone metastases, prior bisphosphonate (BP) treatment, and blood collection after chemotherapy had a significant impact on biomarker levels. After excluding these cases and controlling for blood collection time, several factors, including age, race/ethnicity, body mass index, physical activity, alcohol consumption, smoking, and hormonal replacement therapy, were significantly associated with bone biomarkers, while vitamin D or calcium supplements and tumor characteristics were not. When prior BP users were included in, recent history of osteoporosis and fracture was also associated. Our findings support further investigation of these biomarkers with bone health outcomes after endocrine therapy initiation in women with breast cancer.

Bone remodeling and regulating biomarkers in women at the time of breast cancer diagnosis

PubMed Central

Yao, Song; Zhang, Yali; Tang, Li; Roh, Janise M.; Laurent, Cecile A.; Hong, Chi-Chen; Hahn, Theresa; Lo, Joan C.; Ambrosone, Christine B.; Kushi, Lawrence H.; Kwan, Marilyn L.

2016-01-01

The majority of breast cancer patients receive endocrine therapy, including aromatase inhibitors known to cause increased bone resorption. Bone-related biomarkers at the time of breast cancer diagnosis may predict future risk of osteoporosis and fracture after endocrine therapy. In a large population of 2,401 female breast cancer patients who later underwent endocrine therapy, we measured two bone remodeling biomarkers, TRAP5b and BAP, and two bone regulating biomarkers, RANKL and OPG, in serum samples collected at the time of breast cancer diagnosis. We analyzed these biomarkers and their ratios with patients’ demographic, lifestyle, clinical tumor characteristics, as well as bone health history. The presence of bone metastases, prior bisphosphonate (BP) treatment and blood collection after chemotherapy had a significant impact on biomarker levels. After excluding these cases and controlling for blood collection time, age, race/ethnicity, body mass index, physical activity, alcohol consumption, smoking, and hormonal replacement therapy were significantly associated with bone biomarkers, while vitamin D or calcium supplements and tumor characteristics did not. When prior BP users were included in, recent history of osteoporosis and fracture was also associated. These findings support further investigation of these biomarkers with bone health outcomes after endocrine therapy initiation in women with breast cancer. PMID:27915435

Palbociclib: A Review in HR-Positive, HER2-Negative, Advanced or Metastatic Breast Cancer.

PubMed

Kim, Esther S; Scott, Lesley J

2017-06-01

Oral palbociclib (Ibrance®) is a first-in-class, highly selective inhibitor of cyclin-dependent kinases 4 and 6 (i.e. a CDK4/6 inhibitor). It is indicated for the treatment of women with HR-positive, HER2-negative advanced or metastatic breast cancer, in combination with an aromatase inhibitor as initial endocrine-based therapy, and in combination with fulvestrant (with or without a luteinizing hormone-releasing hormone agonist) in those previously treated with endocrine therapy. In clinical trials, palbociclib in combination with letrozole as initial endocrine-based therapy in postmenopausal women (PALOMA-1 and PALOMA-2), or in combination with fulvestrant in pre-, peri-, or postmenopausal women with disease progression after endocrine therapy (PALOMA-3), significantly prolonged progression-free survival (PFS) and improved clinical benefit response (CBR) rates. Neutropenia was the most commonly reported any-grade and grade ≥ 3 adverse event. It was infrequently associated with febrile neutropenia (<2%) and generally manageable with a palbociclib dose delay, interruption or reduction, without the routine use of growth factors, and without affecting efficacy. In conclusion, oral palbociclib combination therapy is a valuable emerging option for use in patients with HR-positive, HER2-negative advanced or metastatic breast cancer.

[Advanced luminal breast cancer (hormone receptor-positive, HER2 negative): New therapeutic options in 2015].

PubMed

Vanacker, Hélène; Bally, Olivia; Kassem, Loay; Tredan, Olivier; Heudel, Pierre; Bachelot, Thomas

2015-06-01

Despite improvements in early detection, surgery and systemic therapy, metastatic breast cancer remains a major cause of death. Luminal type breast cancers expressing hormone estrogen receptor (ER) or progesterone (PR) and without HER2 overexpression are generally sensitive to endocrine therapy, but raise the issue of the occurrence of resistance to treatment, particularly at metastatic stage. A better understanding of hormone resistance may guide the development of new therapeutics. New strategies aim at enhancing and prolonging of endocrine sensitivity, by optimizing existing schemes, or by combining an endocrine therapy with a targeted therapies specific to hormone resistance pathways: ER signaling, PI3K/AKT/mTOR and Cyclin Dependent Kinase (CDK). Key corners of 2014 include confirmation of benefit of high dose fulvestrant, and commercialization of everolimus as the first mTOR inhibitor in this indication. Other strategies are being tested dealing with new endocrine therapies or new molecular targets such as PI3K inhibitors, insulin-like growth factor receptor (IGF-R) and histone deacetylase (HDAC) inhibitors. Coming years may be fruitful and might radically change our way to treat these patients. Copyright © 2015 Société Françise du Cancer. Publié par Elsevier Masson SAS. Tous droits réservés. Published by Elsevier Masson SAS. All rights reserved.

The effects of fractional microablative CO2 laser therapy on sexual function in postmenopausal women and women with a history of breast cancer treated with endocrine therapy.

PubMed

Gittens, Paul; Mullen, Gregory

2018-06-08

To examine the outcomes of sexual function in postmenopausal women and women with a history of breast cancer treated with endocrine therapy who were experiencing the symptoms of GSM for which they were treated with fractional microablative CO 2 laser. From July 2015 to October 2016, a retrospective chart review of women who underwent fractional microablative CO 2 laser therapy (MonaLisa Touch, DEKA) for GSM was conducted. Several validated questionnaires were used to assess changes in symptoms and sexual function including the Female Sexual Function Index (FSFI), the Wong-Baker Faces Scale (WBFS), and the Female Sexual Distress Scale-Revised (FSDSR). Comparisons of mean symptom scores were described at baseline and six weeks after each treatment. There was a statistically significant improvement in every domain of FSFI, WBFS, and FSDS-R when comparing baseline symptom scores to after treatment three symptom scores for all patients. The secondary outcome was to evaluate the differences, if any, in outcomes of sexual function between postmenopausal women and women with a history of breast cancer treated with endocrine therapy. Both groups had statistically significant improvements in many domains studied. Fractional microablative CO 2 laser therapy (MonaLisa Touch, DEKA) is an effective modality in treating the symptoms of GSM in postmenopausal women and women with a history of breast cancer treated with endocrine therapy.

[Effects of magnesium valproate on endocrine system and reproductive functions of female epileptics].

PubMed

Xiang, Li; Ding, Jun-Qing; Huang, Xi-Shun

2011-08-09

To explore the effects of valproate (VPA) on endocrine system in adolescent and reproductive female patients with epilepsy. A total of 30 adolescent and reproductive female patients with a diagnosis of epilepsy at our hospital during July 2009 to March 2010 were recruited. All cases with magnesium VPA alone were included. The levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), estradiol (E2), progesterone (P) and testosterone (T) were detected respectively at pre-therapy and 3, 6 and 12 months post-therapy. And the changes of menstruation and ovaries were recorded. The serum concentration of PRL was lower at 3 and 6 months post-therapy than that at pre-therapy. There was significant difference (P = 0.010 and 0.014). The serum concentration of E2 significantly decreased after a 3-month therapy of valproate (P < 0.05). While comparing the parameter's level between the initial test and at a 3, 6 and 12-month follow-up, the level of P significantly decreased in the later groups than that of the former one while the level of T showed a marked increase. The levels of FSH and LH were not significantly different at pre- and post-therapy. And 6 (20%) of them presented with menstrual dysfunctions and 3 (10%) polycystic ovary. The valproate therapy can not only cause the changes of endocrine system and hormonal levels, but also induce such endocrine dysfunction syndromes as menstrual suspension and polycystic ovary. It eventually causes polycystic ovary syndrome.

Endocrine therapy use among elderly hormone receptor-positive breast cancer patients enrolled in Medicare Part D

PubMed Central

Riley, Gerald F.; Warren, Joan L.; Harlan, Linda C.; Blackwell, Steven A.

2011-01-01

Background Clinical guidelines recommend that women with hormone-receptor positive breast cancer receive endocrine therapy (selective estrogen receptor modulators [SERMs] or aromatase inhibitors [AIs]) for five years following diagnosis. Objective To examine utilization and adherence to therapy for SERMs and AIs in Medicare Part D prescription drug plans. Data Linked Surveillance, Epidemiology, and End Results (SEER)-Medicare data. Study design We identified 15,542 elderly women diagnosed with hormone-receptor positive breast cancer in years 2003-2005 (the latest SEER data at the time of the study) and enrolled in a Part D plan in 2006 or 2007 (the initial years of Part D). This permitted us to compare utilization and adherence to therapy at various points within the recommended five-year timeframe for endocrine therapy. SERM and AI use was measured from claim records. Non-adherence to therapy was defined as a medication possession ratio of less than 80 percent. Principal findings Between May 2006 and December 2007, 22 percent of beneficiaries received SERM, 52 percent AI, and 26 percent received neither. The percent receiving any endocrine therapy decreased with time from diagnosis. Among SERM and AI users, 20-30 percent were non-adherent to therapy; out-of-pocket costs were higher for AI than SERM and were strongly associated with non-adherence. For AI users without a low income subsidy, adherence to therapy deteriorated after reaching the Part D coverage gap. Conclusions Many elderly breast cancer patients were not receiving therapy for the recommended five years following diagnosis. Choosing a Part D plan that minimizes out-of-pocket costs is critical to ensuring beneficiary access to essential medications. PMID:22340780

Erlotinib Versus Radiation Therapy for Brain Metastases in Patients With EGFR-Mutant Lung Adenocarcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gerber, Naamit K.; Yamada, Yoshiya; Rimner, Andreas

2014-06-01

Purpose/Objectives: Radiation therapy (RT) is the principal modality in the treatment of patients with brain metastases (BM). However, given the activity of EGFR tyrosine kinase inhibitors in the central nervous system, it is uncertain whether upfront brain RT is necessary for patients with EGFR-mutant lung adenocarcinoma with BM. Methods and Materials: Patients with EGFR-mutant lung adenocarcinoma and newly diagnosed BM were identified. Results: 222 patients were identified. Exclusion criteria included prior erlotinib use, presence of a de novo erlotinib resistance mutation, or incomplete data. Of the remaining 110 patients, 63 were treated with erlotinib, 32 with whole brain RT (WBRT), andmore » 15 with stereotactic radiosurgery (SRS). The median overall survival (OS) for the whole cohort was 33 months. There was no significant difference in OS between the WBRT and erlotinib groups (median, 35 vs 26 months; P=.62), whereas patients treated with SRS had a longer OS than did those in the erlotinib group (median, 64 months; P=.004). The median time to intracranial progression was 17 months. There was a longer time to intracranial progression in patients who received WBRT than in those who received erlotinib upfront (median, 24 vs 16 months, P=.04). Patients in the erlotinib or SRS group were more likely to experience intracranial failure as a component of first failure, whereas WBRT patients were more likely to experience failure outside the brain (P=.004). Conclusions: The survival of patients with EGFR-mutant adenocarcinoma with BM is notably long, whether they receive upfront erlotinib or brain RT. We observed longer intracranial control with WBRT, even though the WBRT patients had a higher burden of intracranial disease. Despite the equivalent survival between the WBRT and erlotinib group, this study underscores the role of WBRT in producing durable intracranial control in comparison with a targeted biologic agent with known central nervous system activity.« less

The International (Ludwig) Breast Cancer Study Group Trials I-IV: 15 years follow-up.

PubMed

Castiglione-Gertsch, M; Johnsen, C; Goldhirsch, A; Gelber, R D; Rudenstam, C M; Collins, J; Lindtner, J; Hacking, A; Cortes-Funes, H; Forbes, J

1994-10-01

Adjuvant systemic therapy prolongs disease-free and overall survival in both pre- and postmenopausal patients. Available data shown benefit from multi-agent chemotherapy, prolonged tamoxifen treatment, and ovarian ablation, and that the combination of chemo- and endocrine therapy might be advantageous. In 1978 the International (Ludwig) Breast Cancer Study Group (IBCSG) initiated four complementary randomized controlled clinical trials to evaluate the roles of chemo-endocrine combinations or endocrine therapy alone in specific populations defined by risk (for pre- and perimenopausal patients) or by age (for postmenopausal patients). The results at 10 and 13 years' median follow-up for these trials are summarized in this report and are compared to those of the Overview meta-analysis with regard to chemo-endocrine or endocrine therapy combinations. Furthermore, types of first relapses by sites and second malignant diseases are reported. 1601 evaluable patients with node positive disease were included into the studies I-IV. In Trial I (491 premenopausal patients with 1-3 positive axillary nodes) we studied the addition of low-dose continuous prednisone (p) to a cyclophosphamide-methotrexate-fluorouracil (CMF) combination. In Trial II 327 premenopausal patients with four or more positive axillary nodes were randomized to one year CMFp or to a surgical oophorectomy followed by CMFp. In Trial III (463 postmenopausal patients 65 years old or younger), combined chemoendocrine therapy (one year of CMFp plus tamoxifen (T)) was compared to endocrine therapy (1 year of p + T) or to surgery alone. In Trial IV 320 postmenopausal patients 66 to 80 years old were treated either by surgery alone or by surgery followed by 1 year prednisone and tamoxifen. In Trial I the addition of prednisone allowed a higher dose of cytotoxics to be administered compared with CMF alone. Despite this increased dose intensity, 13-year disease-free survival (DFS) and overall survival (OS) were similar for the two treatment groups (49% vs. 52% DFS, 59% vs. 65% OS for CMFp vs. CMF). In Trial II the addition of surgical oophorectomy to CMFp yielded an improved outcome which approached statistical significance for the subset of 107 patients known to have estrogen receptor-positive tumors (DFS, 23% vs. 15%, p = 0.13; OS, 41% vs. 30%, p = 0.12). In Trial III combined chemoendocrine therapy improved DFS and OS compared with endocrine therapy alone (p + T) given for the same duration, or no adjuvant treatment (DFS, 35% vs. 25% vs. 14%, p < 0.0001; OS, 48% vs. 36% vs. 32%, p = 0.01). In Trial IV p + T improved DFS compared with no adjuvant therapy (27% vs. 15%, p = 0.004). Despite competing risks for this elderly population, OS was also improved but the result was not statistically significant (34% vs. 22%, p = 0.08). The overall results of these four trials indicate that the continuation of investigations on combined chemo-endocrine therapies is warranted. The prognosis of the patients, all node-positive, treated with the most effective adjuvant treatment is such that there is a large potential for improvement.

Analysis of Factors Associated With Radiation-Induced Bronchiolitis Obliterans Organizing Pneumonia Syndrome After Breast-Conserving Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Katayama, Norihisa; Sato, Shuhei; Katsui, Kuniaki

Purpose: To evaluate factors associated with radiation-induced bronchiolitis obliterans organizing pneumonia (BOOP) syndrome after breast-conserving therapy. Methods and Materials: A total of 702 women with breast cancer who received radiotherapy after breast-conserving surgery at seven institutions between July 1995 and December 2006 were analyzed. In all patients, the whole breast was irradiated with two tangential photon beams. The criteria used for the diagnosis of radiation-induced BOOP syndrome were as follows: (1) radiotherapy to the breast within 12 months, (2) general and/or respiratory symptoms lasting for {>=}2 weeks, (3) radiographs showing lung infiltration outside the radiation port, and (4) no evidencemore » of a specific cause. Results: Radiation-induced BOOP syndrome was seen in 16 patients (2.3%). Eleven patients (68.8%) were administered steroids. The duration of steroid administration ranged from 1 week to 3.7 years (median, 1.1 years). Multivariate analysis revealed that age ({>=}50 years; odds ratio [OR] 8.88; 95% confidence interval [CI] 1.16-67.76; p = 0.04) and concurrent endocrine therapy (OR 3.05; 95% CI 1.09-8.54; p = 0.03) were significantly associated with BOOP syndrome. Of the 161 patients whose age was {>=}50 years and who received concurrent endocrine therapy, 10 (6.2%) developed BOOP syndrome. Conclusions: Age ({>=}50 years) and concurrent endocrine therapy can promote the development of radiation-induced BOOP syndrome after breast-conserving therapy. Physicians should carefully follow patients who received breast-conserving therapy, especially those who are older than 50 years and received concurrent endocrine therapy during radiotherapy.« less

Observation versus late reintroduction of letrozole as adjuvant endocrine therapy for hormone receptor-positive breast cancer (ANZ0501 LATER): an open-label randomised, controlled trial.

PubMed

Zdenkowski, N; Forbes, J F; Boyle, F M; Kannourakis, G; Gill, P G; Bayliss, E; Saunders, C; Della-Fiorentina, S; Kling, N; Campbell, I; Mann, G B; Coates, A S; Gebski, V; Davies, L; Thornton, R; Reaby, L; Cuzick, J; Green, M

2016-05-01

Despite the effectiveness of adjuvant endocrine therapy in preventing breast cancer recurrence, breast cancer events continue at a high rate for at least 10 years after completion of therapy. This randomised open label phase III trial recruited postmenopausal women from 29 Australian and New Zealand sites, with hormone receptor-positive early breast cancer, who had completed ≥4 years of endocrine therapy [aromatase inhibitor (AI), tamoxifen, ovarian suppression, or sequential combination] ≥1 year prior, to oral letrozole 2.5 mg daily for 5 years, or observation. Treatment allocation was by central computerised randomisation, stratified by institution, axillary node status and prior endocrine therapy. The primary outcome was invasive breast cancer events (new invasive primary, local, regional or distant recurrence, or contralateral breast cancer), analysed by intention to treat. The secondary outcomes were disease-free survival (DFS), overall survival, and safety. Between 16 May 2007 and 14 March 2012, 181 patients were randomised to letrozole and 179 to observation (median age 64.3 years). Endocrine therapy was completed at a median of 2.6 years before randomisation, and 47.5% had tumours of >2 cm and/or node positive. At 3.9 years median follow-up (interquartile range 3.1-4.8), 2 patients assigned letrozole (1.1%) and 17 patients assigned observation (9.5%) had experienced an invasive breast cancer event (difference 8.4%, 95% confidence interval 3.8% to 13.0%, log-rank test P = 0.0004). Twenty-four patients (13.4%) in the observation and 14 (7.7%) in the letrozole arm experienced a DFS event (log-rank P = 0.067). Adverse events linked to oestrogen depletion, but not serious adverse events, were more common with letrozole. These results should be considered exploratory, but lend weight to emerging data supporting longer duration endocrine therapy for hormone receptor-positive breast cancer, and offer insight into reintroduction of AI therapy. Australian New Zealand Clinical Trials Registry (www.anzctr.org.au), ACTRN12607000137493. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Comparative effectiveness of upfront esophagectomy versus induction chemoradiation in clinical stage T2N0 esophageal cancer: A decision analysis.

PubMed

Semenkovich, Tara R; Panni, Roheena Z; Hudson, Jessica L; Thomas, Theodore; Elmore, Leisha C; Chang, Su-Hsin; Meyers, Bryan F; Kozower, Benjamin D; Puri, Varun

2018-05-01

We compared the effectiveness of upfront esophagectomy versus induction chemoradiation followed by esophagectomy for overall survival in patients with clinical T2N0 (cT2N0) esophageal cancer. We also assessed the influence of the diagnostic uncertainty of endoscopic ultrasound on the expected benefit of chemoradiation. We created a decision analysis model representing 2 treatment strategies for cT2N0 esophageal cancer: upfront esophagectomy that may be followed by adjuvant therapy for upstaged patients and induction chemoradiation for all patients with cT2N0 esophageal cancer followed by esophagectomy. Parameter values within the model were obtained from published data, and median survival for pathologic subgroups was derived from the National Cancer Database. In sensitivity analyses, staging uncertainty of endoscopic ultrasound was introduced by varying the probability of pathologic upstaging. The baseline model showed comparable median survival for both strategies: 48.3 months for upfront esophagectomy versus 45.9 months for induction chemoradiation and surgery. The sensitivity analysis demonstrated induction chemoradiation was beneficial, with probability of upstaging > 48.1%, which is within the published range of 32% to 65% probability of pathologic upstaging after cT2N0 diagnosis. The presence of any of 3 key variables (size larger than 3 cm, high grade, or lymphovascular invasion) was associated with > 48.1% risk of upstaging, thus conferring a survival advantage to induction chemoradiation. The optimal treatment strategy for cT2N0 esophageal cancer depends on the accuracy of endoscopic ultrasound staging. High-risk features that confer increased probability of upstaging can inform clinical decision making to recommend induction chemoradiation for select cT2N0 patients. Copyright © 2018 The American Association for Thoracic Surgery. All rights reserved.

Prognostic and predictive impact of central necrosis and fibrosis in early breast cancer. Results from two International Breast Cancer Study Group randomized trials of chemoendocrine adjuvant therapy

PubMed Central

Maiorano, Eugenio; Regan, Meredith M.; Viale, Giuseppe; Mastropasqua, Mauro G.; Colleoni, Marco; Castiglione-Gertsch, Monica; Price, Karen N.; Gelber, Richard D.; Goldhirsch, Aron; Coates, Alan S.

2013-01-01

Purpose A minority of early invasive breast cancers show a pattern of central necrosis and fibrosis (CNF). Previous studies have documented an adverse prognostic impact and association with other adverse pathological features, but its predictive importance for therapy selection is unknown. Methods We examined the prognostic and predictive value of CNF in two randomized clinical trials comparing chemoendocrine therapy with endocrine therapy alone in patients with node-negative breast cancer. A total of 1850 patients randomly assigned to treatment groups comparing endocrine with chemoendocrine therapy, and with centrally-assessed CNF, ER, PgR and HER2 were included in the analytic cohort. The median follow up was 10 years. Results CNF was present in 84 of 1850 trial patients (4.5%). It was associated with tumor characteristics suggesting poor outcome, but was an independent adverse factor for disease-free survival. In the presence of CNF outcome was worse regardless of tumor grade, whereas in the absence of CNF, patients with grade 3 tumors had poorer outcome than those with grade 1-2 tumors. Among patients with estrogen receptor-absent tumors chemoendocrine therapy was superior to endocrine therapy alone only in the absence of CNF [HR (chemoendocrine:endocrine)=0.46 in CNF-absent, 0.90 in CNF-present], while among those with receptor-positive disease chemoendocrine therapy was beneficial only in the presence of CNF [HR=0.34 CNF-present, 0.96 CNF-absent]. Conclusion The results suggest that the presence of CNF reflects a biological difference in early breast cancer that is important in modulating the efficacy of standard therapies. Accordingly we believe that its presence should be routinely reported. PMID:19280340

Proton Radiation Therapy for Pediatric Medulloblastoma and Supratentorial Primitive Neuroectodermal Tumors: Outcomes for Very Young Children Treated With Upfront Chemotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jimenez, Rachel B., E-mail: rbjimenez@partners.org; Sethi, Roshan; Depauw, Nicolas

Purpose: To report the early outcomes for very young children with medulloblastoma or supratentorial primitive neuroectodermal tumor (SPNET) treated with upfront chemotherapy followed by 3-dimensional proton radiation therapy (3D-CPT). Methods and Materials: All patients aged <60 months with medulloblastoma or SPNET treated with chemotherapy before 3D-CPT from 2002 to 2010 at our institution were included. All patients underwent maximal surgical resection, chemotherapy, and adjuvant 3D-CPT with either craniospinal irradiation followed by involved-field radiation therapy or involved-field radiation therapy alone. Results: Fifteen patients (median age at diagnosis, 35 months) were treated with high-dose chemotherapy and 3D-CPT. Twelve of 15 patients hadmore » medulloblastoma; 3 of 15 patients had SPNET. Median time from surgery to initiation of radiation was 219 days. Median craniospinal irradiation dose was 21.6 Gy (relative biologic effectiveness); median boost dose was 54.0 Gy (relative biologic effectiveness). At a median of 39 months from completion of radiation, 1 of 15 was deceased after a local failure, 1 of 15 had died from a non-disease-related cause, and the remaining 13 of 15 patients were alive without evidence of disease recurrence. Ototoxicity and endocrinopathies were the most common long-term toxicities, with 2 of 15 children requiring hearing aids and 3 of 15 requiring exogenous hormones. Conclusions: Proton radiation after chemotherapy resulted in good disease outcomes for a small cohort of very young patients with medulloblastoma and SPNET. Longer follow-up and larger numbers of patients are needed to assess long-term outcomes and late toxicity.« less

ESR1 mutations as a mechanism for acquired endocrine resistance in breast cancer

PubMed Central

Jeselsohn, Rinath; Buchwalter, Gilles; De Angelis, Carmine; Brown, Myles; Schiff, Rachel

2016-01-01

Most breast cancers are estrogen receptor α (ER)-positive (+) and are treated with endocrine therapies targeting ER activity. Despite efforts, the mechanisms of the frequent clinical resistance to these therapies remain largely unknown. Several recent parallel studies unveiled gain-of-function recurrent ESR1 mutations in up to 20% of patients with metastatic ER+ disease who all received endocrine therapies, which for more cases included an aromatase inhibitor. These mutations, clustered in a hotspot within the ligand-binding domain (LBD), lead to ligand independent ER activity and tumor growth, partial resistance to tamoxifen and fulvestrant, and potentially increased metastatic capacity. Together, these findings suggest that the ESR1 LBD mutations account for acquired endocrine resistance in a substantial fraction of patients with metastatic disease. The absence of detectable ESR1 mutations in treatment-naïve disease and the correlation with the number of endocrine treatments indicate a clonal expansion of rare mutant clones, selected under the pressure of treatment. New technologies to detect low/ultra rare ESR1 mutations together with tissue and liquid biopsies are required to fully expose their clinical relevance in prognosis and treatment. Pre-clinical and clinical development of rationale-based novel therapeutic strategies to inhibit these mutants has the potential to substantially improve treatment outcomes. PMID:26122181

Treatment challenges for community oncologists treating postmenopausal women with endocrine-resistant, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer

PubMed Central

Gradishar, William J

2016-01-01

Community-based oncologists are faced with challenges and opportunities when delivering quality patient care, including high patient volumes and diminished resources; however, there may be the potential to deliver increased patient education and subsequently improve outcomes. This review discusses the treatment of postmenopausal women with endocrine-resistant, hormone receptor-positive, human epidermal growth factor receptor 2- negative advanced breast cancer in order to illustrate considerations in the provision of pertinent quality education in the treatment of these patients and the management of therapy-related adverse events. An overview of endocrine-resistant breast cancer and subsequent treatment challenges is also provided. Approved treatment options for endocrine-resistant breast cancer include hormonal therapies and mammalian target of rapamycin inhibitors. Compounds under clinical investigation are also discussed. PMID:27468248

Upregulation of mucin4 in ER-positive/HER2-overexpressing breast cancer xenografts with acquired resistance to endocrine and HER2-targeted therapies.

PubMed

Chen, Albert C; Migliaccio, Ilenia; Rimawi, Mothaffar; Lopez-Tarruella, Sara; Creighton, Chad J; Massarweh, Suleiman; Huang, Catherine; Wang, Yen-Chao; Batra, Surinder K; Gutierrez, M Carolina; Osborne, C Kent; Schiff, Rachel

2012-07-01

We studied resistance to endocrine and HER2-targeted therapies using a xenograft model of estrogen receptor positive (ER)/HER2-overexpressing breast cancer. Here, we report a novel phenotype of drug resistance in this model. MCF7/HER2-18 xenografts were treated with endocrine therapy alone or in combination with lapatinib and trastuzumab (LT) to inhibit HER2. Archival tumor tissues were stained with hematoxylin and eosin and with mucicarmine. RNA extracted from tumors at early time points and late after acquired resistance were analyzed for mucin4 (MUC4) expression by microarray and quantitative reverse transcriptase-PCR. Protein expression of the MUC4, ER, and HER2 signaling pathways was measured by immunohistochemistry and western blotting. The combination of the potent anti-HER2 regimen LT with either tamoxifen (Tam + LT) or estrogen deprivation (ED + LT) can cause complete eradication of ER-positive/HER2-overexpressing tumors in mice. Tumors developing resistance to this combination, as well as those acquiring resistance to endocrine therapy alone, exhibited a distinct histological and molecular phenotype-a striking increase in mucin-filled vacuoles and upregulation of several mucins including MUC4. At the onset of resistance, MUC4 mRNA and protein were increased. These tumors also showed upregulation and reactivation of HER2 signaling, while losing ER protein and the estrogen-regulated gene progesterone receptor. Mucins are upregulated in a preclinical model of ER-positive/HER2-overexpressing breast cancer as resistance develops to the combination of endocrine and anti-HER2 therapy. These mucin-rich tumors reactivate the HER2 pathway and shift their molecular phenotype to become more ER-negative/HER2-positive.

Upregulation of Mucin4 in ER-positive/HER2-Overexpressing Breast Cancer Xenografts with Acquired Resistance to Endocrine and HER2-Targeted Therapies

PubMed Central

Chen, Albert C.; Migliaccio, Ilenia; Rimawi, Mothaffar; Lopez-Tarruella, Sara; Creighton, Chad J.; Massarweh, Suleiman; Huang, Catherine; Wang, Yen-Chao; Batra, Surinder K.; Gutierrez, M. Carolina; Osborne, C. Kent; Schiff, Rachel

2012-01-01

Background We studied resistance to endocrine and HER2-targeted therapies using a xenograft model of estrogen receptor positive (ER)/HER2-overexpressing breast cancer. Here, we report a novel phenotype of drug resistance in this model. Methods MCF7/HER2-18 xenografts were treated with endocrine therapy alone or in combination with lapatinib and trastuzumab (LT) to inhibit HER2. Archival tumor tissues were stained with hematoxylin & eosin and mucicarmine. RNA extracted from tumors at early time points and late after acquired resistance were analyzed for mucin4 (MUC4) expression by microarray and quantitative reverse transcriptase-PCR. Protein expression of the MUC4, ER and HER2 signaling pathways was measured by immunohistochemistry and Western blotting. Results The combination of the potent anti-HER2 regimen LT with either tamoxifen (Tam+LT) or estrogen deprivation (ED+LT) can cause complete eradication of ER-positive/HER2-overexpressing tumors in mice. Tumors developing resistance to this combination, as well as those acquiring resistance to endocrine therapy alone, exhibited a distinct histological and molecular phenotype—a striking increase in mucin-filled vacuoles and upregulation of several mucins including MUC4. At the onset of resistance, MUC4 mRNA and protein were increased. These tumors also showed upregulation and reactivation of HER2 signaling, while losing ER protein and the estrogen-regulated gene, progesterone receptor. Conclusions Mucins are upregulated in a preclinical model of ER-positive/HER2-overexpressing breast cancer as resistance develops to the combination of endocrine and anti-HER2 therapy. These mucin-rich tumors reactivate the HER2 pathway and shift their molecular phenotype to become more ER-negative/HER2-positive. PMID:22644656

Towards an understanding of the biology and targeted treatment of paediatric relapsed acute lymphoblastic leukaemia.

PubMed

Irving, Julie A E

2016-03-01

Acute lymphoblastic leukaemia is the most common childhood cancer and for those children who relapse, prognosis is poor and new therapeutic strategies are needed. Recurrent pathways implicated in relapse include RAS, JAK STAT, cell cycle, epigenetic regulation, B cell development, glucocorticoid response, nucleotide metabolism and DNA repair. Targeting these pathways is a rational therapeutic strategy and may deliver novel, targeted therapies into the clinic. Relapse often stems from a minor clone present at diagnosis and thus analysis of persisting leukaemia during upfront therapy may allow targeted drug intervention to prevent relapse. © 2015 John Wiley & Sons Ltd.

Nab-paclitaxel and Gemcitabine vs Gemcitabine Alone as Adjuvant Therapy for Patients With Resected Pancreatic Cancer (the "Apact" Study)

ClinicalTrials.gov

2018-03-26

Pancreatic Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Digestive System Diseases; Endocrine System Diseases; Gemcitabine; Antimetabolites, Antineoplastic

Herbal Medicine for Hot Flushes Induced by Endocrine Therapy in Women with Breast Cancer: A Systematic Review and Meta-Analysis.

PubMed

Li, Yuanqing; Zhu, Xiaoshu; Bensussan, Alan; Li, Pingping; Moylan, Eugene; Delaney, Geoff; McPherson, Luke

2016-01-01

Objective. This systematic review was conducted to evaluate the clinical effectiveness and safety of herbal medicine (HM) as an alternative management for hot flushes induced by endocrine therapy in breast cancer patients. Methods. Key English and Chinese language databases were searched from inception to July 2015. Randomized Controlled Trials (RCTs) evaluating the effects of HM on hot flushes induced by endocrine therapy in women with breast cancer were retrieved. We conducted data collection and analysis in accordance with the Cochrane Handbook for Systematic Reviews of Interventions. Statistical analysis was performed with the software (Review Manager 5.3). Results. 19 articles were selected from the articles retrieved, and 5 articles met the inclusion criteria for analysis. Some included individual studies showed that HM can relieve hot flushes as well as other menopausal symptoms induced by endocrine therapy among women with breast cancer and improve the quality of life. There are minor side effects related to HM which are well tolerated. Conclusion. Given the small number of included studies and relatively poor methodological quality, there is insufficient evidence to draw positive conclusions regarding the objective benefit of HM. Additional high quality studies are needed with more rigorous methodological approach to answer this question.

Insulin-Like Growth Factor and Epidermal Growth Factor Signaling in Breast Cancer Cell Growth: Focus on Endocrine Resistant Disease

PubMed Central

Berdiaki, Aikaterini; Tzardi, Maria

2015-01-01

Breast cancer is the most common type of cancer for women worldwide with a lifetime risk amounting to a staggering total of 10%. It is well established that the endogenous synthesis of insulin-like growth factor (IGF) and epidermal growth factor (EGF) polypeptide growth factors are closely correlated to malignant transformation and all the steps of the breast cancer metastatic cascade. Numerous studies have demonstrated that both estrogens and growth factors stimulate the proliferation of steroid-dependent tumor cells, and that the interaction between these signaling pathways occurs at several levels. Importantly, the majority of breast cancer cases are estrogen receptor- (ER-) positive which have a more favorable prognosis and pattern of recurrence with endocrine therapy being the backbone of treatment. Unfortunately, the majority of patients progress to endocrine therapy resistant disease (acquired resistance) whereas a proportion of patients may fail to respond to initial therapy (de novo resistance). The IGF-I and EGF downstream signaling pathways are closely involved in the process of progression to therapy resistant disease. Modifications in the bioavailability of these growth factors contribute critically to disease progression. In the present review therefore, we will discuss in depth how IGF and EGF signaling participate in breast cancer pathogenesis and progression to endocrine resistant disease. PMID:26258011

Treatment of Peripheral T-Cell Lymphoma: Many Shades of Gray.

PubMed

Lunning, Matthew A

2015-08-01

Previously obscured within other designations of aggressive lymphomas, peripheral T-cell lymphoma (PTCL) now represents 23 different subtypes of non-Hodgkin lymphoma (NHL). Despite the many subtypes now recognized, PTCL represents only approximately 10% of all NHL cases diagnosed. Positron emission tomography/computed tomography has become essential to accurate staging and response-evaluation for PTCL. In comparison to aggressive B-cell NHL, patients with PTCL will more often be refractory to initial therapy, and chemosensitive patients will have shorter disease-free periods. Anthracycline-based regimens, often with the inclusion of etoposide, are commonly used during induction therapy. Consolidation with high-dose therapy and autologous stem cell transplantation (ASCT) in first chemosensitive remission appears to provide the best outcome in common nodal PTCL subtypes. The commonly defined nodal subtypes are PTCL not otherwise specified, angioimmunoblastic T-cell lymphoma, and anaplastic lymphoma kinase (ALK)-positive or ALK-negative anaplastic large-cell lymphoma (ALCL). Four agents have been approved by the US Food and Drug Administration for use in the relapsed/refractory (rel/ref) setting, including belinostat (2014), romidepsin (2011), brentuximab vedotin (2011), and pralatrexate (2009). Brentuximab vedotin was approved only for the ALCL subtype. These agents continue to be studied as combinations in the rel/ref setting and as additions or substitutions for other agents in upfront multiagent chemotherapy regimens. Patients who have responded to treatment in the rel/ref setting and are considered transplant-eligible should be considered for allogeneic stem cell transplantation, especially those with previous ASCT. Upfront allogeneic stem cell transplantation remains a research question in the majority of PTCL subtypes, but data are emerging.

Optimizing Quality of Life in Patients with Hormone Receptor-Positive Metastatic Breast Cancer: Treatment Options and Considerations.

PubMed

Chalasani, Pavani

2017-01-01

The treatment landscape for hormone receptor-positive metastatic breast cancer continues to evolve as the molecular mechanisms of this heterogeneous disease are better understood and targeted treatment strategies are developed. Patients are now living for extended periods of time with this disease as they progress through sequential lines of treatment. With a rapidly expanding therapeutic armamentarium, the prevalence of metastatic breast cancer patients with prolonged survival is expected to increase, as is the duration of survival. Practice guidelines recommend endocrine therapy alone as first-line therapy for the majority of patients with metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. The approval of new agents and expanded combination options has extended their use beyond first line, but endocrine therapy is not used as widely in clinical practice as recommended. As all treatments are palliative, even as survival is prolonged, optimizing and maintaining patient quality of life is crucial. This article surveys data relevant to the use of endocrine therapy in the setting of hormone receptor-positive metastatic breast cancer, including key clinical evidence regarding approved therapies and the impact of these therapies on patient quality of life. © 2017 S. Karger AG, Basel.

Recurrent hyperactive ESR1 fusion proteins in endocrine therapy-resistant breast cancer.

PubMed

Hartmaier, R J; Trabucco, S E; Priedigkeit, N; Chung, J H; Parachoniak, C A; Vanden Borre, P; Morley, S; Rosenzweig, M; Gay, L M; Goldberg, M E; Suh, J; Ali, S M; Ross, J; Leyland-Jones, B; Young, B; Williams, C; Park, B; Tsai, M; Haley, B; Peguero, J; Callahan, R D; Sachelarie, I; Cho, J; Atkinson, J M; Bahreini, A; Nagle, A M; Puhalla, S L; Watters, R J; Erdogan-Yildirim, Z; Cao, L; Oesterreich, S; Mathew, A; Lucas, P C; Davidson, N E; Brufsky, A M; Frampton, G M; Stephens, P J; Chmielecki, J; Lee, A V

2018-04-01

Estrogen receptor-positive (ER-positive) metastatic breast cancer is often intractable due to endocrine therapy resistance. Although ESR1 promoter switching events have been associated with endocrine-therapy resistance, recurrent ESR1 fusion proteins have yet to be identified in advanced breast cancer. To identify genomic structural rearrangements (REs) including gene fusions in acquired resistance, we undertook a multimodal sequencing effort in three breast cancer patient cohorts: (i) mate-pair and/or RNAseq in 6 patient-matched primary-metastatic tumors and 51 metastases, (ii) high coverage (>500×) comprehensive genomic profiling of 287-395 cancer-related genes across 9542 solid tumors (5216 from metastatic disease), and (iii) ultra-high coverage (>5000×) genomic profiling of 62 cancer-related genes in 254 ctDNA samples. In addition to traditional gene fusion detection methods (i.e. discordant reads, split reads), ESR1 REs were detected from targeted sequencing data by applying a novel algorithm (copyshift) that identifies major copy number shifts at rearrangement hotspots. We identify 88 ESR1 REs across 83 unique patients with direct confirmation of 9 ESR1 fusion proteins (including 2 via immunoblot). ESR1 REs are highly enriched in ER-positive, metastatic disease and co-occur with known ESR1 missense alterations, suggestive of polyclonal resistance. Importantly, all fusions result from a breakpoint in or near ESR1 intron 6 and therefore lack an intact ligand binding domain (LBD). In vitro characterization of three fusions reveals ligand-independence and hyperactivity dependent upon the 3' partner gene. Our lower-bound estimate of ESR1 fusions is at least 1% of metastatic solid breast cancers, the prevalence in ctDNA is at least 10× enriched. We postulate this enrichment may represent secondary resistance to more aggressive endocrine therapies applied to patients with ESR1 LBD missense alterations. Collectively, these data indicate that N-terminal ESR1 fusions involving exons 6-7 are a recurrent driver of endocrine therapy resistance and are impervious to ER-targeted therapies.

Sensitivity to systemic therapy for metastatic breast cancer in CHEK2 1100delC mutation carriers.

PubMed

Kriege, Mieke; Jager, Agnes; Hollestelle, Antoinette; Berns, Els M J J; Blom, Jannet; Meijer-van Gelder, Marion E; Sieuwerts, Anieta M; van den Ouweland, Ans; Collée, J Margriet; Kroep, Judith R; Martens, John W M; Hooning, Maartje J; Seynaeve, Caroline

2015-10-01

The role of CHEK2 in DNA repair by homologous recombination suggests that CHEK2-associated breast cancer (BC) patients might be more sensitive to chemotherapy inducing double-strand DNA breaks, but results hereon are lacking. We compared the sensitivity to first-line chemotherapy and endocrine therapy between CHEK2 1100delC and non-CHEK2 metastatic breast cancer (MBC) patients. Sixty-two CHEK2 1100delC MBC patients were selected from three cohorts genotyped for CHEK2 1100delC (one non-BRCA1/2 cohort and two sporadic cohorts). Controls were 62 non-CHEK2 MBC patients, matched for age at and year of primary BC diagnosis, and year of metastatic disease. Objective response rate (complete and partial response) to, and progression-free survival (PFS) and overall survival (OS) after start of first-line chemotherapy and endocrine therapy were compared between CHEK2 and non-CHEK2 patients. Median age at BC diagnosis was 46 and 51 years at MBC diagnosis. First-line chemotherapy consisted of anthracycline-based chemotherapy (n = 73), taxanes (n = 16), CMF(-like) chemotherapy (n = 33) and taxane/anthracycline regimens (n = 2). CHEK2 and non-CHEK2 patients had a comparable objective response rate (44 vs. 52 %). Also, PFS and OS after start of chemotherapy were comparable between both patient groups (hazard ratio 0.91; 95 % confidence interval 0.63-1.30 and 1.03; 95 % CI 0.71-1.49, respectively). Thirty-six CHEK2 and 32 non-CHEK2 patients received first-line endocrine therapy (mainly tamoxifen) for MBC. No significant differences were observed in objective response rate to, and PFS and OS after start of endocrine therapy. No differential efficacy of chemotherapy and endocrine therapy given for MBC was observed in CHEK2 versus non-CHEK2 patients.

Adjuvant psychological therapy in long-term endocrine conditions.

PubMed

Daniels, J; Turner-Cobb, J M

2017-06-01

Consideration of psychological distress in long-term endocrine conditions is of vital importance given the prevalence of anxiety and depression in such disorders. Poor mental health can lead to compromised self-care, higher utilization of health services, lower rates of adherence, reduced quality of life and ultimately poorer outcomes. Adjuvant psychological therapy offers an effective resource to reduce distress in endocrine conditions. While the vast majority of work in this area has focused on psychological screening and intervention in diabetes, identification and recognition of psychological distress are equally important in other endocrinological conditions, with supportive evidence in polycystic ovary syndrome and Addison's disease. Referral pathways and recommendations set out by UK guidelines and the Department of Health mandate requires greater attention across a wider range of long-term endocrine conditions to facilitate improved quality of life and health outcome. © 2017 John Wiley & Sons Ltd.

Controversial endocrine interventions for the aged.

PubMed

Leow, M K S; Loh, K C

2006-07-01

Specific endocrine changes occur with the ageing process. The last decade has witnessed significant progress in the basic and clinical science of ageing, thereby rejuvenating the interest in anti-ageing medicine, especially that of hormone replacement, by medical professionals and the lay public. However, endocrine manipulation as a therapeutic strategy for ageing is still evolving as continuing research attempts to answer the many questions of what it can achieve at the risk of incurring unknown long-term adverse effects. The current day doctor is confronted with a host of options, and will benefit from a synopsis of the latest evidence before making the most appropriate decision for aged patients seeking hormonal replacement therapy as a means to counter the effects of ageing. This review aims to give a rapid overview of the endocrine profile of geriatric population and the studies on the more controversial hormonal replacement therapies for the aged.

miR-378a-3p modulates tamoxifen sensitivity in breast cancer MCF-7 cells through targeting GOLT1A

PubMed Central

Ikeda, Kazuhiro; Horie-Inoue, Kuniko; Ueno, Toshihide; Suzuki, Takashi; Sato, Wataru; Shigekawa, Takashi; Osaki, Akihiko; Saeki, Toshiaki; Berezikov, Eugene; Mano, Hiroyuki; Inoue, Satoshi

2015-01-01

Breast cancer is a hormone-dependent cancer and usually treated with endocrine therapy using aromatase inhibitors or anti-estrogens such as tamoxifen. A majority of breast cancer, however, will often fail to respond to endocrine therapy. In the present study, we explored miRNAs associated with endocrine therapy resistance in breast cancer. High-throughput miRNA sequencing was performed using RNAs prepared from breast cancer MCF-7 cells and their derivative clones as endocrine therapy resistant cell models, including tamoxifen-resistant (TamR) and long-term estrogen-deprived (LTED) MCF-7 cells. Notably, miR-21 was the most abundantly expressed miRNA in MCF-7 cells and overexpressed in TamR and LTED cells. We found that miR-378a-3p expression was downregulated in TamR and LTED cells as well as in clinical breast cancer tissues. Additionally, lower expression levels of miR-378a-3p were associated with poor prognosis for tamoxifen-treated patients with breast cancer. GOLT1A was selected as one of the miR-378a-3p candidate target genes by in silico analysis. GOLT1A was overexpressed in breast cancer specimens and GOLT1A-specific siRNAs inhibited the growth of TamR cells. Low GOLT1A levels were correlated with better survival in patients with breast cancer. These results suggest that miR-378a-3p-dependent GOLT1A expression contributes to the mechanisms underlying breast cancer endocrine resistance. PMID:26255816

Effect of prior chemotherapy regimens on the efficacy of endocrine therapy within a German cohort of the TEAM trial.

PubMed

Bossart, Michaela; Hadji, Peyman; Klar, Maximilian; Kieback, Dirk G; Hasenburg, Annette

2014-01-01

Prior chemotherapy may affect the efficacy of endocrine therapy. The tamoxifen exemestane adjuvant multinational (TEAM) trial compared 5 years of adjuvant exemestane with the sequence of tamoxifen followed by exemestane in postmenopausal women with hormone-receptor-positive breast cancer. A total of 1,502 patients were enrolled in Germany (739 received tamoxifen followed by exemestan and 610 exemestan alone). A retrospective analysis of the German cohort of TEAM was conducted to determine whether prior chemotherapy affected clinical outcome of endocrine therapy. Overall survival, disease-free survival and distant recurrence were similar between patients who received sequential therapy and those who received exemestane monotherapy, irrespective of prior chemotherapy. Overall survival was not significantly different between patients who had received prior chemotherapy and those who had not (P = 0.2836). Disease-free survival and distant recurrence were significantly better in patients who had not received prior chemotherapy versus those who had (P = 0.0308 and P = 0.0001). In patients receiving sequential therapy, there were no significant differences in overall survival according to prior chemotherapy use (P = 0.1812). However, disease-free survival and distant recurrence were significantly different dependent on prior chemotherapy (P = 0.0143 and P = 0.0053). In conclusion, there was no difference in overall survival between breast cancer patients who did receive prior chemotherapy before endocrine therapy and those who had not. Patients who had not received prior chemotherapy had significantly improved disease-free survival and less distant recurrence versus those who had received chemotherapy.

Endocrine therapy for postmenopausal women with hormone receptor-positive her2-negative advanced breast cancer after progression or recurrence on nonsteroidal aromatase inhibitor therapy: a Canadian consensus statement.

PubMed

Pritchard, K I; Gelmon, K A; Rayson, D; Provencher, L; Webster, M; McLeod, D; Verma, S

2013-02-01

Approximately 22,700 Canadian women were expected to be diagnosed with breast cancer in 2012. Despite improvements in screening and adjuvant treatment options, a substantial number of postmenopausal women with hormone receptor positive (hr+) breast cancer will continue to develop metastatic disease during or after adjuvant endocrine therapy. Guidance on the selection of endocrine therapy for patients with hr+ disease that is negative for the human epidermal growth factor receptor 2 (her2-) and that has relapsed or progressed on earlier nonsteroidal aromatase inhibitor (nsai) therapy is of increasing clinical importance. Exemestane, fulvestrant, and tamoxifen are approved therapeutic options in this context. Four phase iii trials involving 2876 patients-efect, sofea, confirm, and bolero-2-have assessed the efficacy of various treatment options in this clinical setting. Data from those trials suggest that standard-dose fulvestrant (250 mg monthly) and exemestane are of comparable efficacy, that doubling the dose of fulvestrant from 250 mg to 500 mg monthly results in a 15% reduction in the risk of progression, and that adding everolimus to exemestane (compared with exemestane alone) results in a 57% reduction in the risk of progression, albeit with increased toxicity. Multiple treatment options are now available to women with hr+ her2- advanced breast cancer recurring or progressing on earlier nsai therapy, although current clinical trial data suggest more robust clinical efficacy with everolimus plus exemestane. Consideration should be given to the patient's age, functional status, and comorbidities during selection of an endocrine therapy, and use of a proactive everolimus safety management strategy is encouraged.

Endocrine therapy for postmenopausal women with hormone receptor–positive her2–negative advanced breast cancer after progression or recurrence on nonsteroidal aromatase inhibitor therapy: a Canadian consensus statement

PubMed Central

Pritchard, K.I.; Gelmon, K.A.; Rayson, D.; Provencher, L.; Webster, M.; McLeod, D.; Verma, S.

2013-01-01

Approximately 22,700 Canadian women were expected to be diagnosed with breast cancer in 2012. Despite improvements in screening and adjuvant treatment options, a substantial number of postmenopausal women with hormone receptor positive (hr+) breast cancer will continue to develop metastatic disease during or after adjuvant endocrine therapy. Guidance on the selection of endocrine therapy for patients with hr+ disease that is negative for the human epidermal growth factor receptor 2 (her2–) and that has relapsed or progressed on earlier nonsteroidal aromatase inhibitor (nsai) therapy is of increasing clinical importance. Exemestane, fulvestrant, and tamoxifen are approved therapeutic options in this context. Four phase iii trials involving 2876 patients—efect, sofea, confirm, and bolero-2—have assessed the efficacy of various treatment options in this clinical setting. Data from those trials suggest that standard-dose fulvestrant (250 mg monthly) and exemestane are of comparable efficacy, that doubling the dose of fulvestrant from 250 mg to 500 mg monthly results in a 15% reduction in the risk of progression, and that adding everolimus to exemestane (compared with exemestane alone) results in a 57% reduction in the risk of progression, albeit with increased toxicity. Multiple treatment options are now available to women with hr+ her2– advanced breast cancer recurring or progressing on earlier nsai therapy, although current clinical trial data suggest more robust clinical efficacy with everolimus plus exemestane. Consideration should be given to the patient’s age, functional status, and comorbidities during selection of an endocrine therapy, and use of a proactive everolimus safety management strategy is encouraged. PMID:23443928

Role of Epidermal Growth Factor Receptors and Their Ligands in Normal Mammary Epithelial and Breast Cancer Cells

DTIC Science & Technology

1997-07-01

have an estrogen receptor and progesterone receptor negative phenotype, high proliferation rates, poor response to endocrine therapy, and reduced...mitogenic effects of estrogen, progesterone and prolactin in breast cancer cell lines (3), and part of the growth promoting effects of an activated ras...of the cases (51,52), and an inverse relationship with estrogen and progesterone receptors; in such tumors, a poor response to endocrine therapy

Combining Src inhibitors and aromatase inhibitors: a novel strategy for overcoming endocrine resistance and bone loss.

PubMed

Hiscox, Stephen; Barrett-Lee, Peter; Borley, Annabel C; Nicholson, Robert I

2010-08-01

Aromatase inhibitors have largely replaced tamoxifen as the first-line treatment for postmenopausal women with metastatic, hormone receptor-positive (HR+) breast cancer. However, many patients develop clinical resistance with prolonged treatment, and oestrogen deprivation following aromatase inhibition can result in loss of bone mineral density. Furthermore, most patients with metastatic breast cancer develop bone metastases, and the resulting adverse skeletal-related events are a significant cause of patient morbidity. Src, a non-receptor tyrosine kinase, is a component of signalling pathways that regulate breast cancer cell proliferation, invasion and metastasis as well as osteoclast-mediated bone turnover. Preclinical evidence also suggests a role for Src in acquired endocrine resistance. As such, Src inhibition represents a logical strategy for the treatment of metastatic breast cancer. In vitro, combination therapy with Src inhibitors and endocrine agents, including aromatase inhibitors, has been shown to inhibit the proliferation and metastasis of both endocrine-responsive and endocrine-resistant breast cancer cell lines more effectively than either of the therapy alone. Src inhibition has also been shown to suppress osteoclast formation and activity. Combination therapy with aromatase inhibitors and Src inhibitors therefore represents a novel approach through which the development of both acquired resistance and bone pathology could be delayed. Data from clinical trials utilising such combinations will reveal if this strategy has the potential to improve patient outcomes. Copyright 2010 Elsevier Ltd. All rights reserved.

Introducing Upfront Money Can Decrease Discounting in Intertemporal Choices with Losses

PubMed Central

Jiang, Cheng-Ming; Sun, Hong-Yue; Zheng, Sheng-Hua; Wang, Liang-Jun; Qin, Yu

2016-01-01

People generally tend to advance gains and postpone losses in intertemporal choice. Jiang et al. (2014) recently showed that adding upfront losses or gains to both smaller and sooner (SS) and larger and later (LL) rewards can decrease people’s discounting. To account for this decrease, they proposed the salience hypothesis, which states that introducing upfront losses or gains makes the money dimension more salient than not, thus increasing people’s preference for LL rewards. Considering that decreasing the discounting of delayed losses is imperative and that most previous studies have focused on intertemporal choices with gains, in the current paper we conducted two experiments and used hypothetical money outcomes to examine whether the effect of upfront money could be extended to intertemporal choices with losses. The results showed that when both SS and LL intertemporal losses were combined with an upfront loss or gain, people’s discounting rate decreased and the preference for the SS option increased. This finding further supports the salience account. PMID:27597839

Introducing Upfront Money Can Decrease Discounting in Intertemporal Choices with Losses.

PubMed

Jiang, Cheng-Ming; Sun, Hong-Yue; Zheng, Sheng-Hua; Wang, Liang-Jun; Qin, Yu

2016-01-01

People generally tend to advance gains and postpone losses in intertemporal choice. Jiang et al. (2014) recently showed that adding upfront losses or gains to both smaller and sooner (SS) and larger and later (LL) rewards can decrease people's discounting. To account for this decrease, they proposed the salience hypothesis, which states that introducing upfront losses or gains makes the money dimension more salient than not, thus increasing people's preference for LL rewards. Considering that decreasing the discounting of delayed losses is imperative and that most previous studies have focused on intertemporal choices with gains, in the current paper we conducted two experiments and used hypothetical money outcomes to examine whether the effect of upfront money could be extended to intertemporal choices with losses. The results showed that when both SS and LL intertemporal losses were combined with an upfront loss or gain, people's discounting rate decreased and the preference for the SS option increased. This finding further supports the salience account.

Human immunodeficiency virus endocrinopathy

PubMed Central

Sinha, Uma; Sengupta, Nilanjan; Mukhopadhyay, Prasanta; Roy, Keshab Sinha

2011-01-01

Human immunodeficiency virus (HIV) endocrinopathy encompasses a broad spectrum of disorders. Almost all the endocrine organs are virtually affected by HIV infection. HIV can directly alter glandular function. More commonly secondary endocrine dysfunction occurs due to opportunistic infections and neoplasms in immunocompromised state. The complex interaction between HIV infection and endocrine system may be manifested as subtle biochemical and hormonal perturbation to overt glandular failure. Antiretroviral therapy as well as other essential medications often result in adverse endocrinal consequences. Apart from adrenal insufficiency, hypogonadism, diabetes and bone loss, AIDS wasting syndrome and HIV lipodystrophy need special reference. Endocrinal evaluation should proceed as in other patients with suspected endocrine dysfunction. Available treatment options have been shown to improve quality of life and long-term mortality in AIDS patients. PMID:22028995

Prospectively isolated NGN3-expressing progenitors from human embryonic stem cells give rise to pancreatic endocrine cells.

PubMed

Cai, Qing; Bonfanti, Paola; Sambathkumar, Rangarajan; Vanuytsel, Kim; Vanhove, Jolien; Gysemans, Conny; Debiec-Rychter, Maria; Raitano, Susanna; Heimberg, Harry; Ordovas, Laura; Verfaillie, Catherine M

2014-04-01

Pancreatic endocrine progenitors obtained from human embryonic stem cells (hESCs) represent a promising source to develop cell-based therapies for diabetes. Although endocrine pancreas progenitor cells have been isolated from mouse pancreata on the basis of Ngn3 expression, human endocrine progenitors have not been isolated yet. As substantial differences exist between human and murine pancreas biology, we investigated whether it is possible to isolate pancreatic endocrine progenitors from differentiating hESC cultures by lineage tracing of NGN3. We targeted the 3' end of NGN3 using zinc finger nuclease-mediated homologous recombination to allow selection of NGN3eGFP(+) cells without disrupting the coding sequence of the gene. Isolated NGN3eGFP(+) cells express PDX1, NKX6.1, and chromogranin A and differentiate in vivo toward insulin, glucagon, and somatostatin single hormone-expressing cells but not to ductal or exocrine pancreatic cells or other endodermal, mesodermal, or ectodermal lineages. This confirms that NGN3(+) cells represent pancreatic endocrine progenitors in humans. In addition, this hESC reporter line constitutes a unique tool that may aid in gaining insight into the developmental mechanisms underlying fate choices in human pancreas and in developing cell-based therapies.

Patients treated with immunosuppressive steroids are less aware of sick day rules Than those on endocrine replacement therapy and may be at greater risk of adrenal crisis.

PubMed

Salehmohamed, M R; Griffin, M; Branigan, T; Cuesta, M; Thompson, C J

2018-02-01

Patients taking corticosteroids for immune suppression are vulnerable to adrenal crisis during acute illness or if steroids are stopped abruptly. Although patients treated for adrenal failure in endocrine units are routinely provided with sick day guidelines, we wished to ascertain whether patients on immunosuppressive steroids are appropriately advised. This study sets out to compare patient awareness of steroid sick day rules in endocrine and non-endocrine patients. A short case history is presented to illustrate the clinical impact of adrenal crisis in a patient on immune suppression. Subsequently, we present the results of a 9-point questionnaire, devised to determine knowledge of steroid sick day rules, in two patient cohorts. In group 1, patients on immunosuppressive steroids were recruited from non-endocrine clinics to complete the questionnaire. In group 2, patients on replacement steroids were recruited from endocrine clinics. Endocrine patients exhibited better steroid use awareness; they were more likely to double their steroid dose when ill (89 v/s 23%), to obtain parenteral steroid during vomiting (83 v/s 27%), or during surgery (87 v/s 30%), and were aware of the need to carry a MedicAlert bracelet or a steroid-aware card (82 v/s 21%), (p < 0.001 for all comparisons). Endocrine patients exhibited a significantly greater knowledge of sick day rules. The data does highlight the lack of patient awareness of the precautions for steroid use in patients on immunosuppressive steroid therapy for non-endocrine conditions, and the case presentation illustrates the potential hazards of this lack of awareness.

Targeting tumour re-wiring by triple blockade of mTORC1, epidermal growth factor, and oestrogen receptor signalling pathways in endocrine-resistant breast cancer.

PubMed

Ribas, Ricardo; Pancholi, Sunil; Rani, Aradhana; Schuster, Eugene; Guest, Stephanie K; Nikitorowicz-Buniak, Joanna; Simigdala, Nikiana; Thornhill, Allan; Avogadri-Connors, Francesca; Cutler, Richard E; Lalani, Alshad S; Dowsett, Mitch; Johnston, Stephen R; Martin, Lesley-Ann

2018-06-08

Endocrine therapies are the mainstay of treatment for oestrogen receptor (ER)-positive (ER + ) breast cancer (BC). However, resistance remains problematic largely due to enhanced cross-talk between ER and growth factor pathways, circumventing the need for steroid hormones. Previously, we reported the anti-proliferative effect of everolimus (RAD001-mTORC1 inhibitor) with endocrine therapy in resistance models; however, potential routes of escape from treatment via ERBB2/3 signalling were observed. We hypothesised that combined targeting of three cellular nodes (ER, ERBB, and mTORC1) may provide enhanced long-term clinical utility. A panel of ER + BC cell lines adapted to long-term oestrogen deprivation (LTED) and expressing ESR1 wt or ESR1 Y537S , modelling acquired resistance to an aromatase-inhibitor (AI), were treated in vitro with a combination of RAD001 and neratinib (pan-ERBB inhibitor) in the presence or absence of oestradiol (E2), tamoxifen (4-OHT), or fulvestrant (ICI182780). End points included proliferation, cell signalling, cell cycle, and effect on ER-mediated transactivation. An in-vivo model of AI resistance was treated with monotherapies and combinations to assess the efficacy in delaying tumour progression. RNA-seq analysis was performed to identify changes in global gene expression as a result of the indicated therapies. Here, we show RAD001 and neratinib (pan-ERBB inhibitor) caused a concentration-dependent decrease in proliferation, irrespective of the ESR1 mutation status. The combination of either agent with endocrine therapy further reduced proliferation but the maximum effect was observed with a triple combination of RAD001, neratinib, and endocrine therapy. In the absence of oestrogen, RAD001 caused a reduction in ER-mediated transcription in the majority of the cell lines, which associated with a decrease in recruitment of ER to an oestrogen-response element on the TFF1 promoter. Contrastingly, neratinib increased both ER-mediated transactivation and ER recruitment, an effect reduced by the addition of RAD001. In-vivo analysis of an LTED model showed the triple combination of RAD001, neratinib, and fulvestrant was most effective at reducing tumour volume. Gene set enrichment analysis revealed that the addition of neratinib negated the epidermal growth factor (EGF)/EGF receptor feedback loops associated with RAD001. Our data support the combination of therapies targeting ERBB2/3 and mTORC1 signalling, together with fulvestrant, in patients who relapse on endocrine therapy and retain a functional ER.

Predominant Improvement of Alpha Cell Function after Steroid Therapy in a Patient with Autoimmune Pancreatitis: Case Report.

PubMed

Takeshima, Ken; Ariyasu, Hiroyuki; Iwakura, Hiroshi; Kawai, Shintaro; Uraki, Shinsuke; Inaba, Hidefumi; Furuta, Machi; Warigaya, Kenji; Murata, Shin-Ichi; Akamizu, Takashi

2018-06-01

Autoimmune pancreatitis (AIP) is a subset of inflammatory pancreatic disease, responsive to corticosteroid therapy. It is prone to being affected by diabetes mellitus, but the effectiveness of steroid therapy on pancreatic endocrine function is still controversial. We present a case of AIP, focusing on pancreatic endocrine function after steroid therapy. The patient was referred to our hospital with exacerbation of diabetic control and pancreatic swelling. By admission, the insulin secretory capacity was severely impaired. The patient was diagnosed with AIP and treated with prednisolone, resulting in marked improvement of the pancreatic swelling. Glycemic control worsened transiently after initiation of steroid therapy, but insulin requirements decreased along with tapering prednisolone dosage. Pancreatic cytology showed that the acinar structure had been destroyed, and the islets had disappeared. Insulin and glucagon immunostaining revealed slightly scattered alpha and beta cells within the fibrotic stroma. The patient notably showed improved pancreatic alpha cell function predominantly after steroid therapy, despite partial improvement of beta cell function. An imbalance between alpha and beta cell function may contribute to insufficient diabetic control in some patients with AIP. The pancreatic endocrine function test in combination with pancreatic cytology could be helpful when considering the treatment strategy for diabetic control in patients with AIP.

Consolidative autologous hematopoietic stem-cell transplantation in first remission for non-Hodgkin lymphoma: current indications and future perspective.

PubMed

Iams, Wade; Reddy, Nishitha M

2014-10-01

The non-Hodgkin lymphomas (NHLs) are a heterogeneous group of diseases with variable clinical outcomes. Autologous hematopoietic stem-cell transplantation (ASCT) as frontline, consolidative therapy has been evaluated based upon histological subtype of NHL. In this review, we summarize the major clinical trials guiding the use of frontline ASCT in NHL. With the constantly changing landscape of upfront therapy and multiple promising novel agents, the ability to conduct randomized trials to evaluate the benefit of consolidative ASCT is not only challenging but may be considered by some an inept utilization of resources. Our recommendation for consolidative ASCT is based on analyzing the current available data.

Survival benefit for patients with diffuse intrinsic pontine glioma (DIPG) undergoing re-irradiation at first progression: A matched-cohort analysis on behalf of the SIOP-E-HGG/DIPG working group.

PubMed

Janssens, Geert O; Gandola, Lorenza; Bolle, Stephanie; Mandeville, Henry; Ramos-Albiac, Monica; van Beek, Karen; Benghiat, Helen; Hoeben, Bianca; Morales La Madrid, Andres; Kortmann, Rolf-Dieter; Hargrave, Darren; Menten, Johan; Pecori, Emilia; Biassoni, Veronica; von Bueren, Andre O; van Vuurden, Dannis G; Massimino, Maura; Sturm, Dominik; Peters, Max; Kramm, Christof M

2017-03-01

Overall survival (OS) of patients with diffuse intrinsic pontine glioma (DIPG) is poor. The purpose of this study is to analyse benefit and toxicity of re-irradiation at first progression. At first progression, 31 children with DIPG, aged 2-16 years, underwent re-irradiation (dose 19.8-30.0 Gy) alone (n = 16) or combined with systemic therapy (n = 15). At initial presentation, all patients had typical symptoms and characteristic MRI features of DIPG, or biopsy-proven high-grade glioma. An interval of ≥3 months after upfront radiotherapy was required before re-irradiation. Thirty-nine patients fulfilling the same criteria receiving radiotherapy at diagnosis, followed by best supportive care (n = 20) or systemic therapy (n = 19) at progression but no re-irradiation, were eligible for a matched-cohort analysis. Median OS for patients undergoing re-irradiation was 13.7 months. For a similar median progression-free survival after upfront radiotherapy (8.2 versus 7.7 months; P = .58), a significant benefit in median OS (13.7 versus 10.3 months; P = .04) was observed in favour of patients undergoing re-irradiation. Survival benefit of re-irradiation increased with a longer interval between end-of-radiotherapy and first progression (3-6 months: 4.0 versus 2.7; P < .01; 6-12 months: 6.4 versus 3.3; P = .04). Clinical improvement with re-irradiation was observed in 24/31 (77%) patients. No grade 4-5 toxicity was recorded. On multivariable analysis, interval to progression (corrected hazard ratio = .27-.54; P < .01) and re-irradiation (corrected hazard ratio = .18-.22; P < .01) remained prognostic for survival. A risk score (RS), comprising 5 categories, was developed to predict survival from first progression (ROC: .79). Median survival ranges from 1.0 month (RS-1) to 6.7 months (RS-5). The majority of patients with DIPG, responding to upfront radiotherapy, do benefit of re-irradiation with acceptable tolerability. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cholesterol, Cholesterol-Lowering Medication Use, and Breast Cancer Outcome in the BIG 1-98 Study.

PubMed

Borgquist, Signe; Giobbie-Hurder, Anita; Ahern, Thomas P; Garber, Judy E; Colleoni, Marco; Láng, István; Debled, Marc; Ejlertsen, Bent; von Moos, Roger; Smith, Ian; Coates, Alan S; Goldhirsch, Aron; Rabaglio, Manuela; Price, Karen N; Gelber, Richard D; Regan, Meredith M; Thürlimann, Beat

2017-04-10

Purpose Cholesterol-lowering medication (CLM) has been reported to have a role in preventing breast cancer recurrence. CLM may attenuate signaling through the estrogen receptor by reducing levels of the estrogenic cholesterol metabolite 27-hydroxycholesterol. The impact of endocrine treatment on cholesterol levels and hypercholesterolemia per se may counteract the intended effect of aromatase inhibitors. Patients and Methods The Breast International Group (BIG) conducted a randomized, phase III, double-blind trial, BIG 1-98, which enrolled 8,010 postmenopausal women with early-stage, hormone receptor-positive invasive breast cancer from 1998 to 2003. Systemic levels of total cholesterol and use of CLM were measured at study entry and every 6 months up to 5.5 years. Cumulative incidence functions were used to describe the initiation of CLM in the presence of competing risks. Marginal structural Cox proportional hazards modeling investigated the relationships between initiation of CLM during endocrine therapy and outcome. Three time-to-event end points were considered: disease-free-survival, breast cancer-free interval, and distant recurrence-free interval. Results Cholesterol levels were reduced during tamoxifen therapy. Of 789 patients who initiated CLM during endocrine therapy, the majority came from the letrozole monotherapy arm (n = 318), followed by sequential tamoxifen-letrozole (n = 189), letrozole-tamoxifen (n = 176), and tamoxifen monotherapy (n = 106). Initiation of CLM during endocrine therapy was related to improved disease-free-survival (hazard ratio [HR], 0.79; 95% CI, 0.66 to 0.95; P = .01), breast cancer-free interval (HR, 0.76; 95% CI, 0.60 to 0.97; P = .02), and distant recurrence-free interval (HR, 0.74; 95% CI, 0.56 to 0.97; P = .03). Conclusion Cholesterol-lowering medication during adjuvant endocrine therapy may have a role in preventing breast cancer recurrence in hormone receptor-positive early-stage breast cancer. We recommend that these observational results be addressed in prospective randomized trials.

Relative effectiveness of adjuvant chemotherapy for invasive lobular compared with invasive ductal carcinoma of the breast.

PubMed

Marmor, Schelomo; Hui, Jane Yuet Ching; Huang, Jing Li; Kizy, Scott; Beckwith, Heather; Blaes, Anne H; Rueth, Natasha M; Tuttle, Todd M

2017-08-15

Invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) have distinct clinical, pathologic, and genomic characteristics. The objective of the current study was to compare the relative impact of adjuvant chemotherapy on the survival of patients with ILC versus those with IDC. Women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 1 (HER2) -negative, stage I/II IDC and ILC who received endocrine therapy were identified from the 2000 to 2014 California Cancer Registry. Patient, tumor, and treatment characteristics were collected. Ten-year overall survival (OS) was estimated using the Kaplan-Meier method and Cox proportional-hazards modeling. In total, 32,997 women with IDC and 4638 with ILC were identified. The receipt of chemotherapy significantly decreased during the study for both subtypes. For patients with IDC, the 10-year OS rate was 95% among those who received endocrine therapy alone versus 93% (P < .01) among those who received endocrine therapy plus chemotherapy. For patients with ILC, the 10-year OS rate was 94% among those who received endocrine therapy alone versus 92% (P < .01) among those who received endocrine therapy plus chemotherapy. After adjusting for patient and treatment factors, adjuvant chemotherapy was significantly associated with a decreased 10-year hazard of death for patients with IDC (hazard ratio, 0.83; 95% confidence interval, 0.74-0.92). In contrast, adjuvant chemotherapy was not independently associated with the adjusted 10-year hazard of death for patients with ILC (hazard ratio, 1.14; 95% confidence interval, 0.90-1.46). Adjuvant chemotherapy was not associated with improved OS for patients with ER-positive, HER2-negative, stage I/II ILC. Avoidance of ineffective chemotherapy will markedly reduce the adverse effects and economic burden of breast cancer treatment for a large proportion of patients with breast cancer. Cancer 2017;123:3015-21. © 2017 American Cancer Society. © 2017 American Cancer Society.

Endocrine therapy toxicity: management options.

PubMed

Henry, N Lynn

2014-01-01

Treatment with adjuvant endocrine therapy, including tamoxifen and the aromatase inhibitors, has resulted in notable improvements in disease-free and overall survival for patients with hormone receptor-positive breast cancer. Despite their proven benefit, however, adherence to and persistence with the medications is poor in part because of bothersome side effects that can negatively affect quality of life. Retrospective analyses have identified possible predictors of development of toxicity. Reports have also suggested that development of toxicity may be a biomarker of better response to therapy. In addition, there has been considerable research investment into the management of these side effects, which may lead to improved adherence and persistence with therapy. However, although notable advances have been made, much more remains to be done to provide patients with truly personalized therapy for hormone receptor-positive breast cancer.

A differential diagnosis of inherited endocrine tumors and their tumor counterparts

PubMed Central

Toledo, Sergio P. A.; Lourenço, Delmar M.; Toledo, Rodrigo A.

2013-01-01

Inherited endocrine tumors have been increasingly recognized in clinical practice, although some difficulties still exist in differentiating these conditions from their sporadic endocrine tumor counterparts. Here, we list the 12 main topics that could add helpful information and clues for performing an early differential diagnosis to distinguish between these conditions. The early diagnosis of patients with inherited endocrine tumors may be performed either clinically or by mutation analysis in at-risk individuals. Early detection usually has a large impact in tumor management, allowing preventive clinical or surgical therapy in most cases. Advice for the clinical and surgical management of inherited endocrine tumors is also discussed. In addition, recent clinical and genetic advances for 17 different forms of inherited endocrine tumors are briefly reviewed. PMID:23917672

The endocrine effects of nicotine and cigarette smoke

PubMed Central

Tweed, Jesse Oliver; Hsia, Stanley H.; Lutfy, Kabirullah; Friedman, Theodore C.

2012-01-01

With a current prevalence of approximately 20%, smoking continues to impact negatively upon health. Tobacco or nicotine use influences the endocrine system, with important clinical implications. In this review we critically evaluate the literature concerning the impact of nicotine as well as tobacco use on several parameters of the endocrine system and on glucose and lipid homeostasis. Emphasis is on the effect of smoking on diabetes mellitus and obesity and the consequences of smoking cessation on these disorders. Understanding the effects of nicotine and cigarettes on the endocrine system and how these changes contribute to the pathogenesis of various endocrine diseases will allow for targeted therapies and more effective approaches for smoking cessation. PMID:22561025

TFF3 is a valuable predictive biomarker of endocrine response in metastatic breast cancer

PubMed Central

May, Felicity E B; Westley, Bruce R

2015-01-01

The stratification of breast cancer patients for endocrine therapies by oestrogen or progesterone receptor expression is effective but imperfect. The present study aims were to validate microarray studies that demonstrate TFF3 regulation by oestrogen and its association with oestrogen receptors in breast cancer, to evaluate TFF3 as a biomarker of endocrine response, and to investigate TFF3 function. Microarray data were validated by quantitative RT-PCR and northern and western transfer analyses. TFF3 was induced by oestrogen, and its induction was inhibited by antioestrogens, tamoxifen, 4-hydroxytamoxifen and fulvestrant in oestrogen-responsive breast cancer cells. The expression of TFF3 mRNA was associated with oestrogen receptor mRNA in breast tumours (Pearson's coefficient=0.762, P=0.000). Monoclonal antibodies raised against the TFF3 protein detected TFF3 by immunohistochemistry in oesophageal submucosal glands, intestinal goblet and neuroendocrine cells, Barrett's metaplasia and intestinal metaplasia. TFF3 protein expression was associated with oestrogen receptor, progesterone receptor and TFF1 expression in malignant breast cells. TFF3 is a specific and sensitive predictive biomarker of response to endocrine therapy, degree of response and duration of response in unstratified metastatic breast cancer patients (P=0.000, P=0.002 and P=0.002 respectively). Multivariate binary logistic regression analysis demonstrated that TFF3 is an independent biomarker of endocrine response and degree of response, and this was confirmed in a validation cohort. TFF3 stimulated migration and invasion of breast cancer cells. In conclusion, TFF3 expression is associated with response to endocrine therapy, and outperforms oestrogen receptor, progesterone receptor and TFF1 as an independent biomarker, possibly because it mediates the malign effects of oestrogen on invasion and metastasis. PMID:25900183

Adverse prognostic value of peritumoral vascular invasion: is it abrogated by adequate endocrine adjuvant therapy? Results from two International Breast Cancer Study Group randomized trials of chemoendocrine adjuvant therapy for early breast cancer

PubMed Central

Viale, G.; Giobbie-Hurder, A.; Gusterson, B. A.; Maiorano, E.; Mastropasqua, M. G.; Sonzogni, A.; Mallon, E.; Colleoni, M.; Castiglione-Gertsch, M.; Regan, M. M.; Brown, R. W.; Golouh, R.; Crivellari, D.; Karlsson, P.; Öhlschlegel, C.; Gelber, R. D.; Goldhirsch, A.; Coates, A. S.

2010-01-01

Background: Peritumoral vascular invasion (PVI) may assist in assigning optimal adjuvant systemic therapy for women with early breast cancer. Patients and methods: Patients participated in two International Breast Cancer Study Group randomized trials testing chemoendocrine adjuvant therapies in premenopausal (trial VIII) or postmenopausal (trial IX) node-negative breast cancer. PVI was assessed by institutional pathologists and/or central review on hematoxylin–eosin-stained slides in 99% of patients (analysis cohort 2754 patients, median follow-up >9 years). Results: PVI, present in 23% of the tumors, was associated with higher grade tumors and larger tumor size (trial IX only). Presence of PVI increased locoregional and distant recurrence and was significantly associated with poorer disease-free survival. The adverse prognostic impact of PVI in trial VIII was limited to premenopausal patients with endocrine-responsive tumors randomized to therapies not containing goserelin, and conversely the beneficial effect of goserelin was limited to patients whose tumors showed PVI. In trial IX, all patients received tamoxifen: the adverse prognostic impact of PVI was limited to patients with receptor-negative tumors regardless of chemotherapy. Conclusion: Adequate endocrine adjuvant therapy appears to abrogate the adverse impact of PVI in node-negative disease, while PVI may identify patients who will benefit particularly from adjuvant therapy. PMID:19633051

A review of a novel, Bruton's tyrosine kinase inhibitor, ibrutinib.

PubMed

Lee, Chung-Shien; Rattu, Mohammad A; Kim, Sara S

2016-02-01

Ibrutinib, a Bruton's kinase inhibitor, was granted an accelerated approval by the US Food and Drug Administration in November, 2013, for the treatment of relapsed or refractory mantle cell lymphoma and subsequently for the treatment of relapsed refractory chronic lymphocytic leukemia in February, 2014. In the pivotal phase 2 study of 111 patients with relapsed or refractory mantle cell lymphoma, the overall response rate in patients who received ibrutinib 560 mg daily was 68%. The median progression-free survival was 13.9 months, and the overall survival was 58% at 18 months. In a recently published phase 3 trial (RESONATE) that compared ibrutinib and ofatumumab for the treatment of relapsed and refractory chronic lymphocytic leukemia or small lymphocytic lymphoma, ibrutinib at the daily dosage of 420 mg demonstrated a significantly higher overall response rate (43% in ibrutinib vs. 4% in ofatumumab) and a significantly improved overall survival at 12 months (90% ibrutinib vs. 81% ofatumumab). Similar clinical benefits were shown regardless of del (17 p). Ibrutinib was well tolerated, and dose-limiting toxicity was not observed. Ibrutinib has shown durable remission, improved progression-free survival and overall survival, and favorable safety profile in indolent B-cell lymphoid malignancies. Ibrutinib, as a monotherapy, is an effective treatment modality as a salvage therapy for treatment of mantle cell lymphoma and chronic lymphocytic leukemia / small lymphocytic lymphoma, particularly in older patients (age ≥70 years) who are not a candidate for intensive chemotherapy and/or those with del (17 p). In patients with chronic lymphocytic leukemia and del (17 p), the current practice guideline recommends ibrutinib as an upfront treatment option. Current on-going trials will further define its role as upfront therapy and/or as a combination therapy in indolent B-cell lymphoid malignancies. © The Author(s) 2014.

The impact of opioids on the endocrine system.

PubMed

Katz, Nathaniel; Mazer, Norman A

2009-02-01

Opioids have been used for medicinal and analgesic purposes for centuries. However, their negative effects on the endocrine system, which have been known for some times, are barely discussed in modern medicine. Therefore, we conducted a systematic review of the impact of opioids on the endocrine system. A review of the English language literature on preclinical and clinical studies of any type on the influence of opioids on the endocrine system was conducted. Preliminary recommendations for monitoring and managing these problems were provided. Long-term opioid therapy for either addiction or chronic pain often induces hypogonadism owing to central suppression of hypothalamic secretion of gonadotropin-releasing hormone. Symptoms of opioid-induced hypogonadism include loss of libido, infertility, fatigue, depression, anxiety, loss of muscle strength and mass, osteoporosis, and compression fractures in both men and women; impotence in men; and menstrual irregularities and galactorrhea in women. In view of the increased use of opioids for chronic pain, it has become increasingly important to monitor patients taking opioids and manage endocrine complications. Therefore, patients on opioid therapy should be routinely screened for such symptoms and for laboratory abnormalities in sex hormones. Opioid-induced hypogonadism seems to be a common complication of therapeutic or illicit opioid use. Patients on long-term opioid therapy should be prospectively monitored, and in cases of opioid-induced hypogonadism, we recommend nonopioid pain management, opioid rotation, or sex hormone supplementation after careful consideration of the risks and benefits.

Endocrine-Therapy-Resistant ESR1 Variants Revealed by Genomic Characterization of Breast-Cancer-Derived Xenografts

PubMed Central

Li, Shunqiang; Shen, Dong; Shao, Jieya; Crowder, Robert; Liu, Wenbin; Prat, Aleix; He, Xiaping; Liu, Shuying; Hoog, Jeremy; Lu, Charles; Ding, Li; Griffith, Obi L.; Miller, Christopher; Larson, Dave; Fulton, Robert S.; Harrison, Michelle; Mooney, Tom; McMichael, Joshua F.; Luo, Jingqin; Tao, Yu; Goncalves, Rodrigo; Schlosberg, Christopher; Hiken, Jeffrey F.; Saied, Laila; Sanchez, Cesar; Giuntoli, Therese; Bumb, Caroline; Cooper, Crystal; Kitchens, Robert T.; Lin, Austin; Phommaly, Chanpheng; Davies, Sherri R.; Zhang, Jin; Kavuri, Megha Shyam; McEachern, Donna; Dong, Yi Yu; Ma, Cynthia; Pluard, Timothy; Naughton, Michael; Bose, Ron; Suresh, Rama; McDowell, Reida; Michel, Loren; Aft, Rebecca; Gillanders, William; DeSchryver, Katherine; Wilson, Richard K.; Wang, Shaomeng; Mills, Gordon B.; Gonzalez-Angulo, Ana; Edwards, John R.; Maher, Christopher; Perou, Charles M.; Mardis, Elaine R.; Ellis, Matthew J.

2013-01-01

SUMMARY To characterize patient-derived xenografts (PDXs) for functional studies, we made whole-genome comparisons with originating breast cancers representative of the major intrinsic subtypes. Structural and copy number aberrations were found to be retained with high fidelity. However, at the single-nucleotide level, variable numbers of PDX-specific somatic events were documented, although they were only rarely functionally significant. Variant allele frequencies were often preserved in the PDXs, demonstrating that clonal representation can be transplantable. Estrogen-receptor-positive PDXs were associated with ESR1 ligand-binding-domain mutations, gene amplification, or an ESR1/YAP1 translocation. These events produced different endocrine-therapy-response phenotypes in human, cell line, and PDX endocrine-response studies. Hence, deeply sequenced PDX models are an important resource for the search for genome-forward treatment options and capture endocrine-drug-resistance etiologies that are not observed in standard cell lines. The originating tumor genome provides a benchmark for assessing genetic drift and clonal representation after transplantation. PMID:24055055

Recurrent hyperactive ESR1 fusion proteins in endocrine therapy-resistant breast cancer

PubMed Central

Trabucco, S E; Priedigkeit, N; Parachoniak, C A; Vanden Borre, P; Morley, S; Rosenzweig, M; Gay, L M; Goldberg, M E; Suh, J; Ali, S M; Ross, J; Leyland-Jones, B; Young, B; Williams, C; Park, B; Tsai, M; Haley, B; Peguero, J; Callahan, R D; Sachelarie, I; Cho, J; Atkinson, J M; Bahreini, A; Nagle, A M; Puhalla, S L; Watters, R J; Erdogan-Yildirim, Z; Cao, L; Oesterreich, S; Mathew, A; Lucas, P C; Davidson, N E; Brufsky, A M; Frampton, G M; Stephens, P J; Chmielecki, J; Lee, A V

2018-01-01

Abstract Background Estrogen receptor-positive (ER-positive) metastatic breast cancer is often intractable due to endocrine therapy resistance. Although ESR1 promoter switching events have been associated with endocrine-therapy resistance, recurrent ESR1 fusion proteins have yet to be identified in advanced breast cancer. Patients and methods To identify genomic structural rearrangements (REs) including gene fusions in acquired resistance, we undertook a multimodal sequencing effort in three breast cancer patient cohorts: (i) mate-pair and/or RNAseq in 6 patient-matched primary-metastatic tumors and 51 metastases, (ii) high coverage (>500×) comprehensive genomic profiling of 287–395 cancer-related genes across 9542 solid tumors (5216 from metastatic disease), and (iii) ultra-high coverage (>5000×) genomic profiling of 62 cancer-related genes in 254 ctDNA samples. In addition to traditional gene fusion detection methods (i.e. discordant reads, split reads), ESR1 REs were detected from targeted sequencing data by applying a novel algorithm (copyshift) that identifies major copy number shifts at rearrangement hotspots. Results We identify 88 ESR1 REs across 83 unique patients with direct confirmation of 9 ESR1 fusion proteins (including 2 via immunoblot). ESR1 REs are highly enriched in ER-positive, metastatic disease and co-occur with known ESR1 missense alterations, suggestive of polyclonal resistance. Importantly, all fusions result from a breakpoint in or near ESR1 intron 6 and therefore lack an intact ligand binding domain (LBD). In vitro characterization of three fusions reveals ligand-independence and hyperactivity dependent upon the 3′ partner gene. Our lower-bound estimate of ESR1 fusions is at least 1% of metastatic solid breast cancers, the prevalence in ctDNA is at least 10× enriched. We postulate this enrichment may represent secondary resistance to more aggressive endocrine therapies applied to patients with ESR1 LBD missense alterations. Conclusions Collectively, these data indicate that N-terminal ESR1 fusions involving exons 6–7 are a recurrent driver of endocrine therapy resistance and are impervious to ER-targeted therapies. PMID:29360925

DOE saves time and money with ORAU's upfront characterization

ScienceCinema

Cange, Sue

2018-02-06

Acting DOE Assistant Manager for Environmental Management Sue Cange shares how ORAU provided valuable upfront characterization work that helped accelerate the cleanup efforts on the Oak Ridge Reservation.

DOE saves time and money with ORAU's upfront characterization

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cange, Sue

2012-03-08

Acting DOE Assistant Manager for Environmental Management Sue Cange shares how ORAU provided valuable upfront characterization work that helped accelerate the cleanup efforts on the Oak Ridge Reservation.

ESR1 mutations: Moving towards guiding treatment decision-making in metastatic breast cancer patients.

PubMed

Angus, Lindsay; Beije, Nick; Jager, Agnes; Martens, John W M; Sleijfer, Stefan

2017-01-01

Mutations in the gene coding for the estrogen receptor (ER), ESR1, have been associated with acquired endocrine resistance in patients with ER-positive metastatic breast cancer (MBC). Functional studies revealed that these ESR1 mutations lead to constitutive activity of the ER, meaning that the receptor is active in absence of its ligand estrogen, conferring resistance against several endocrine agents. While recent clinical studies reported that the occurrence of ESR1 mutations is rare in primary breast cancer tumors, these mutations are more frequently observed in metastatic tissue and circulating cell-free DNA of MBC patients pretreated with endocrine therapy. Given the assumed impact that the presence of ESR1 mutations has on outcome to endocrine therapy, assessing ESR1 mutations in MBC patients is likely to be of significant interest to further individualize treatment for MBC patients. Here, ESR1 mutation detection methods and the most relevant pre-clinical and clinical studies on ESR1 mutations regarding endocrine resistance are reviewed, with particular interest in the ultimate goal of guiding treatment decision-making based on ESR1 mutations. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Mutation testing for directing upfront targeted therapy and post-progression combination therapy strategies in lung adenocarcinoma

PubMed Central

Salgia, Ravi

2016-01-01

ABSTRACT Introduction: Advances in the biology of non-small-cell lung cancer, especially adenocarcinoma, reveal multiple molecular subtypes driving oncogenesis. Accordingly, individualized targeted therapeutics are based on mutational diagnostics. Areas covered: Advances in strategies and techniques for individualized treatment, particularly of adenocarcinoma, are described through literature review. Approved therapies are established for some molecular subsets, with new driver mutations emerging that represent increasing proportions of patients. Actionable mutations are de novo oncogenic drivers or acquired resistance mediators, and mutational profiling is important for directing therapy. Patients should be monitored for emerging actionable resistance mutations. Liquid biopsy and associated multiplex diagnostics will be important means to monitor patients during treatment. Expert commentary: Outcomes with targeted agents may be improved by integrating mutation screens during treatment to optimize subsequent therapy. In order for this to be translated into impactful patient benefit, appropriate platforms and strategies need to be optimized and then implemented universally. PMID:27139190

Subjective cognitive complaints one year after ceasing adjuvant endocrine treatment for early-stage breast cancer.

PubMed

Ribi, K; Aldridge, J; Phillips, K-A; Thompson, A; Harvey, V; Thürlimann, B; Cardoso, F; Pagani, O; Coates, A S; Goldhirsch, A; Price, K N; Gelber, R D; Bernhard, J

2012-05-08

In the BIG 1-98 trial objective cognitive function improved in postmenopausal women 1 year after cessation of adjuvant endocrine therapy for breast cancer. This report evaluates changes in subjective cognitive function (SCF). One hundred postmenopausal women, randomised to receive 5 years of adjuvant tamoxifen, letrozole, or a sequence of the two, completed self-reported measures on SCF, psychological distress, fatigue, and quality of life during the fifth year of trial treatment (year 5) and 1 year after treatment completion (year 6). Changes between years 5 and 6 were evaluated using the Wilcoxon signed-rank test. Subjective cognitive function and its correlates were explored. Subjective cognitive function and the other patient-reported outcomes did not change significantly after cessation of endocrine therapy with the exception of improvement for hot flushes (P=0.0005). No difference in changes was found between women taking tamoxifen or letrozole. Subjective cognitive function was the only psychosocial outcome with a substantial correlation between year 5 and 6 (Spearman's R=0.80). Correlations between SCF and the other patient-reported outcomes were generally low. Improved objective cognitive function but not SCF occur following cessation of adjuvant endocrine therapy in the BIG 1-98 trial. The substantial correlation of SCF scores over time may represent a stable attribute.

Significance of Ovarian Function Suppression in Endocrine Therapy for Breast Cancer in Pre-Menopausal Women

PubMed Central

Scharl, A.; Salterberg, A.

2016-01-01

Ovarian function suppression (OFS) for treating breast cancer in pre-menopausal women was introduced for the first time in the late 19th century as bilateral oophorectomy. It was not until the 1960s that the oestrogen receptor was identified and a test for detecting endocrine sensitivity of the breast cancer was developed. A weakness of early trials on OFS for breast cancer treatment is therefore their failure to take receptor sensitivity into account when selecting participants. A meta-analysis performed in the early 1990s first proved that adjuvant OFS significantly improved the cure rate of oestrogen receptor-positive breast cancer in pre-menopausal women regardless of whether it was carried out through oophorectomy, radiation-induced ablation or drug therapy. In the 1970s, tamoxifen was synthesized. It became one of the most important cancer drugs and today constitutes the gold standard for endocrine adjuvant therapy. Taking tamoxifen for a five-year period lowers mortality by 30 % over 15 years. Ten years of tamoxifen therapy reduces mortality even further, with increased side effects, however. Research over the past ten years has proven that for post-menopausal women, aromatase inhibitors have benefits over tamoxifen. Current trial results have rekindled the debate about the combination of OFS with tamoxifen or with aromatase inhibitors for adjuvant breast cancer treatment of pre-menopausal women. These trials have reported an improvement in disease-free survival in patients with a high risk of recurrence when they are treated with a combination of OFS plus tamoxifen or aromatase inhibitors, especially in women younger than 35. However, combination therapy causes significantly more side effects, which could negatively impact compliance. Endocrine treatments administered over a period of many years show waning compliance, which tends to be only around 50 % after five years. Inadequate compliance compromises efficacy and increases the risk of mortality. For this reason, when indicating and supporting endocrine adjuvant therapy, physicians must ensure that compliance will be good. To prevent recurrence in the long run, it is much more effective to prescribe a somewhat less effective therapy that will actually be carried out than to prescribe one that is theoretically more effective, but is not adhered to consistently. PMID:27239060

Radiotherapy induced dermatitis is a strong predictor for late fibrosis in head and neck cancer. The development of a predictive model for late fibrosis.

PubMed

Nevens, Daan; Duprez, Fréderic; Daisne, Jean Francois; Laenen, Annouschka; De Neve, Wilfried; Nuyts, Sandra

2017-02-01

To determine if the severity of radiodermatitis at the end of radio(chemo)therapy (R(C)T) for head and neck cancer (HNC) is a predictive factor for late fibrosis of the neck and to find a model to predict neck fibrosis grade⩾2 (fibrosis RTOG 2-4 ) at 6months following R(C)T for HNC. 161 patients were prospectively included. We correlated radiodermatitis at the end of RCT, age, sex, T/N stage, tumor site, concomitant chemotherapy, upfront neck dissection, neo-adjuvant chemotherapy, accelerated RT, smoking, alcohol consumption, HPV status and the dose prescribed to the elective neck with fibrosis RTOG 2-4 6months after the end of treatment. Radiodermatitis at the end of R(C)T ⩾grade 3 proved to be associated with the incidence of fibrosis RTOG 2-4 at 6months (p<0.01). Furthermore, upfront neck dissection (p<0.01), increasing N stage (p<0.01) and tumor site (p=0.02) are significantly associated in univariate analysis with fibrosis RTOG 2-4 at 6months of follow-up. Upfront neck dissection and radiodermatitis grade⩾3 at the end of R(C)T were identified by our multivariate model. Additionally, increasing N stage was selected as an independent predictor variable. The AUC for this model was 0.92. A model for the prediction of fibrosis RTOG 2-4 following R(C)T for head and neck cancer is presented with an AUC of 0.92. Interestingly, radiodermatitis grade⩾3 at the end of R(C)T is associated with RTOG 2-4 fibrosis at 6months. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Molecular essence and endocrine responsiveness of estrogen receptor-negative, progesterone receptor-positive, and HER2-negative breast cancer.

PubMed

Yu, Ke-Da; Jiang, Yi-Zhou; Hao, Shuang; Shao, Zhi-Ming

2015-10-05

The clinical significance of progesterone receptor (PgR) expression in estrogen receptor-negative (ER-) breast cancer is controversial. Herein, we systemically investigate the clinicopathologic features, molecular essence, and endocrine responsiveness of ER-/PgR+/HER2- phenotype. Four study cohorts were included. The first and second cohorts were from the Surveillance, Epidemiology, and End Results database (n = 67,932) and Fudan University Shanghai Cancer Center (n = 2,338), respectively, for clinicopathologic and survival analysis. The third and fourth cohorts were from two independent publicly available microarray datasets including 837 operable cases and 483 cases undergoing neoadjuvant chemotherapy, respectively, for clinicopathologic and gene-expression analysis. Characterized genes defining subgroups within the ER-/PgR+/HER2- phenotype were determined and further validated. Clinicopathologic features and survival outcomes of the ER-/PgR+ phenotype fell in between the ER+/PgR+ and ER-/PgR- phenotypes, but were more similar to ER-/PgR-. Among the ER-/PgR+ phenotype, 30% (95% confidence interval [CI] 17-42%, pooled by a fixed-effects method) were luminal-like and 59% (95% CI 45-72%, pooled by a fixed-effects method) were basal-like. We further refined the characterized genes for subtypes within the ER-/PgR+ phenotype and developed an immunohistochemistry-based method that could determine the molecular essence of ER-/PgR+ using three markers, TFF1, CK5, and EGFR. Either PAM50-defined or immunohistochemistry-defined basal-like ER-/PgR+ cases have a lower endocrine therapy sensitivity score compared with luminal-like ER-/PgR+ cases (P <0.0001 by Mann-Whitney test for each study set and P <0.0001 for pooled standardized mean difference in meta-analysis). Immunohistochemistry-defined basal-like ER-/PgR+ cases might not benefit from adjuvant endocrine therapy (log-rank P = 0.61 for sufficient versus insufficient endocrine therapy). The majority of ER-/PgR+/HER2- phenotype breast cancers are basal-like and associated with a lower endocrine therapy sensitivity score. Additional studies are needed to validate these findings.

A randomised trial of the cool pad pillow topper versus standard care for sleep disturbance and hot flushes in women on endocrine therapy for breast cancer.

PubMed

Marshall-McKenna, R; Morrison, A; Stirling, L; Hutchison, C; Rice, A M; Hewitt, C; Paul, L; Rodger, M; Macpherson, I R; McCartney, E

2016-04-01

Quality of life in women receiving adjuvant endocrine therapy for breast cancer (BC) may be impaired by hot flushes and night sweats. The cool pad pillow topper (CPPT) is a commercial product, promoted to improve quality of sleep disrupted by hot flushes. This study aimed to identify if the CPPT reduces severity of sleep disturbance by minimising effects of hot flushes. This randomised phase II trial, recruited women with BC, on adjuvant endocrine therapy, experiencing hot flushes and insomnia. Participants were randomised (stratified by baseline sleep efficiency score (SES) and menopausal status) to the intervention arm (CPPT + standard care) or control arm (standard care). Participants completed Hospital Anxiety and Depression Scale and Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaires and fortnightly sleep/hot flush diaries (where responses were averaged over 2-week periods). The primary endpoint was change in average SES from -2 to 0 weeks to 2 to 4 weeks. Seventy-four pre- (68.9 %) and post-menopausal (31.1 %) women were recruited. Median age was 49.5 years. Endocrine therapies included tamoxifen (93.2 %). Median SES at weeks 2 to 4 improved in both arms but the increase on the intervention arm was almost twice that on the control arm (p = 0.024). There were significantly greater reductions in hot flushes and HADS depression in the intervention arm (p = 0.09 and p = 0.036, respectively). There were no significant differences in FACT-B or HADS anxiety. This study supports the use of the CPPT as an aid to reduce sleep disturbance and the frequency/severity of hot flushes.

Exocrine and endocrine pancreatic function in 21 patients suffering from autoimmune pancreatitis before and after steroid treatment.

PubMed

Frulloni, Luca; Scattolini, Chiara; Katsotourchi, Anna Maria; Amodio, Antonio; Gabbrielli, Armando; Zamboni, Giuseppe; Benini, Luigi; Vantini, Italo

2010-01-01

Autoimmune pancreatitis (AIP) responds rapidly and dramatically to steroid therapy. The aim of this study was to evaluate pancreatic exocrine and endocrine function in patients suffering from AIP both before and after steroid therapy. Fecal elastase 1 and diabetes were evaluated before steroid therapy and within 1 month of its suspension in 21 patients (13 males and 8 females, mean age 43 +/- 16.5 years) diagnosed as having AIP between 2006 and 2008. At clinical onset, fecal elastase 1 was 107 +/- 126 microg/g stool. Thirteen patients (62%) showed severe pancreatic insufficiency (<100 microg/g stool), 4 (19%) had mild insufficiency (100-200 microg/g stool), while 4 (19%) had normal pancreatic function (>200 microg/g stool). Before steroids, diabetes was diagnosed in 5 patients (24%), all of whom had very low levels of fecal elastase 1 (<19 microg/g stool). Following steroids, fecal elastase 1 increased in all patients (237 +/- 193 microg/g stool) and observed levels were significantly higher than those seen before steroids (p = 0.001). Patients suffering from AIP display exocrine and/or endocrine pancreatic insufficiency at clinical onset. These insufficiencies improve after steroid therapy. Copyright 2010 S. Karger AG, Basel.

[Perioperative fluid therapy for surgical patients with chronic kidney disease].

PubMed

Iijima, Takehiko

2013-11-01

Chronic kidney disease (CKD) often accompanies cardiovascular complications, causing postoperative morbidity and even mortality. Since fluid and electrolyte homeostasis is deregulated in CKD patients, fluid therapy itself may cause postoperative morbidity. Recent studies have shown that forced diuresis through fluid overload offers no renoprotective effect and instead has harmful consequences. Fluid overload should be avoided, and the volume load should be used as the rationale for controlling hemodynamics. The emerging concept of a "zero-fluid balance policy" may be beneficial even for CKD patients. Hydroxyethylstarch might not be preferentially used for CKD patients. Hydroxyethylstarch is not contraindicated for CKD patients except in cases with long-term accumulation caused by increased vascular permeability, such as cases with sepsis, as long as an efficient volume expansion is beneficial to the patient. The regulation of renal function through the endocrine system (i.e., renin-angiotensin-aldosterone and vasopressin) is a key target for protecting the kidney in CKD. The recent development of a receptor blocker targeting these endocrine systems may be beneficial for correcting the fluid balance caused by excess intraoperative fluid therapy. The main issue for fluid therapy in surgical CKD patients may not be the quantity of fluid, but rational intervention affecting the endocrine system.

Male Breast Cancer Treatment (PDQ®)—Health Professional Version

Cancer.gov

Male breast cancer treatment may include surgery with or without radiation therapy, chemotherapy, endocrine therapy, and/or HER2-directed therapy. Get detailed information about the diagnosis and treatment of newly diagnosed and recurrent male breast cancer in this summary for clinicians.

Treatment decisions and the impact of adverse events before and during extended endocrine therapy in postmenopausal early breast cancer.

PubMed

Blok, Erik J; Kroep, Judith R; Meershoek-Klein Kranenbarg, Elma; Duijm-de Carpentier, Marjolijn; Putter, Hein; Liefers, Gerrit-Jan; Nortier, Johan W R; Rutgers, Emiel J Th; Seynaeve, Caroline M; van de Velde, Cornelis J H

2018-05-01

Extended endocrine therapy beyond 5 years for postmenopausal breast cancer has been studied within multiple phase III trials. Treatment compliance in these trials is generally poor. In this analysis, we aimed to determine factors that were associated with participation in the phase III Investigation on the Duration of Extended Adjuvant Letrozole (IDEAL) trial and with early treatment discontinuation, and how this influenced survival outcome. In the IDEAL trial, postmenopausal patients were randomised between 2.5 or 5 years of extended letrozole, after completing 5 years of endocrine therapy for hormone receptor-positive early breast cancer. A subgroup of this population participated earlier in the Tamoxifen Exemestane Adjuvant Multinational trial (5 years of exemestane or 2.5 years of tamoxifen followed by exemestane as primary adjuvant therapy) in which we explored which factors were determinative for enrolment in the IDEAL study. In the IDEAL cohort, we evaluated which factors predicted for early treatment discontinuation and the effect of early treatment discontinuation on disease-free survival (DFS). Nodal status, younger age and adjuvant chemotherapy were significantly associated with higher enrolment in the IDEAL trial. In the IDEAL cohort, adverse events (AEs), the type of primary endocrine therapy and the interval between primary and extended therapy were associated with early treatment discontinuation. Among the reported AEs, depressive feelings (56%) were most frequently associated with early treatment discontinuation. Early treatment discontinuation was not associated with worse DFS (hazard ratio [HR] = 1.02, 95% confidence interval = 0.76-1.37). In this analysis, we found that risk factors were most strongly associated enrolment in the IDEAL trial. In contrast, patient experiences were the most significant factors leading to early treatment discontinuation, with no effect on DFS. Copyright © 2018 Elsevier Ltd. All rights reserved.

Oestrogen receptor negativity in breast cancer: a cause or consequence?

PubMed Central

Gajulapalli, Vijaya Narasihma Reddy; Malisetty, Vijaya Lakshmi; Chitta, Suresh Kumar; Manavathi, Bramanandam

2016-01-01

Endocrine resistance, which occurs either by de novo or acquired route, is posing a major challenge in treating hormone-dependent breast cancers by endocrine therapies. The loss of oestrogen receptor α (ERα) expression is the vital cause of establishing endocrine resistance in this subtype. Understanding the mechanisms that determine the causes of this phenomenon are therefore essential to reduce the disease efficacy. But how we negate oestrogen receptor (ER) negativity and endocrine resistance in breast cancer is questionable. To answer that, two important approaches are considered: (1) understanding the cellular origin of heterogeneity and ER negativity in breast cancers and (2) characterization of molecular regulators of endocrine resistance. Breast tumours are heterogeneous in nature, having distinct molecular, cellular, histological and clinical behaviour. Recent advancements in perception of the heterogeneity of breast cancer revealed that the origin of a particular mammary tumour phenotype depends on the interactions between the cell of origin and driver genetic hits. On the other hand, histone deacetylases (HDACs), DNA methyltransferases (DNMTs), miRNAs and ubiquitin ligases emerged as vital molecular regulators of ER negativity in breast cancers. Restoring response to endocrine therapy through re-expression of ERα by modulating the expression of these molecular regulators is therefore considered as a relevant concept that can be implemented in treating ER-negative breast cancers. In this review, we will thoroughly discuss the underlying mechanisms for the loss of ERα expression and provide the future prospects for implementing the strategies to negate ER negativity in breast cancers. PMID:27884978

24 CFR Appendix A to Part 4001 - Calculation of Upfront Payment or Future Appreciation Payment

Code of Federal Regulations, 2010 CFR

2010-04-01

... to Housing and Urban Development (Continued) BOARD OF DIRECTORS OF THE HOPE FOR HOMEOWNERS PROGRAM HOPE FOR HOMEOWNERS PROGRAM Pt. 4001, App. A Appendix A to Part 4001—Calculation of Upfront Payment or...

Stem cell therapy and its potential role in pituitary disorders.

PubMed

Lara-Velazquez, Montserrat; Akinduro, Oluwaseun O; Reimer, Ronald; Woodmansee, Whitney W; Quinones-Hinojosa, Alfredo

2017-08-01

The pituitary gland is one of the key components of the endocrine system. Congenital or acquired alterations can mediate destruction of cells in the gland leading to hormonal dysfunction. Even though pharmacological treatment for pituitary disorders is available, exogenous hormone replacement is neither curative nor sustainable. Thus, alternative therapies to optimize management and improve quality of life are desired. An alternative modality to re-establish pituitary function is to promote endocrine cell regeneration through stem cells that can be obtained from the pituitary parenchyma or pluripotent cells. Stem cell therapy has been successfully applied to a plethora of other disorders, and is a promising alternative to hormonal supplementation for resumption of normal hormone homeostasis. In this review, we describe the common causes for pituitary deficiencies and the advances in cellular therapy to restore the physiological pituitary function.

The effect of a combination therapy with myo-inositol and a combined oral contraceptive pill versus a combined oral contraceptive pill alone on metabolic, endocrine, and clinical parameters in polycystic ovary syndrome.

PubMed

Minozzi, Massimo; Costantino, Demetrio; Guaraldi, Claudia; Unfer, Vittorio

2011-11-01

Compare the effects of a combined contraceptive pill (OCP) in combination with myo-inositol (MI) on endocrine, metabolic, and clinical parameters in patients with polycystic ovary syndrome (PCOS). One hundred fifty-five patients with PCOS were enrolled in this prospective, open-label clinical study. Patients were assigned to receive oral treatment with OCP alone (estradiol (EE) 30 μg/gestodene 75 μg) or in combination with myo-inositol 4 g/die, for 12 months. OCP plus MI therapy resulted in a higher reduction of FG score compared with OCP alone therapy. The combined therapy (OCP plus MI) significantly decreased hyperinsulinaemia, by positively affecting the fasting insulin and glucose levels and homeostasis model assessment-insulin resistance parameters, while no significant changes were observed in the OCP group. Androgens serum levels decreased in both groups, but significantly more in the combined therapy group. The lipid profile was improved in the combined therapy group, by reducing low-density lipoprotein cholesterol levels and enhancing high-density lipoprotein cholesterol levels. Our data show that a combination of combined contraceptive pill and MI may be more effective in controlling endocrine, metabolic, and clinical profile in patients with PCOS than OCP alone, and may reduce insulin levels and insulin resistance. Hence, combined treatment may become a more effective long-term therapeutic choice for controlling PCOS symptoms.

Potential role for mammalian target of rapamycin inhibitors as first-line therapy in hormone receptor–positive advanced breast cancer

PubMed Central

Beck, J Thaddeus

2015-01-01

Despite advances in cytotoxic chemotherapy and targeted therapies, 5-year survival rates remain low for patients with advanced breast cancer at diagnosis. This highlights the limited effectiveness of current treatment options. An improved understanding of cellular functions associated with the development and progression of breast cancer has resulted in the creation of a number of novel targeted molecular therapies. However, more work is needed to improve outcomes, particularly in the first-line recurrent or metastatic hormone receptor–positive breast cancer setting. The phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (mTOR) pathway is a major intracellular signaling pathway that is often upregulated in breast cancer, and overactivation of this pathway has been associated with primary or developed resistance to endocrine treatment. Clinical data from the Phase III Breast Cancer Trials of Oral Everolimus-2 (BOLERO-2) study of the mTOR inhibitor everolimus combined with exemestane in hormone receptor–positive advanced breast cancer were very promising, highlighting the potential role of mTOR inhibitors in combination with endocrine therapies as a first-line treatment option for these patients. It is hoped that the use of mTOR inhibitors combined with current standard-of-care endocrine therapies, such as aromatase inhibitors, in the first-line advanced breast cancer setting may result in greater antitumor effects and also delay or reverse treatment resistance. PMID:26675495

Comprehensive profiling of DNA repair defects in breast cancer identifies a novel class of endocrine therapy resistance drivers.

PubMed

Anurag, Meenakshi; Punturi, Nindo; Hoog, Jeremy; Bainbridge, Matthew N; Ellis, Matthew J; Haricharan, Svasti

2018-05-23

This study was undertaken to conduct a comprehensive investigation of the role of DNA damage repair (DDR) defects in poor outcome ER+ disease. Expression and mutational status of DDR genes in ER+ breast tumors were correlated with proliferative response in neoadjuvant aromatase inhibitor therapy trials (discovery data set), with outcomes in METABRIC, TCGA and Loi data sets (validation data sets), and in patient derived xenografts. A causal relationship between candidate DDR genes and endocrine treatment response, and the underlying mechanism, was then tested in ER+ breast cancer cell lines. Correlations between loss of expression of three genes: CETN2 (p<0.001) and ERCC1 (p=0.01) from the nucleotide excision repair (NER) and NEIL2 (p=0.04) from the base excision repair (BER) pathways were associated with endocrine treatment resistance in discovery data sets, and subsequently validated in independent patient cohorts. Complementary mutation analysis supported associations between mutations in NER and BER pathways and reduced endocrine treatment response. A causal role for CETN2, NEIL2 and ERCC1 loss in intrinsic endocrine resistance was experimentally validated in ER+ breast cancer cell lines, and in ER+ patient-derived xenograft models. Loss of CETN2, NEIL2 or ERCC1 induced endocrine treatment response by dysregulating G1/S transition, and therefore, increased sensitivity to CDK4/6 inhibitors. A combined DDR signature score was developed that predicted poor outcome in multiple patient cohorts. This report identifies DDR defects as a new class of endocrine treatment resistance drivers and indicates new avenues for predicting efficacy of CDK4/6 inhibition in the adjuvant treatment setting. Copyright ©2018, American Association for Cancer Research.

Use of Charity Financial Assistance for Novel Oral Anticancer Agents.

PubMed

Olszewski, Adam J; Zullo, Andrew R; Nering, Christopher R; Huynh, Justin P

2018-04-01

Novel oral targeted drugs are increasingly used for cancer therapy, but their extreme cost, often exceeding $10,000 per month, poses a significant barrier for patients and insurers alike, leading to the potential breakdown of traditional cost-sharing strategies. Insured patients' routine use of charity assistance to supplement their coverage would indicate a major deficiency in the current health care policies. By using data from a specialty pharmacy affiliated with an academic center (1,557 prescriptions dispensed between January 2014 and March 2017), we examined sources of payment for novel oral anticancer agents, distinguishing contributions from health insurance, patients, and from charitable assistance organizations. Thirty-six percent of 211 patients received charity assistance, including 47% of patients who were 65 years old or older. Charity sources covered 4% of total drug costs and 64% of out-of-pocket expenditures. The proportion of patients receiving financial assistance ranged from 7% when the upfront out-of-pocket requirement was less than $100 to 67% when it exceeded $1,000. When patients' out-of-pocket requirement exceeded $1,000, the median direct cash contribution paradoxically fell to $0 because of extensive use of charity support. Receipt of upfront charity assistance was associated with a longer time to filling the first prescription (median 9 v 7 days; P = .011) and with longer overall duration of therapy (median, 261 v 134 days; P = .014). These findings indicate that high out-of-pocket burden for expensive novel oral anticancer drugs leads to widespread use of charity support in the United States and that a significant financial barrier disparately affects older Medicare beneficiaries.

Epidermal growth factor receptor (EGFr) status associated with failure of primary endocrine therapy in elderly postmenopausal patients with breast cancer.

PubMed Central

Nicholson, S.; Halcrow, P.; Sainsbury, J. R.; Angus, B.; Chambers, P.; Farndon, J. R.; Harris, A. L.

1988-01-01

We have used primary endocrine therapy for 61 elderly women with operable breast cancer (median age 77 years). Eleven patients (18%) had complete and 24 (39%) partial tumour regression, 12 (20%) had stable disease for a minimum of six months and 14 (23%) no response. Salvage surgery was undertaken in the 14 with no response and 8/9 with progressive disease following initial response, thus samples were available from relapse patients only. Assays for EGFr (two point radioreceptor assay) and oestrogen receptors (ER) (dextran coated charcoal method and an immunohistochemical method) were performed on 20/22 patients. Ten of these 20 tumours were EGFr+ (greater than 10 fmol mg-1 binding) and 9/13 patients progressing within six months had EGFr+ tumours. 15/22 were available for ER evaluation and there was no such association with ER status. EGFr status was also associated with early recurrence after surgery and death in the endocrine failure group (P less than 0.005 and P less than 0.05 respectively). Of a control population of 33 patients (median age 72 years) treated by primary surgery, only 6 were EGFr+. In this group early relapse was predicted by EGFr status, but not by ER status (median disease free survival for EGFr+ patients 15 months, and for EGFr- patients 40 months, P less than 0.01, logrank test). There was a significantly higher proportion of EGFr+ tumours in the endocrine failure group compared with the control population (P less than 0.001). EGFr status is a marker for rapid early progression on primary endocrine therapy and the development of non-excisional methods of EGFr analysis would allow better directed therapeutic decisions. PMID:3224082

Clinical activity of fulvestrant in metastatic breast cancer previously treated with endocrine therapy and/or chemotherapy.

PubMed

Heo, Mi Hwa; Kim, Hee Kyung; Lee, Hansang; Kim, Ji-Yeon; Ahn, Jin-Seok; Im, Young-Hyuck; Park, Yeon Hee

2018-03-16

We conducted a retrospective analysis of the clinical activity of fulvestrant in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) previously treated with endocrine therapy and/or chemotherapy. We reviewed the medical records of all patients with MBC treated at Samsung Medical Center between January 2009 and August 2016. Patients received fulvestrant 250 mg intramuscularly every 28 days (from January 2009 to November 2010) or 500 mg intramuscularly every 28 days (from December 2010 to August 2016). Tumor responses were assessed every 8 weeks and at the end of treatment, as well as when disease progression was suspected. A total of 84 patients were included in this study. A median of two previous endocrine treatments had been performed; 79% of the patients had received two or more endocrine treatments. Forty-five patients (54%) had been treated with chemotherapy for MBC before the fulvestrant treatment course. Visceral metastasis was found in 49 patients (58%). The estimated median progression-free survival and overall survival were 4.4 months (95% confidence interval [CI], 3.4 to 5.5) and 32.5 months (95% CI, 17.6 to 47.4), respectively. The disease control rate was 40.5% (95% CI, 30.5 to 51.5); partial response was observed in 16% of the patients and stable disease was observed in 25% of the patients. The most frequently reported adverse reactions were mild-to-moderate grade myalgia (10.5% of the patients), injection site pain (7%), and fatigue (7%). Fulvestrant was generally well tolerated. Fulvestrant showed encouraging clinical activity and favorable feasibility in postmenopausal women with MBC who had been treated with multiple endocrine therapies and/or cytotoxic chemotherapies.

The endocrine pharmacology of testosterone therapy in men

NASA Astrophysics Data System (ADS)

Oettel, Michael

The review starts off by outlining the history of the discovery of the male sex hormone testosterone and the historical background to the various, often dubious, approaches to the treatment of age-related endocrine disorders in older men. A discussion of congenital androgen deficiency in young men is followed by methods of diagnosing hypogonadism in older men. Among therapeutic options, the alternatives to direct testosterone replacement are discussed, although none of them have proved to be particularly successful in clinical practice. For testosterone replacement itself, various routes of administration and pharmaceutical formulations are now available, facilitating good monitoring and individualized therapy.

Metastatic breast cancer: Endocrine therapy landscape reshaped

PubMed Central

Salkeni, Mohamad Adham; Hall, Samantha June

2017-01-01

Endocrine therapy (ET) of hormone receptor (HR)-positive and human epidermal growth factor receptor 2-(HER2)-negative metastatic breast cancer (MBC) historically focused on estrogen deprivation and antagonism. The identification of several intracellular pathways promoting resistance to antiestrogen therapy led to the introduction of novel endocrine drug combinations that reformed treatment schema and expanded therapeutic options. There is no doubt that efforts to overcome or delay resistance to ET are fruiting, particularly with the introduction of cyclin-dependent kinase 4/6 inhibitors such as palbociclib and ribociclib, and mechanistic target of rapamycin inhibitors such as everolimus. Although still considered incurable by currently available treatment modalities, many patients with MBC nowadays enjoy several years of good quality life coupled with decent tumor control. The diversity of therapies and unusual pattern of side effects can be quite perplexing to the treating physician. The sequence of variable agents and management of side effects, in addition to the timing of initiation of cytotoxic chemotherapy, is among the challenges faced by oncologists. In this review, we shed a spotlight on mechanisms of resistance to ET, and provide a review of landmark studies that have recently reshaped the landscape of treatment options for patients with metastatic HR-positive, HER2-negative MBC. A suggested treatment strategy for newly diagnosed patients is also discussed herein. PMID:29119080

Prevalence of endocrine complications and short stature in patients with thalassaemia major: a multicenter study by the Thalassaemia International Federation (TIF).

PubMed

De Sanctis, Vincenzo; Eleftheriou, Androulla; Malaventura, Cristina

2004-12-01

Although numerous studies are available in the literature on endocrine complications in thalassaemia, little is known about this subject in developing countries. Therefore, an international multicenter study was conducted in a large series of children and adolescents with beta thalassaemia major in order to obtain more information on the prevalence of short stature and endocrine complications in different areas of the world and to elucidate the problems that must be dealt with in the future. A questionnaire was sent to 29 Centres treating a total of 3817 beta thalassaemia major patients. Thirty-six per cent of patients were over the age of 16 years. Short stature was present in 31.1% of males and 30.5% of females, and the prevalence of growth hormone deficiency was 7.9% in males and 8.8% in females. Lack of pubertal changes was the most common endocrine complication (40.5%) followed by hypoparathyroidism (6.9%), impaired glucose tolerance (6.5%), insulin-dependent diabetes mellitus (3.2%) and primary hypothyroidism (3.2%). The prevalence of endocrine complications differed among centres, particularly for growth hormone deficiency, hypoparathyroidism and hypothyroidism. Compliance to chelation therapy was poor in 51% of patients and serum liver enzymes were high in 65% of patients. Since several endocrine glands may be affected in patients with thalassaemia major, and their life expectancy is now much longer, it is important that physicians be aware of the endocrine abnormalities that may develop. Therefore, periodic evaluation of these problems should be carried out in thalassaemic patients with iron overload, particularly after the age of 11 years. In conclusion, since iron overload and liver damage seem to be the most important factors responsible for endocrine complications, adequate compliance to chelation therapy and rigid precautions against liver infections are imperative.

Individualised second line anti-tuberculous therapy for an extensively resistant pulmonary tuberculosis (XDR PTB) in East Malaysia.

PubMed

Muhammad Redzwan, S R A; Ralph, A P; Sivaraman Kannan, K K; William, T

2015-06-01

Clinical experience with extensively Drug Resistant tuberculosis (XDR-TB) has not been reported in Malaysia before. We describe the clinical characteristics, risk factors, progress and therapeutic regimen for a healthcare worker with XDR-TB, who had failed therapy for multidrug resistant TB (MDR TB) in our institution. This case illustrates the risk of TB among healthcare workers in high TB-burden settings, the importance of obtaining upfront culture and susceptibility results in all new TB cases, the problem of acquired drug resistance developing during MDR-TB treatment, the challenges associated with XDR-TB treatment regimens, the value of surgical resection in refractory cases, and the major quality of life impact this disease can have on young, economically productive individuals.

Defining pancreatic endocrine precursors and their descendants.

PubMed

White, Peter; May, Catherine Lee; Lamounier, Rodrigo N; Brestelli, John E; Kaestner, Klaus H

2008-03-01

The global incidence of diabetes continues to increase. Cell replacement therapy and islet transplantation offer hope, especially for severely affected patients. Efforts to differentiate insulin-producing beta-cells from progenitor or stem cells require knowledge of the transcriptional programs that regulate the development of the endocrine pancreas. Differentiation toward the endocrine lineage is dependent on the transcription factor Neurogenin 3 (Neurog3, Ngn3). We utilize a Neurog3-enhanced green fluorescent protein knock-in mouse model to isolate endocrine progenitor cells from embryonic pancreata (embryonic day [E]13.5 through E17.5). Using advanced genomic approaches, we generate a comprehensive gene expression profile of these progenitors and their immediate descendants. A total of 1,029 genes were identified as being temporally regulated in the endocrine lineage during fetal development, 237 of which are transcriptional regulators. Through pathway analysis, we have modeled regulatory networks involving these proteins that highlight the complex transcriptional hierarchy governing endocrine differentiation. We have been able to accurately capture the gene expression profile of the pancreatic endocrine progenitors and their descendants. The list of temporally regulated genes identified in fetal endocrine precursors and their immediate descendants provides a novel and important resource for developmental biologists and diabetes researchers alike.

A case report of mixed acinar-endocrine carcinoma of the pancreas treated with S-1 chemotherapy: Does it work or induce endocrine differentiation?

PubMed

Yokode, Masataka; Itai, Ryosuke; Yamashita, Yukimasa; Zen, Yoh

2017-11-01

Acinar cell carcinomas (ACCs) and mixed acinar-endocrine carcinomas (MAECs) of the pancreas are rare, accounting for only 1% of pancreatic tumors. Although both typically present at an advanced stage, chemotherapeutic regimes have not yet been standardized. A 65-year-old man presented with a large mass in the pancreatic tail with multiple liver metastases. He was initially treated with gemcitabine for suspected ductal carcinoma of the pancreas, but no response was observed. S-1, administered as second-line chemotherapy, showed an approximately 38% reduction in the size of the primary tumor and metastatic deposits with therapeutic effects being maintained for 12 months. When the tumor progressed again, he underwent a percutaneous liver biopsy, which led to the diagnosis of MAEC. Combination therapy with cisplatin and etoposide targeting the endocrine component was administered, and this was based on the endocrine component potentially being less sensitive to S-1 than the ACC element. However, therapy was stopped due to the development of neutropenia, and the patient is currently receiving best supportive care. Given the previous studies suggested that S-1 is more effective for ACCs than gemcitabine, MAECs may also respond to S-1 chemotherapy, similar to ACCs. Another potential interpretation is that S-1 was effective when the condition was ACC, and eventually showed decreased effectiveness when the condition shifted to MAEC. Future studies are needed to conclude whether S-1 chemotherapy truly works against MAECs or induces endocrine differentiation in ACCs as a part of the drug-resistance process.

Does mesenteric venous imaging assessment accurately predict pathologic invasion in localized pancreatic ductal adenocarcinoma?

PubMed

Clanton, Jesse; Oh, Stephen; Kaplan, Stephen J; Johnson, Emily; Ross, Andrew; Kozarek, Richard; Alseidi, Adnan; Biehl, Thomas; Picozzi, Vincent J; Helton, William S; Coy, David; Dorer, Russell; Rocha, Flavio G

2018-05-09

Accurate prediction of mesenteric venous involvement in pancreatic ductal adenocarcinoma (PDAC) is necessary for adequate staging and treatment. A retrospective cohort study was conducted in PDAC patients at a single institution. All patients with resected PDAC and staging CT and EUS between 2003 and 2014 were included and sub-divided into "upfront resected" and "neoadjuvant chemotherapy (NAC)" groups. Independent imaging re-review was correlated to venous resection and venous invasion. Sensitivity, specificity, positive and negative predictive values were then calculated. A total of 109 patients underwent analysis, 60 received upfront resection, and 49 NAC. Venous resection (30%) and vein invasion (13%) was less common in patients resected upfront than those who received NAC (53% and 16%, respectively). Both CT and EUS had poor sensitivity (14-44%) but high specificity (75-95%) for detecting venous resection and vein invasion in patients resected upfront, whereas sensitivity was high (84-100%) and specificity was low (27-44%) after NAC. Preoperative CT and EUS in PDAC have similar efficacy but different predictive capacity in assessing mesenteric venous involvement depending on whether patients are resected upfront or received NAC. Both modalities appear to significantly overestimate true vascular involvement and should be interpreted in the appropriate clinical context. Copyright © 2018 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.

Diagnosis and management of endocrine gland neoplasmas. Revision 1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weller, R.E.

1994-03-01

Functional and nonfunctional neoplasms of the endocrine glands constitute some of the more challenging diagnostic and therapeutic problems in veterinary cancer medicine. This discussion will focus on the clinical signs and syndromes associated with neoplasms of the thyroid, adrenal, and parathyroid glands, and pancreas in companion animals and will concentrate on the mechanisms producing the clinical signs, diagnosis, staging, therapy and prognosis.

Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study

PubMed Central

Bergsten, Elisabet; Horne, AnnaCarin; Aricó, Maurizio; Astigarraga, Itziar; Egeler, R. Maarten; Filipovich, Alexandra H.; Ishii, Eiichi; Janka, Gritta; Ladisch, Stephan; Lehmberg, Kai; McClain, Kenneth L.; Minkov, Milen; Montgomery, Scott; Nanduri, Vasanta; Rosso, Diego

2017-01-01

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome comprising familial/genetic HLH (FHL) and secondary HLH. In the HLH-94 study, with an estimated 5-year probability of survival (pSu) of 54% (95% confidence interval, 48%-60%), systemic therapy included etoposide, dexamethasone, and, from week 9, cyclosporine A (CSA). Hematopoietic stem cell transplantation (HSCT) was indicated in patients with familial/genetic, relapsing, or severe/persistent disease. In HLH-2004, CSA was instead administered upfront, aiming to reduce pre-HSCT mortality and morbidity. From 2004 to 2011, 369 children aged <18 years fulfilled HLH-2004 inclusion criteria (5 of 8 diagnostic criteria, affected siblings, and/or molecular diagnosis in FHL-causative genes). At median follow-up of 5.2 years, 230 of 369 patients (62%) were alive (5-year pSu, 61%; 56%-67%). Five-year pSu in children with (n = 168) and without (n = 201) family history/genetically verified FHL was 59% (52%-67%) and 64% (57%-71%), respectively (familial occurrence [n = 47], 58% [45%-75%]). Comparing with historical data (HLH-94), using HLH-94 inclusion criteria, pre-HSCT mortality was nonsignificantly reduced from 27% to 19% (P = .064 adjusted for age and sex). Time from start of therapy to HSCT was shorter compared with HLH-94 (P = .020 adjusted for age and sex) and reported neurological alterations at HSCT were 22% in HLH-94 and 17% in HLH-2004 (using HLH-94 inclusion criteria). Five-year pSu post-HSCT overall was 66% (verified FHL, 70% [63%-78%]). Additional analyses provided specific suggestions on potential pre-HSCT treatment improvements. HLH-2004 confirms that a majority of patients may be rescued by the etoposide/dexamethasone combination but intensification with CSA upfront, adding corticosteroids to intrathecal therapy, and reduced time to HSCT did not improve outcome significantly. PMID:28935695

Discovery of naturally occurring ESR1 mutations in breast cancer cell lines modelling endocrine resistance.

PubMed

Martin, Lesley-Ann; Ribas, Ricardo; Simigdala, Nikiana; Schuster, Eugene; Pancholi, Sunil; Tenev, Tencho; Gellert, Pascal; Buluwela, Laki; Harrod, Alison; Thornhill, Allan; Nikitorowicz-Buniak, Joanna; Bhamra, Amandeep; Turgeon, Marc-Olivier; Poulogiannis, George; Gao, Qiong; Martins, Vera; Hills, Margaret; Garcia-Murillas, Isaac; Fribbens, Charlotte; Patani, Neill; Li, Zheqi; Sikora, Matthew J; Turner, Nicholas; Zwart, Wilbert; Oesterreich, Steffi; Carroll, Jason; Ali, Simak; Dowsett, Mitch

2017-11-30

Resistance to endocrine therapy remains a major clinical problem in breast cancer. Genetic studies highlight the potential role of estrogen receptor-α (ESR1) mutations, which show increased prevalence in the metastatic, endocrine-resistant setting. No naturally occurring ESR1 mutations have been reported in in vitro models of BC either before or after the acquisition of endocrine resistance making functional consequences difficult to study. We report the first discovery of naturally occurring ESR1 Y537C and ESR1 Y537S mutations in MCF7 and SUM44 ESR1-positive cell lines after acquisition of resistance to long-term-estrogen-deprivation (LTED) and subsequent resistance to fulvestrant (ICIR). Mutations were enriched with time, impacted on ESR1 binding to the genome and altered the ESR1 interactome. The results highlight the importance and functional consequence of these mutations and provide an important resource for studying endocrine resistance.

Treatment Modification in Young Breast Cancer Patients.

PubMed

Scharl, Anton; Salterberg, Annette; Untch, Michael; Liedtke, Cornelia; Stickeler, Elmar; Papathemelis, Thomas

2016-01-01

Patients not older than 40 years are referred to as young patients. These women benefit from chemo-, endocrine and anti-HER2 therapy to a similar degree as older women. Surgery and radiation therapy also follow the same recommendations. This manuscript deals with the following topics that need special consideration in young women: endocrine therapy and ovarian suppression; fertility protection and family planning; and genetic counselling. There is an on-going debate on whether tamoxifen is sufficient as an endocrine treatment in young patients with endocrine-responsive tumours or whether suppression of ovarian function in combination with tamoxifen or aromatase inhibitor should be preferred. Recent data suggest a benefit from ovarian suppression plus exemestane in women of 35 years or younger with high-risk breast cancer. However, increased side effects bear the risk of lesser compliance, which eventually results in higher mortality. Child bearing is nowadays frequently postponed to the 4th decade of life, thereby increasing the number of women who have not yet finished their reproductive desires when diagnosed with breast cancer. These patients are in urgent need of counselling for fertility protection. Breast cancer diagnosis at young age is an indication for a possible mutation in breast cancer susceptibility genes. This has an impact on the cancer risk of the whole family, especially the offspring. Drugs that are specifically targeted to cancer cells with genetic alterations that impair DNA repair are already entering the arsenal of oncologists. © 2016 S. Karger GmbH, Freiburg.

NEOCENT: a randomised feasibility and translational study comparing neoadjuvant endocrine therapy with chemotherapy in ER-rich postmenopausal primary breast cancer.

PubMed

Palmieri, C; Cleator, S; Kilburn, L S; Kim, S B; Ahn, S-H; Beresford, M; Gong, G; Mansi, J; Mallon, E; Reed, S; Mousa, K; Fallowfield, L; Cheang, M; Morden, J; Page, K; Guttery, D S; Rghebi, B; Primrose, L; Shaw, J A; Thompson, A M; Bliss, J M; Coombes, R C

2014-12-01

Neoadjuvant endocrine therapy is an alternative to chemotherapy for women with oestrogen receptor (ER)-positive early breast cancer (BC). We aimed to assess feasibility of recruiting patients to a study comparing chemotherapy versus endocrine therapy in postmenopausal women with ER-rich primary BC, and response as well as translational endpoints were assessed. Patients requiring neoadjuvant therapy were randomised to chemotherapy: 6 × 3-weekly cycles FE₁₀₀C or endocrine therapy: letrozole 2.5 mg, daily for 18-23 weeks. Primary endpoints were recruitment feasibility and tissue collection. Secondary endpoints included clinical, radiological and pathological response rates, quality of life and translational endpoints. 63/80 patients approached were eligible, of those 44 (70, 95% CI 57-81) were randomised. 12 (54.5, 95% CI 32.2-75.6) chemotherapy patients showed radiological objective response compared with 13 (59.1, 95% CI 36.4-79.3) letrozole patients. Compared with baseline, mean Ki-67 levels fell in both groups at days 2-4 and at surgery [fold change: 0.24 (95% CI 0.12-0.51) and 0.24; (95% CI 0.15-0.37), respectively]. Plasma total cfDNA levels rose from baseline to week 8 [fold change: chemotherapy 2.10 (95% CI 1.47-3.00), letrozole 1.47(95% CI 0.98-2.20)], and were maintained at surgery in the chemotherapy group [chemotherapy 2.63; 95% CI 1.56-4.41), letrozole 0.95 (95% CI 0.71-1.26)]. An increase in plasma let-7a miRNA was seen at surgery for patients with objective radiological response to chemotherapy. Recruitment and tissue collection endpoints were met; however, a larger trial was deemed unfeasible due to slow accrual. Both regimens were equally efficacious. Dynamic changes were seen in Ki-67 and circulating biomarkers in both groups with increases in cfDNA and let-7a miRNA persisting until surgery for chemotherapy patients.

24 CFR 290.27 - Up-front grants and loans.

Code of Federal Regulations, 2010 CFR

2010-04-01

... URBAN DEVELOPMENT HUD-OWNED PROPERTIES DISPOSITION OF MULTIFAMILY PROJECTS AND SALE OF HUD-HELD...) Eligible projects. An up-front grant or loan can be made available in the sale of a HUD-owned multifamily... income in a competitive market to cover all operating expenses, meet after sale debt service requirements...

24 CFR 290.27 - Up-front grants and loans.

Code of Federal Regulations, 2011 CFR

2011-04-01

... may provide up-front grants and loans for rehabilitation, demolition, rebuilding and other related... determination that such a grant or loan, plus any additional project-based assistance made available, would be more cost-effective than the use of the maximum permissible project-based rental assistance alone. (b...

24 CFR 290.27 - Up-front grants and loans.

Code of Federal Regulations, 2014 CFR

2014-04-01

... URBAN DEVELOPMENT HUD-OWNED PROPERTIES DISPOSITION OF MULTIFAMILY PROJECTS AND SALE OF HUD-HELD MULTIFAMILY MORTGAGES Disposition of Multifamily Projects § 290.27 Up-front grants and loans. (a) General. HUD... development costs as part of the disposition of a multifamily housing project that is HUD-owned, upon making a...

24 CFR 290.27 - Up-front grants and loans.

Code of Federal Regulations, 2012 CFR

2012-04-01

... URBAN DEVELOPMENT HUD-OWNED PROPERTIES DISPOSITION OF MULTIFAMILY PROJECTS AND SALE OF HUD-HELD MULTIFAMILY MORTGAGES Disposition of Multifamily Projects § 290.27 Up-front grants and loans. (a) General. HUD... development costs as part of the disposition of a multifamily housing project that is HUD-owned, upon making a...

24 CFR 4001.203 - Calculation of upfront and annual mortgage insurance premiums for Program mortgages.

Code of Federal Regulations, 2010 CFR

2010-04-01

... mortgage insurance premiums for Program mortgages. 4001.203 Section 4001.203 Housing and Urban Development... HOMEOWNERS PROGRAM HOPE FOR HOMEOWNERS PROGRAM Rights and Obligations Under the Contract of Insurance § 4001.203 Calculation of upfront and annual mortgage insurance premiums for Program mortgages. (a...

24 CFR 4001.203 - Calculation of upfront and annual mortgage insurance premiums for Program mortgages.

Code of Federal Regulations, 2011 CFR

2011-04-01

... mortgage insurance premiums for Program mortgages. 4001.203 Section 4001.203 Housing and Urban Development... HOMEOWNERS PROGRAM HOPE FOR HOMEOWNERS PROGRAM Rights and Obligations Under the Contract of Insurance § 4001.203 Calculation of upfront and annual mortgage insurance premiums for Program mortgages. (a...

24 CFR 4001.120 - Appreciation sharing or upfront payment.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 24 Housing and Urban Development 5 2010-04-01 2010-04-01 false Appreciation sharing or upfront payment. 4001.120 Section 4001.120 Housing and Urban Development Regulations Relating to Housing and Urban Development (Continued) BOARD OF DIRECTORS OF THE HOPE FOR HOMEOWNERS PROGRAM HOPE FOR HOMEOWNERS PROGRAM...

78 FR 14323 - Notice of Proposed Information Collection: Comment Request: Single Family Premium Collection...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-05

... information: Title of Proposal: Single Family Premium Collection Subsystem- Upfront (SFPCS-U). OMB Control... Information Collection: Comment Request: Single Family Premium Collection Subsystem-Upfront (SFPCS-U) AGENCY... OMB Control Number and should be sent to: Reports Liaison Officer, Department of Housing and Urban...

Palbociclib Combined with Fulvestrant in Premenopausal Women with Advanced Breast Cancer and Prior Progression on Endocrine Therapy: PALOMA-3 Results.

PubMed

Loibl, Sibylle; Turner, Nicholas C; Ro, Jungsil; Cristofanilli, Massimo; Iwata, Hiroji; Im, Seock-Ah; Masuda, Norikazu; Loi, Sherene; André, Fabrice; Harbeck, Nadia; Verma, Sunil; Folkerd, Elizabeth; Puyana Theall, Kathy; Hoffman, Justin; Zhang, Ke; Bartlett, Cynthia Huang; Dowsett, Mitchell

2017-09-01

The efficacy and safety of palbociclib, a cyclin-dependent kinase 4/6 inhibitor, combined with fulvestrant and goserelin was assessed in premenopausal women with advanced breast cancer (ABC) who had progressed on prior endocrine therapy (ET). One hundred eight premenopausal endocrine-refractory women ≥18 years with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) ABC were among 521 women randomized 2:1 (347:174) to fulvestrant (500 mg) ± goserelin with either palbociclib (125 mg/day orally, 3 weeks on, 1 week off) or placebo. This analysis assessed whether the overall tolerable safety profile and significant progression-free survival (PFS) improvement extended to premenopausal women. Potential drug-drug interactions (DDIs) and ovarian suppression with goserelin were assessed via plasma pharmacokinetics and biochemical analyses, respectively. (ClinicalTrials.gov identifier: NCT01942135) RESULTS: Median PFS for premenopausal women in the palbociclib ( n  = 72) versus placebo arm ( n  = 36) was 9.5 versus 5.6 months, respectively (hazard ratio, 0.50, 95% confidence interval: 0.29-0.87), and consistent with the significant PFS improvement in the same arms for postmenopausal women. Any-grade and grade ≤3 neutropenia, leukopenia, and infections were among the most frequent adverse events reported in the palbociclib arm with concurrent goserelin administration. Hormone concentrations were similar between treatment arms and confirmed sustained ovarian suppression. Clinically relevant DDIs were not observed. Palbociclib combined with fulvestrant and goserelin was an effective and well-tolerated treatment for premenopausal women with prior endocrine-resistant HR+/HER2- ABC. Inclusion of both premenopausal and postmenopausal women in pivotal combination ET trials facilitates access to novel drugs for young women and should be considered as a new standard for clinical trial design. PALOMA-3, the first registrational study to include premenopausal women in a trial investigating a CDK4/6 inhibitor combined with endocrine therapy, has the largest premenopausal cohort reported in an endocrine-resistant setting. In pretreated premenopausal women with hormone receptor-positive advanced breast cancer, palbociclib plus fulvestrant and goserelin (luteinizing hormone-releasing hormone [LHRH] agonist) treatment almost doubled median progression-free survival (PFS) and significantly increased the objective response rate versus endocrine monotherapy, achieving results comparable to those reported for chemotherapy without apparently interfering with LHRH agonist-induced ovarian suppression. The significant PFS gain and tolerable safety profile strongly support use of this regimen in premenopausal women with endocrine-resistant disease who could possibly delay chemotherapy. © AlphaMed Press 2017.

Comprehensive Profiling of the Androgen Receptor in Liquid Biopsies from Castration-resistant Prostate Cancer Reveals Novel Intra-AR Structural Variation and Splice Variant Expression Patterns.

PubMed

De Laere, Bram; van Dam, Pieter-Jan; Whitington, Tom; Mayrhofer, Markus; Diaz, Emanuela Henao; Van den Eynden, Gert; Vandebroek, Jean; Del-Favero, Jurgen; Van Laere, Steven; Dirix, Luc; Grönberg, Henrik; Lindberg, Johan

2017-08-01

Expression of the androgen receptor splice variant 7 (AR-V7) is associated with poor response to second-line endocrine therapy in castration-resistant prostate cancer (CRPC). However, a large fraction of nonresponding patients are AR-V7-negative. To investigate if a comprehensive liquid biopsy-based AR profile may improve patient stratification in the context of second-line endocrine therapy. Peripheral blood was collected from patients with CRPC (n=30) before initiation of a new line of systemic therapy. We performed profiling of circulating tumour DNA via low-pass whole-genome sequencing and targeted sequencing of the entire AR gene, including introns. Targeted RNA sequencing was performed on enriched circulating tumour cell fractions to assess the expression levels of seven AR splice variants (ARVs). Somatic AR variations, including copy-number alterations, structural variations, and point mutations, were combined with ARV expression patterns and correlated to clinicopathologic parameters. Collectively, any AR perturbation, including ARV, was detected in 25/30 patients. Surprisingly, intra-AR structural variation was present in 15/30 patients, of whom 14 expressed ARVs. The majority of ARV-positive patients expressed multiple ARVs, with AR-V3 the most abundantly expressed. The presence of any ARV was associated with progression-free survival after second-line endocrine treatment (hazard ratio 4.53, 95% confidence interval 1.424-14.41; p=0.0105). Six out of 17 poor responders were AR-V7-negative, but four carried other AR perturbations. Comprehensive AR profiling, which is feasible using liquid biopsies, is necessary to increase our understanding of the mechanisms underpinning resistance to endocrine treatment. Alterations in the androgen receptor are associated with endocrine treatment outcomes. This study demonstrates that it is possible to identify different types of alterations via simple blood draws. Follow-up studies are needed to determine the effect of such alterations on hormonal therapy. Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Optimal treatment strategies in postmenopausal women with hormone-receptor-positive and HER2-negative metastatic breast cancer.

PubMed

Gligorov, Joseph; Lotz, Jean-Pierre

2008-12-01

Metastatic breast cancer (MBC) is unfortunately still considered incurable; treatment aims to prolong progression-free and overall survival, relieve disease symptoms, and maintain quality of life. Treatment can include endocrine therapy, radiotherapy, chemotherapy, bisphosphonates, and/or targeted therapy; which is used depends on the characteristics of the disease [e.g., hormone receptor status, disease site(s), and response to previous treatment] and the patient (age, comorbidity, and personal preferences). For most patients with hormone-receptor-positive tumors, the first choice of treatment is further endocrine therapy, but endocrine resistance is a common problem in advanced disease. Several novel anticancer agents have been developed with the aim of overcoming endocrine resistance, many of which target intracellular signaling pathways implicated in disease progression or resistance. Among these, inhibitors of growth factor receptor tyrosine kinases and of mammalian target of rapamycin have shown the most promise in clinical trials. Chemotherapy is the cornerstone of MBC treatment in most women. Important considerations when choosing chemotherapy include the choice of agents, and whether to use single-agent or combination therapy. Anthracyclines are one of the most active cytotoxic agents currently used for the treatment of breast cancer, and for many women, further anthracycline therapy at progression or relapse would be the preferred option. However, lifetime exposure to anthracyclines is limited by cumulative cardiotoxicity, which often prevents rechallenge in later lines of therapy. Newer anthracycline formulations have been developed with lower cardiotoxicity than the conventional anthracycline doxorubicin, but these agents still impair cardiac function, and have maximum recommended lifetime doses. Recently, the concomitant use of cardioprotective agents, such as dexrazoxane, has emerged as an effective approach to reducing the cardiotoxic effects of anthracyclines, thus permitting retreatment. Bisphosphonates, which are not associated with the acute toxicities of cytotoxic chemotherapy drugs, are the established standard of care for patients with metastatic bone disease, and have greatly improved outcomes over the last decade. The search is ongoing for novel agents that will, hopefully, bring a cure closer to reality.

Identification of Patients at Very Low Risk of Local Recurrence After Breast-Conserving Surgery

DOE Office of Scientific and Technical Information (OSTI.GOV)

Smith, Sally L., E-mail: ssmith11@bccancer.bc.ca; Truong, Pauline T.; Lu, Linghong

2014-07-01

Purpose: To identify clinical and pathological factors that identify groups of women with stage I breast cancer with a 5-year risk of local recurrence (LR) ≤1.5% after breast-conserving therapy (BCS) plus whole-breast radiation therapy (RT). Methods and Materials: Study subjects were 5974 patients ≥50 years of age whose cancer was diagnosed between 1989 and 2006, and were referred with pT1 pN0 invasive breast cancer treated with BCS and RT. Cases of 5- and 10-year LR were examined using Kaplan-Meier methods. Recursive partitioning analysis was performed in patients treated with and without endocrine therapy to identify combinations of factors associated withmore » a 5-year LR risk ≤1.5%. Results: The median follow-up was 8.61 years. Median age was 63 years of age (range, 50 to 91). Overall 5-year LR was 1.5% (95% confidence interval [CI], 1.2%-1.9%) and 10-year LR was 3.4% (95% CI, 2.8%-4.0%). Of 2830 patients treated with endocrine therapy, patient subsets identified with 5-year LR ≤1.5% included patients with grade 1 histology (n=1038; LR, 0.2%; 95% CI, 0%-0.5%) or grade 2 histology plus ≥60 years of age (n=843; LR, 0.5%; 95% CI, 0%-1.0%). Ten-year LR for these groups were 0.8% (95% CI, 0.1%-1.6%) and 0.9% (95% CI, 0.2%-1.6%), respectively. Of 3144 patients treated without endocrine therapy, patients with grade 1 histology plus clear margins had 5-year LR ≤1.5% (n=821; LR, 0.6%; 95% CI, 0.1%-1.2%). Ten-year LR for this group was 2.2% (95% CI, 1.0%-3.4%). Conclusions: Histologic grade, age, margin status, and use of endocrine therapy identified 45% of a population-based cohort of female patients over age 50 with stage I breast cancer with a 5-year LR risk ≤1.5% after BCS plus RT. Prospective study is needed to evaluate the safety of omitting RT in patients with such a low risk of LR.« less

New developments in the treatment of multiple myeloma - clinical utility of daratumumab.

PubMed

McEllistrim, Cian; Krawczyk, Janusz; O'Dwyer, Michael E

2017-01-01

Multiple myeloma is a clonal disorder of plasma cells that is currently considered incurable. CD38 is a 46 kDa type II transmembrane glycoprotein that is highly expressed on myeloma cells. Daratumumab is a first in-class human IgG1 monoclonal antibody that targets CD38, and has antimyeloma effects through several mechanisms. Single-agent trials show surprising activity in heavily pretreated myeloma patients. Trials in the relapsed setting, where daratumumab is added to lenalidomide and dexamethasone or bortezomib and dexamethasone, have demonstrated significantly improved progression-free survival with acceptable toxicity. In this review, we discuss the mechanism of action, pharmacology and pharmacokinetics of daratumumab and review the available clinical data in detail. We examine how daratumumab interferes with transfusion testing due to the expression of CD38 on the red blood cells, leading to potential difficulties releasing blood products. Daratumumab also affects disease assessments in multiple myeloma, including serum protein electrophoresis, immunofixation and flow cytometry. Strategies to mitigate these effects are discussed. The optimal use of daratumumab has yet to be decided, and several trials are ongoing in the relapsed and upfront setting. We discuss the potential upfront role of this exciting therapy, which has significant potential for increased minimal residual disease negativity and improved progression-free survival even in high-risk groups.

New developments in the treatment of multiple myeloma – clinical utility of daratumumab

PubMed Central

McEllistrim, Cian; Krawczyk, Janusz; O’Dwyer, Michael E

2017-01-01

Multiple myeloma is a clonal disorder of plasma cells that is currently considered incurable. CD38 is a 46 kDa type II transmembrane glycoprotein that is highly expressed on myeloma cells. Daratumumab is a first in-class human IgG1 monoclonal antibody that targets CD38, and has antimyeloma effects through several mechanisms. Single-agent trials show surprising activity in heavily pretreated myeloma patients. Trials in the relapsed setting, where daratumumab is added to lenalidomide and dexamethasone or bortezomib and dexamethasone, have demonstrated significantly improved progression-free survival with acceptable toxicity. In this review, we discuss the mechanism of action, pharmacology and pharmacokinetics of daratumumab and review the available clinical data in detail. We examine how daratumumab interferes with transfusion testing due to the expression of CD38 on the red blood cells, leading to potential difficulties releasing blood products. Daratumumab also affects disease assessments in multiple myeloma, including serum protein electrophoresis, immunofixation and flow cytometry. Strategies to mitigate these effects are discussed. The optimal use of daratumumab has yet to be decided, and several trials are ongoing in the relapsed and upfront setting. We discuss the potential upfront role of this exciting therapy, which has significant potential for increased minimal residual disease negativity and improved progression-free survival even in high-risk groups. PMID:28442888

Managed Utility Services Contracts | Climate Neutral Research Campuses |

Science.gov Websites

the energy cost savings generated by the project. Managed Utility Services Contracts In a Managed . The owner, in this case the research campus, bears no upfront cost through this agreement, pays the revenue to capital cost repayment and maintenance costs. In addition to removing the burden of an upfront

Endocrine Dysregulation in Anorexia Nervosa Update

PubMed Central

2011-01-01

Context: Anorexia nervosa is a primary psychiatric disorder with serious endocrine consequences, including dysregulation of the gonadal, adrenal, and GH axes, and severe bone loss. This Update reviews recent advances in the understanding of the endocrine dysregulation observed in this state of chronic starvation, as well as the mechanisms underlying the disease itself. Evidence Acquisition: Findings of this update are based on a PubMed search and the author's knowledge of this field. Evidence Synthesis: Recent studies have provided insights into the mechanisms underlying endocrine dysregulation in states of chronic starvation as well as the etiology of anorexia nervosa itself. This includes a more complex understanding of the pathophysiologic bases of hypogonadism, hypercortisolemia, GH resistance, appetite regulation, and bone loss. Nevertheless, the etiology of the disease remains largely unknown, and effective therapies for the endocrine complications and for the disease itself are lacking. Conclusions: Despite significant progress in the field, further research is needed to elucidate the mechanisms underlying the development of anorexia nervosa and its endocrine complications. Such investigations promise to yield important advances in the therapeutic approach to this disease as well as to the understanding of the regulation of endocrine function, skeletal biology, and appetite regulation. PMID:21976742

Is adjuvant chemotherapy of benefit for postmenopausal women who receive endocrine treatment for highly endocrine-responsive, node-positive breast cancer? International Breast Cancer Study Group Trials VII and 12-93.

PubMed

Pagani, Olivia; Gelber, Shari; Simoncini, Edda; Castiglione-Gertsch, Monica; Price, Karen N; Gelber, Richard D; Holmberg, Stig B; Crivellari, Diana; Collins, John; Lindtner, Jurij; Thürlimann, Beat; Fey, Martin F; Murray, Elizabeth; Forbes, John F; Coates, Alan S; Goldhirsch, Aron

2009-08-01

To compare the efficacy of chemoendocrine treatment with that of endocrine treatment (ET) alone for postmenopausal women with highly endocrine responsive breast cancer. In the International Breast Cancer Study Group (IBCSG) Trials VII and 12-93, postmenopausal women with node-positive, estrogen receptor (ER)-positive or ER-negative, operable breast cancer were randomized to receive either chemotherapy or endocrine therapy or combined chemoendocrine treatment. Results were analyzed overall in the cohort of 893 patients with endocrine-responsive disease, and according to prospectively defined categories of ER, age and nodal status. STEPP analyses assessed chemotherapy effect. The median follow-up was 13 years. Adding chemotherapy reduced the relative risk of a disease-free survival event by 19% (P = 0.02) compared with ET alone. STEPP analyses showed little effect of chemotherapy for tumors with high levels of ER expression (P = 0.07), or for the cohort with one positive node (P = 0.03). Chemotherapy significantly improves disease-free survival for postmenopausal women with endocrine-responsive breast cancer, but the magnitude of the effect is substantially attenuated if ER levels are high.

Endocrine resistance in breast cancer – an overview and update

PubMed Central

Clarke, Robert; Tyson, John J.; Dixon, J. Michael

2015-01-01

Tumors that express detectable levels of the product of the ESR1 gene (estrogen receptor-α; ERα) represent the single largest molecular subtype of breast cancer. More women eventually die from ERα+ breast cancer than from either HER2+ disease (almost half of which also express ERα) and/or from triple negative breast cancer (ERα-negative, progesterone receptor-negative, and HER2-negative). Antiestrogens and aromatase inhibitors are largely indistinguishable from each other in their abilities to improve overall survival and almost 50% of ERα+ breast cancers will eventually fail one or more of these endocrine interventions. The precise reasons why these therapies fail in ERα+ breast cancer remain largely unknown. Pharmacogenetic explanations for Tamoxifen resistance are controversial. The role of ERα mutations in endocrine resistance remains unclear. Targeting the growth factors and oncogenes most strongly correlated with endocrine resistance has proven mostly disappointing in their abilities to improve overall survival substantially, particularly in the metastatic setting. Nonetheless, there are new concepts in endocrine resistance that integrate molecular signaling, cellular metabolism, and stress responses including endoplasmic reticulum stress and the unfolded protein response (UPR) that provide novel insights and suggest innovative therapeutic targets. Encouraging evidence that drug combinations with CDK4/CDK6 inhibitors can extend recurrence free survival may yet translate to improvements in overall survival. Whether the improvements seen with immunotherapy in other cancers can be achieved in breast cancer remains to be determined, particularly for ERα+ breast cancers. This review explores the basic mechanisms of resistance to endocrine therapies, concluding with some new insights from systems biology approaches further implicating autophagy and the UPR in detail, and a brief discussion of exciting new avenues and future prospects. PMID:26455641

How patients understand physicians' solicitations of additional concerns: implications for up-front agenda setting in primary care.

PubMed

Robinson, Jeffrey D; Heritage, John

2016-01-01

In the more than 1 billion primary-care visits each year in the United States, the majority of patients bring more than one distinct concern, yet many leave with "unmet" concerns (i.e., ones not addressed during visits). Unmet concerns have potentially negative consequences for patients' health, and may pose utilization-based financial burdens to health care systems if patients return to deal with such concerns. One solution to the problem of unmet concerns is the communication skill known as up-front agenda setting, where physicians (after soliciting patients' chief concerns) continue to solicit patients' concerns to "exhaustion" with questions such as "Are there some other issues you'd like to address?" Although this skill is trainable and efficacious, it is not yet a panacea. This article uses conversation analysis to demonstrate that patients understand up-front agenda-setting questions in ways that hamper their effectiveness. Specifically, we demonstrate that up-front agenda-setting questions are understood as making relevant "new problems" (i.e., concerns that are either totally new or "new since last visit," and in need of diagnosis), and consequently bias answers away from "non-new problems" (i.e., issues related to previously diagnosed concerns, including much of chronic care). Suggestions are made for why this might be so, and for improving up-front agenda setting. Data are 144 videotapes of community-based, acute, primary-care, outpatient visits collected in the United States between adult patients and 20 family-practice physicians.

Neutrophil to lymphocyte ratio (NLR) improves the risk assessment of ISS staging in newly diagnosed MM patients treated upfront with novel agents.

PubMed

Romano, A; Parrinello, N L; Consoli, M L; Marchionni, L; Forte, S; Conticello, C; Pompa, A; Corso, A; Milone, G; Di Raimondo, F; Borrello, I

2015-11-01

Recent reports identify the ratio between absolute neutrophil count (ANC) and absolute lymphocyte count (ALC), called neutrophil to lymphocyte ratio (NLR), as a predictor of progression-free survival (PFS) and overall survival (OS) in various malignancies. We retrospectively examined the NLR in a cohort of 309 newly diagnosed multiple myeloma (MM) patients treated upfront with novel agents. NLR was calculated using data obtained from the complete blood count (CBC) at diagnosis and subsequently correlated with PFS and OS. The median NLR was 1.9 (range 0.4-15.9). Higher NLR was independent of international staging system (ISS) stage, plasma cell infiltration or cytogenetics. The 5-year PFS and OS estimates were, respectively, 18.2 and 36.4 % for patients with NLR ≥ 2 versus 25.5 and 66.6 % in patients with NLR < 2. Among younger patients (age <65 years, N = 179), NLR ≥ 2 had a negative prognostic impact on both PFS and OS, in all ISS stages. By combining ISS stage and NLR in a model limited to young patients, we found that 19 % of the patients were classified as very low risk, 70 % standard risk and 11 % very high risk. The 5-year estimates were 39.3, 19.4 and 10.9 % for PFS and 95.8, 50.9 and 23.6 % for OS for very low, standard-risk and very high-risk groups. We found NLR to be a predictor of PFS and OS in MM patients treated upfront with novel agents. NLR can be combined with ISS staging system to identify patients with dismal outcome. However, larger cohorts and prospective studies are needed to use NLR as additional parameter to personalise MM therapy in the era of novel agents.

Eltrombopag in aplastic anaemia

PubMed Central

Desmond, Ronan; Townsley, Danielle M.; Dunbar, Cynthia; Young, Neal S.

2014-01-01

The treatment of aplastic anemia is currently with immunosuppressive therapy (IST) with antithymocyte globulin and cyclosporine, to which two thirds of patients respond. However, a significant proportion of these responders relapse and many have persistent cytopenias. The management of these patients is challenging. Modifications to this standard approach using alternative immunosuppressive agents or adding hematopoietic cytokines such as G-CSF and erythropoietin have not improved outcome. A recent trial has shown that eltrombopag, a thrombopoeitin mimetic, is efficacious in the treatment of patients with severe aplastic anemia (SAA) refractory to IST. There is evidence that this drug works by directly stimulating marrow stem and progenitor cells thereby promoting hematopoietic recovery in patients with bone marrow failure. Several trials are ongoing in our institution using this very promising drug in combination therapy in the upfront treatment of SAA, in IST refractory SAA and in moderate disease. PMID:25578417

Immunologic Endocrine Disorders

PubMed Central

Michels, Aaron W.; Eisenbarth, George S.

2010-01-01

Autoimmunity affects multiple glands in the endocrine system. Animal models and human studies highlight the importance of alleles in HLA (human leukocyte antigen)-like molecules determining tissue specific targeting that with the loss of tolerance leads to organ specific autoimmunity. Disorders such as type 1A diabetes, Grave's disease, Hashimoto's thyroiditis, Addison's disease, and many others result from autoimmune mediated tissue destruction. Each of these disorders can be divided into stages beginning with genetic susceptibility, environmental triggers, active autoimmunity, and finally metabolic derangements with overt symptoms of disease. With an increased understanding of the immunogenetics and immunopathogenesis of endocrine autoimmune disorders, immunotherapies are becoming prevalent, especially in type 1A diabetes. Immunotherapies are being used more in multiple subspecialty fields to halt disease progression. While therapies for autoimmune disorders stop the progress of an immune response, immunomodulatory therapies for cancer and chronic infections can also provoke an unwanted immune response. As a result, there are now iatrogenic autoimmune disorders arising from the treatment of chronic viral infections and malignancies. PMID:20176260

Differential levels of Neurod establish zebrafish endocrine pancreas cell fates

PubMed Central

Dalgin, Gökhan; Prince, Victoria E.

2015-01-01

During development a network of transcription factors functions to differentiate foregut cells into pancreatic endocrine cells. Differentiation of appropriate numbers of each hormone-expressing endocrine cell type is essential for the normal development of the pancreas and ultimately for effective maintenance of blood glucose levels. A fuller understanding of the details of endocrine cell differentiation may contribute to development of cell replacement therapies to treat diabetes. In this study, by using morpholino and gRNA/Cas9 mediated knockdown we establish that differential levels of the basic-helix loop helix (bHLH) transcription factor Neurod are required for the differentiation of distinct endocrine cell types in developing zebrafish. While Neurod plays a role in the differentiation of all endocrine cells, we find that differentiation of glucagon-expressing alpha cells is disrupted by a minor reduction in Neurod levels, whereas differentiation of insulin-expressing beta cells is less sensitive to Neurod depletion. The endocrine cells that arise during embryonic stages to produce the primary islet, and those that arise subsequently during larval stages from the intra-pancreatic duct (IPD) to ultimately contribute to the secondary islets, show similar dependence on differential Neurod levels. Intriguingly, Neurod-deficiency triggers premature formation of endocrine precursors from the IPD during early larval stages. However, the Neurod-deficient endocrine precursors fail to differentiate appropriately, and the larvae are unable to maintain normal glucose levels. In summary, differential levels of Neurod are required to generate endocrine pancreas subtypes from precursors during both embryonic and larval stages, and Neurod function is in turn critical to endocrine function. PMID:25797153

5-year follow-up of a randomized controlled trial of immediate versus delayed zoledronic acid for the prevention of bone loss in postmenopausal women with breast cancer starting letrozole after tamoxifen: N03CC (Alliance) trial.

PubMed

Wagner-Johnston, Nina D; Sloan, Jeff A; Liu, Heshan; Kearns, Ann E; Hines, Stephanie L; Puttabasavaiah, Suneetha; Dakhil, Shaker R; Lafky, Jacqueline M; Perez, Edith A; Loprinzi, Charles L

2015-08-01

Postmenopausal women with breast cancer receiving aromatase inhibitors are at an increased risk of bone loss. The current study was undertaken to determine whether upfront versus delayed treatment with zoledronic acid (ZA) impacted bone loss. This report described the 5-year follow-up results. A total of 551 postmenopausal women with breast cancer who completed tamoxifen treatment and were undergoing daily letrozole treatment were randomized to either upfront (274 patients) or delayed (277 patients) ZA at a dose of 4 mg intravenously every 6 months. In the patients on the delayed treatment arm, ZA was initiated for a postbaseline bone mineral density T-score of <-2.0 or fracture. The incidence of a 5% decrease in the total lumbar spine bone mineral density at 5 years was 10.2% in the upfront treatment arm versus 41.2% in the delayed treatment arm (P<.0001). A total of 41 patients in the delayed treatment arm were eventually started on ZA. With the exception of increased NCI Common Toxicity Criteria (CTC) grade 1/2 elevated creatinine and fever in the patients treated on the upfront arm and cerebrovascular ischemia among those in the delayed treatment arm, there were no significant differences observed between arms with respect to the most common adverse events of arthralgia and back pain. Osteoporosis occurred less frequently in the upfront treatment arm (2 vs 8 cumulative cases), although this difference was not found to be statistically significant. Bone fractures occurred in 24 patients in the upfront treatment arm versus 25 patients in the delayed treatment arm. Immediate treatment with ZA prevented bone loss compared with delayed treatment in postmenopausal women receiving letrozole and these differences were maintained at 5 years. The incidence of osteoporosis or fractures was not found to be significantly different between treatment arms. © 2015 American Cancer Society.

[Current Status of Targeted Treatment in Breast Cancer].

PubMed

Seiffert, Katharina; Schmalfeldt, Barbara; Müller, Volkmar

2017-11-01

Within the last years, significant improvements have been achieved in breast cancer treatment, particularly with the development of targeted therapies. Major progress has been made in identifying the drivers malignant growth in oestrogen-receptor-positive breast cancer and the mechanisms of resistance to endocrine therapy. This progress has translated into several targeted therapies that enhance the efficacy of endocrine therapy; inhibitors of the cyclin-dependent kinases CDK4 and CDK6 like palbociclib and inhibitors of mTOR substantially improve progression-free survival. For patients with HER2-positive disease the addition of Pertuzumab to Trastuzumab in combination with chemotherapy has been a significant improvement in anti-HER2 therapy in early as well as metastatic breast cancer. Evidence-based further line therapy options in the metastatic setting include T-DM1 and in later lines Lapatinib. For triple negative disease the angiogenesis inhibitor Bevacizumab is approved, which increases progression free survival. Immune checkpoint inhibitors, PARP-inhibitors or anti-androgens represent promising strategies, all of which are currently being evaluated in clinical trials. The development of predictive biomarkers to guide targeted therapies is still the subject of research. © Georg Thieme Verlag KG Stuttgart · New York.

The role of stem-cell transplantation in the treatment of marginal zone lymphoma.

PubMed

Shimoni, Avichai

High-dose chemotherapy and autologous stem-cell transplantation (ASCT) is standard therapy in relapsed/refractory aggressive lymphoma. The optimal therapy of relapsed/refractory disseminated marginal-zone lymphoma (MZL) has not been defined. Limited data on ASCT in this setting suggests outcomes are similar to what is expected in follicular lymphoma. International guidelines suggest that ASCT should be considered in follicular lymphoma in second or subsequent remission, in particular in high-risk disease, or following disease transformation. These guidelines can be extrapolated to MZL. ASCT is not considered curative but a subset of patients achieve very long remissions. The major concern is the occurrence of secondary malignancies possibly related to total-body irradiation. Allogeneic SCT is usually considered after failure of ASCT, but can also be considered upfront in younger patients seeking curative approach. The introduction of novel/targeted therapies may change the role and timing SCT may have in the treatment algorithm of indolent lymphomas. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effect of first-line endocrine therapy in patients with hormone-sensitive advanced breast cancer: a network meta-analysis.

PubMed

Zhang, Tingting; Feng, Fubin; Zhao, Wenge; Tian, Jinhui; Yao, Yan; Zhou, Chao; Dong, Shengjie; Wang, Congcong; Zang, Chuanxin; Lv, Qingliang; Sun, Changgang

2018-01-01

Endocrine therapy is the cornerstone treatment for patients with hormone receptor-positive advanced breast cancer. We aimed to assess the effectiveness of various first-line endocrine monotherapies or combinations to determine the optimal sequence in a network meta-analysis. We searched PubMed, EMBASE, and the Cochrane Library for randomized controlled trials (RCTs) from inception up to November 21, 2017. We included only RCTs that assessed the effectiveness of the following treatments as a monotherapy or in combination as the first-line treatment: tamoxifen, anastrozole, letrozole, exemestane, fulvestrant, palbociclib, and ribociclib. The results were presented with pooled odds ratio or hazard ratio (HR), and 95% credible interval (CrI). The primary outcomes were objective response rate (ORR) and progression-free survival/time to progression. A total of 16 eligible articles (14 RCTs) involving 6,602 patients treated with 10 different first-line endocrine therapies were assessed in our network meta-analysis. Palbociclib plus letrozole was superior to anastrozole, letrozole, exemestane, fulvestrant 500 mg, and anastrozole plus fulvestrant (loading dose) (HR=0.44, 95% CrI: 0.33-0.58; HR=0.56, 95% CrI: 0.45-0.68; HR=0.45, 95% CrI: 0.32-0.61; HR=0.58, 95% CrI: 0.42-0.81; HR=0.50, 95% CrI: 0.37-0.68; respectively). However, there is no significant advantage compared with ribociclib plus letrozole (HR=1.00, 95% CrI: 0.72-1.39). In terms of ORR, ribociclib plus letrozole is more effective than palbociclib plus letrozole (odds ratio=1.30, 95% CrI: 0.83-2.02). Palbociclib plus letrozole and ribociclib plus letrozole might be the optimal first-line endocrine therapeutic choices for hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer due to a longer progression-free survival/time to progression and a more efficacious ORR.

TALEN-engineered AR gene rearrangements reveal endocrine uncoupling of androgen receptor in prostate cancer

PubMed Central

Nyquist, Michael D.; Li, Yingming; Hwang, Tae Hyun; Manlove, Luke S.; Vessella, Robert L.; Silverstein, Kevin A. T.; Voytas, Daniel F.; Dehm, Scott M.

2013-01-01

Androgen receptor (AR) target genes direct development and survival of the prostate epithelial lineage, including prostate cancer (PCa). Thus, endocrine therapies that inhibit the AR ligand-binding domain (LBD) are effective in treating PCa. AR transcriptional reactivation is central to resistance, as evidenced by the efficacy of AR retargeting in castration-resistant PCa (CRPC) with next-generation endocrine therapies abiraterone and enzalutamide. However, resistance to abiraterone and enzalutamide limits this efficacy in most men, and PCa remains the second-leading cause of male cancer deaths. Here we show that AR gene rearrangements in CRPC tissues underlie a completely androgen-independent, yet AR-dependent, resistance mechanism. We discovered intragenic AR gene rearrangements in CRPC tissues, which we modeled using transcription activator-like effector nuclease (TALEN)-mediated genome engineering. This modeling revealed that these AR gene rearrangements blocked full-length AR synthesis, but promoted expression of truncated AR variant proteins lacking the AR ligand-binding domain. Furthermore, these AR variant proteins maintained the constitutive activity of the AR transcriptional program and a CRPC growth phenotype independent of full-length AR or androgens. These findings demonstrate that AR gene rearrangements are a unique resistance mechanism by which AR transcriptional activity can be uncoupled from endocrine regulation in CRPC. PMID:24101480

First-line treatment disruption among post-menopausal women with HR+/HER2- metastatic breast cancer: a retrospective US claims study.

PubMed

Tang, Derek H; Li, Nanxin; Du, Ella X; Peeples, Miranda; Chu, Lihao; Xie, Jipan; Barghout, Victoria

2017-12-01

This study assessed disruption of first-line treatments initiated after the approval of the first CDK 4/6 inhibitor, palbociclib, among post-menopausal women with HR+/HER2- metastatic breast cancer (mBC) in the US. Post-menopausal women with HR+/HER2- mBC who initiated first-line endocrine therapy or chemotherapy (index therapy) between February 3, 2015 (palbociclib approval date) and February 29, 2016 (end of data) were identified from the Symphony Source Lx database. Patients were required to have continuous quarterly activity (defined as ≥1 pharmacy or medical claim) for 12 months prior to and 1 month after the initiation of the index therapy (index date). Treatment disruption was defined as a treatment gap of ≥60 days or adding an agent after the original therapy. Kaplan-Meier analyses were conducted to estimate treatment disruption rates during the 6 months following the index date. Patients without treatment disruption were censored at the end of continuous quarterly activity or end of data. A total of 8,160 and 2,153 eligible patients initiated endocrine therapy or chemotherapy as their first-line mBC treatment, with a median follow-up of 6.7 and 7.6 months, respectively. The three most prevalent metastatic sites were bone (28.1-42.2%), liver (8.8-17.3%), and lung (8.6-9.5%). Overall, 37.7% (n = 3,074) of patients receiving endocrine therapy and 86.1% (n = 1,852) of patients receiving chemotherapy encountered treatment disruption at 6 months (log-rank test p < .05). Treatment disruption rates of first-line therapies were sub-optimal among post-menopausal women with HR+/HER2- mBC, primarily driven by chemotherapy users. New therapies or interventions are needed to reduce treatment disruption in this patient population.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Smith, Grace L.; Department of Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, Texas; Huo, Jinhai

Purpose: To directly compare (1) radiation treatment utilization patterns; (2) risks of subsequent mastectomy; and (3) costs of radiation treatment in patients treated with brachytherapy versus whole-breast irradiation (WBI), in a national, contemporary cohort of women with incident breast cancer, aged 64 years and younger. Methods and Materials: Using MarketScan health care claims data, we identified 45,884 invasive breast cancer patients (aged 18-64 years), treated from 2003 to 2010 with lumpectomy, followed by brachytherapy (n=3134) or whole-breast irradiation (n=42,750). We stratified patients into risk groups according to age (Age<50 vs Age≥50) and endocrine therapy status (Endocrine− vs Endocrine+). “Endocrine+” patients filled an endocrinemore » therapy prescription within 1 year after lumpectomy. Pathologic hormone receptor status was not available in this dataset. In brachytherapy versus WBI patients, utilization trends and 5-year subsequent mastectomy risks were compared. Stratified, adjusted subsequent mastectomy risks were calculated using proportional hazards regression. Results: Brachytherapy utilization increased from 2003 to 2010: in patients Age<50, from 0.6% to 4.9%; patients Age≥50 from 2.2% to 11.3%; Endocrine− patients, 1.3% to 9.4%; Endocrine+ patients, 1.9% to 9.7%. Age influenced treatment selection more than endocrine status: 17% of brachytherapy patients were Age<50 versus 32% of WBI patients (P<.001); whereas 41% of brachytherapy patients were Endocrine–versus 44% of WBI patients (P=.003). Highest absolute 5-year subsequent mastectomy risks occurred in Endocrine−/Age<50 patients (24.4% after brachytherapy vs 9.0% after WBI (hazard ratio [HR] 2.18, 95% confidence interval [CI] 1.37-3.47); intermediate risks in Endocrine−/Age≥50 patients (8.6% vs 4.9%; HR 1.76, 95% CI 1.26-2.46); and lowest risks in Endocrine+ patients of any age: Endocrine+/Age<50 (5.5% vs 4.5%; HR 1.18, 95% CI 0.61-2.31); Endocrine+/Age≥50 (4.2% vs 2.4%; HR 1.71, 95% CI 1.16-2.51). Conclusion: In this younger cohort, endocrine status was a valuable discriminatory factor predicting subsequent mastectomy risk after brachytherapy versus WBI and therefore may be useful for selecting appropriate younger brachytherapy candidates.« less

Decision-making in the management of adult classical Hodgkin's lymphoma: determining the optimal treatment.

PubMed

Mounier, Nicolas; Nicolas, Mounier; Gisselbrecht, Christian; Christian, Gisselbrecht

2015-04-01

This review discusses promising new approaches in classical Hodgkin's lymphoma that have been recently evaluated. There is a focus on the fluorodeoxyglucose PET scanning that is now considered crucial for staging and treatment evaluation, including interim evaluation after two cycles. An up-front treatment strategy is discussed, with the place of radiation therapy and the difficult choice of chemotherapy intensity emphasized. Indications for frail patients are also reviewed, particularly elderly or HIV-positive patients. Emerging data on the antibody drug conjugate brentuximab vedotin and its future potential in the transplantation framework for relapsed/refractory Hodgkin's lymphoma is also discussed.

Meeting highlights--International Consensus Panel on the treatment of primary breast cancer.

PubMed

Taguchi, Tetsuo

2002-03-01

The 7th International Conference on Adjuvant Therapy of Primary Breast Cancer, with several thousand delegates from 70 countries, was held in February 2001 in St. Gallen, Switzerland. Its consensus recommendations were summarized in the Sept. 15 issue of the Journal of Clinical Oncology (Vol. 19, No. 18, 2001: pp 3817-3827). The panel conference developed guidelines advising that all patients with endocrine-responsive tumors receive anti-hormonal therapy, including those at minimal risk of recurrence (defined as a 10% risk at 10 years). The panel further lowered the threshold defining endocrine-responsive disease to tumors containing as few as 1% of cells that stain positive for steroid hormone receptors. Treatment of primary breast cancer should depend on the hormonal status of tumors. The last set of guidelines, issued in 1998, supported a more limited use of endocrine-based therapy, but recent research has convinced the oncology community otherwise. Postmenopausal women have the greatest prevalence of hormone-positive tumors, and more than one-third of breast cancers in women of child-bearing age are estrogen dependent. The panel also highlighted several other important advances, including: the importance of factoring patient preferences into treatment decisions; the value of sentinel lymph node biopsy in avoiding extensive surgery; and incorporation of new agents and improved outcome in the treatment of breast cancer.

Initial incomplete surgery modifies prognosis in advanced ovarian cancer regardless of subsequent management.

PubMed

Bacalbasa, Nicolae; Balescu, Irina; Dima, Simona; Herlea, Vlad; David, Leonard; Brasoveanu, Vladislav; Popescu, Irinel

2015-04-01

Prognosis in ovarian cancer is determined by completeness of cytoreduction and proper management by specialized oncological gynecologists. Incomplete initial debulking surgery in non-specialized Centers is, however, a reality and there is ongoing discussion about the best subsequent management of such patients. Patients with advanced ovarian cancer (International Federation of Gynecology and Obstetrics--FIGO FIGO stages IIIC-IV) who had biopsy by laparotomy or incomplete cytoreduction followed or not by chemotherapy further referred to our Institution between January 2002 and May 2014 were included. The two groups of incomplete cytoreduction [followed by upfront surgery or followed by chemotherapy and interval debulking surgery (IDS)] were compared and also compared against a cohort of 197 patients with similar characteristics who underwent upfront maximal surgery according to the standard at our Iinstitution during the same period. A total of 99 eligible patients were identified. Sixty-seven of them underwent biopsies by laparotomy and 32 underwent incomplete cytoreduction in other institutions. Twenty-eight patients underwent direct re-operation while 71 patients underwent neoadjuvant chemotherapy followed by IDS. The mean overall survival duration for patients with upfront reoperation was 31 months and 54 months for patients with neoadjuvant chemotherapy and IDS, considerably lower than the 72 months obtained for the group of 197 patients with maximal up-front complete cytoreduction at our Institution. Primary biopsy or incomplete cytoreduction reduces survival regardless of the subsequent approach. However, if incomplete cytoreduction has occurred, neoadjuvant chemotherapy followed by IDS is preferable to up-front reoperation. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Uncertainties in endocrine substitution therapy for central endocrine insufficiencies: hypothyroidism.

PubMed

Persani, Luca; Bonomi, Marco

2014-01-01

In patients with primary hypothyroidism (PH), L-T4 replacement therapy can safely be adjusted to the individual needs by testing serum thyrotropin (TSH) concentration exclusively. Central hypothyrodism (CeH) is a particular hypothyroid condition due to an insufficient stimulation by TSH of an otherwise normal thyroid gland. CeH is about 1000-fold rarer than PH and raises several challenges for clinicians, mainly because they cannot rely on the systematic use of the reflex TSH strategy for diagnosis or therapy monitoring. Therefore, L-T4 replacement in CeH should rely on the combined evaluation of several biochemical and clinical parameters in order to overcome the lack of accuracy of the single index. The management of CeH replacement is further complicated by the frequent combination with other pituitary deficiencies and their treatment. © 2014 Elsevier B.V. All rights reserved.

Atrophic Vaginitis in Breast Cancer Survivors: A Difficult Survivorship Issue

PubMed Central

Lester, Joanne; Pahouja, Gaurav; Andersen, Barbara; Lustberg, Maryam

2015-01-01

Management of breast cancer includes systematic therapies including chemotherapy and endocrine therapy can lead to a variety of symptoms that can impair the quality of life of many breast cancer survivors. Atrophic vaginitis, caused by decreased levels of circulating estrogen to urinary and vaginal receptors, is commonly experienced by this group. Chemotherapy induced ovarian failure and endocrine therapies including aromatase inhibitors and selective estrogen receptor modulators can trigger the onset of atrophic vaginitis or exacerbate existing symptoms. Symptoms of atrophic vaginitis include vaginal dryness, dyspareunia, and irritation of genital skin, pruritus, burning, vaginal discharge, and soreness. The diagnosis of atrophic vaginitis is confirmed through patient-reported symptoms and gynecological examination of external structures, introitus, and vaginal mucosa. Lifestyle modifications can be helpful but are usually insufficient to significantly improve symptoms. Non-hormonal vaginal therapies may provide additional relief by increasing vaginal moisture and fluid. Systemic estrogen therapy is contraindicated in breast cancer survivors. Continued investigations of various treatments for atrophic vaginitis are necessary. Local estrogen-based therapies, DHEA, testosterone, and pH-balanced gels continue to be evaluated in ongoing studies. Definitive results are needed pertaining to the safety of topical estrogens in breast cancer survivors. PMID:25815692

Atrophic vaginitis in breast cancer survivors: a difficult survivorship issue.

PubMed

Lester, Joanne; Pahouja, Gaurav; Andersen, Barbara; Lustberg, Maryam

2015-03-25

Management of breast cancer includes systematic therapies including chemotherapy and endocrine therapy can lead to a variety of symptoms that can impair the quality of life of many breast cancer survivors. Atrophic vaginitis, caused by decreased levels of circulating estrogen to urinary and vaginal receptors, is commonly experienced by this group. Chemotherapy induced ovarian failure and endocrine therapies including aromatase inhibitors and selective estrogen receptor modulators can trigger the onset of atrophic vaginitis or exacerbate existing symptoms. Symptoms of atrophic vaginitis include vaginal dryness, dyspareunia, and irritation of genital skin, pruritus, burning, vaginal discharge, and soreness. The diagnosis of atrophic vaginitis is confirmed through patient-reported symptoms and gynecological examination of external structures, introitus, and vaginal mucosa. Lifestyle modifications can be helpful but are usually insufficient to significantly improve symptoms. Non-hormonal vaginal therapies may provide additional relief by increasing vaginal moisture and fluid. Systemic estrogen therapy is contraindicated in breast cancer survivors. Continued investigations of various treatments for atrophic vaginitis are necessary. Local estrogen-based therapies, DHEA, testosterone, and pH-balanced gels continue to be evaluated in ongoing studies. Definitive results are needed pertaining to the safety of topical estrogens in breast cancer survivors.

Palbociclib as single agent or in combination with the endocrine therapy received before disease progression for estrogen receptor-positive, HER2-negative metastatic breast cancer: TREnd trial.

PubMed

Malorni, L; Curigliano, G; Minisini, A M; Cinieri, S; Tondini, C A; D'Hollander, K; Arpino, G; Bernardo, A; Martignetti, A; Criscitiello, C; Puglisi, F; Pestrin, M; Sanna, G; Moretti, E; Risi, E; Biagioni, C; McCartney, A; Boni, L; Buyse, M; Migliaccio, I; Biganzoli, L; Di Leo, A

2018-06-11

The activity of palbociclib as a single agent in advanced breast cancer has not been extensively studied, with the only available clinical data limited to heavily pre-treated patients. Pre-clinical data suggests palbociclib may partially reverse endocrine resistance, though this hypothesis has not been evaluated in previous clinical studies. This phase II, open-label, multi-center study examined the activity of palbociclib monotherapy, as well as palbociclib given in combination with the same endocrine therapy (ET) that was received prior to disease progression, in post-menopausal women with moderately pre-treated, estrogen receptor-positive, HER2 negative advanced breast cancer. Eligible women with advanced disease which had progressed on one or two prior ETs were randomized 1:1 to receive either palbociclib alone, or palbociclib in combination with the ET as previously received. Primary endpoint was clinical benefit rate (CBR); secondary endpoints included progression-free survival (PFS). Between October 2012 and July 2016, a total of 115 patients were randomized. The CBR was 54% (95% CI 41.5 - 63.7) for combination therapy, and 60% (95% CI 47.8 - 72.9) for monotherapy. Median PFS was 10.8 months (95% CI 5.6 - 12.7) for combination therapy, and 6.5 months (95% CI, 5.4 to 8.5) for monotherapy (hazard ratio [HR] 0.69; 95% CI 0.4 - 1.1, exploratory P-value = 0.12). Exploratory analyses revealed the PFS advantage for combination therapy was seen in the subgroup of patients who received prior ET for >6 months (HR 0.53; 95% CI 0.3 - 0.9, exploratory P-value = 0.02), but not in those who received prior ET for ≤6 months. Palbociclib has clinical activity as a single agent in women with moderately pre-treated, oestrogen receptor-positive, HER2-negative advanced breast cancer. Palbociclib may have potential to reverse endocrine resistance in patients with a history of previous durable response to ET. NCT02549430.

Opioid-induced hypogonadism: why and how to treat it.

PubMed

De Maddalena, Chiara; Bellini, Martina; Berra, Marta; Meriggiola, Maria Cristina; Aloisi, Anna Maria

2012-07-01

Gonadal hormones are critical factors in modulating the experience of pain, as suggested by the several sex differences observed: women have a greater risk of many clinical pain conditions, and postoperative and procedural pain may be more severe in them than in men. A growing body of literature demonstrates the role of estrogen in the female pain experience, whereas less attention has been given to testosterone and its functions. Nevertheless, testosterone has an appreciable role in both women and men: adequate serum levels are required in males and females for libido and sexuality; cellular growth; maintenance of muscle mass and bone; healing; blood-brain barrier; and for central nervous system maintenance. Pain therapy, and particularly opioid therapy, has been shown to affect testosterone plasma levels. Thus, the chronic administration of pain killers, such as opioids, requires the physician to be aware of both the consequences that can develop due to long-term testosterone impairment and the available means to restore and maintain physiological testosterone levels. The objective is to highlight to pain physicians that the endocrine changes occurring during chronic pain therapy can participate in the body dysfunctions often present in chronic pain patients and that there are possible hormone replacement methods that can be carried out in men and women to improve their quality of life. A comprehensive review of the literature. A comprehensive review of the literature relating to opioid-induced hypogonadism, as well as other very common forms of hypogonadism, its endocrine effects, and possible therapeutic actions. The literature was collected from electronic and other sources. The reviewed literature included observational studies, case reports, systematic reviews, and guidelines. Evaluation of the endocrine changes described in chronic pain therapy was the primary outcome measure. The secondary outcome measures were functional improvement and adverse effects of hormone replacement. The results of the survey clearly show that sex hormone determination is very rare in pain centers. Given the complexity and widespread nature of pain therapy, there is a paucity of qualitative and quantitative literature regarding its endocrine consequences. The available evidence is weak for pain relief, but is consistent for many collateral effects, possibly deriving from pain therapy, such as fatigue, depression, and neurodegenerative diseases. This is a narrative review without application of methodological quality assessment criteria. Even so, there is a paucity of literature concerning both controlled and observational literature for the endocrine effects of most analgesic drugs. Testosterone replacement suffers from old prejudices about its utility and safety. With this review we illustrate the available therapeutic choices able to maintain T concentration into physiological ranges and reduce nociception with a final goal of improving patients' quality of life.

A Review of Autologous Stem Cell Transplantation in Lymphoma.

PubMed

Zahid, Umar; Akbar, Faisal; Amaraneni, Akshay; Husnain, Muhammad; Chan, Onyee; Riaz, Irbaz Bin; McBride, Ali; Iftikhar, Ahmad; Anwer, Faiz

2017-06-01

Chemotherapy remains the first-line therapy for aggressive lymphomas. However, 20-30% of patients with non-Hodgkin lymphoma (NHL) and 15% with Hodgkin lymphoma (HL) recur after initial therapy. We want to explore the role of high-dose chemotherapy (HDT) and autologous stem cell transplant (ASCT) for these patients. There is some utility of upfront consolidation for-high risk/high-grade B-cell lymphoma, mantle cell lymphoma, and T-cell lymphoma, but there is no role of similar intervention for HL. New conditioning regimens are being investigated which have demonstrated an improved safety profile without compromising the myeloablative efficiency for relapsed or refractory HL. Salvage chemotherapy followed by HDT and rescue autologous stem cell transplant remains the standard of care for relapsed/refractory lymphoma. The role of novel agents to improve disease-related parameters remains to be elucidated in frontline induction, disease salvage, and high-dose consolidation or in the maintenance setting.

Computational prediction of multidisciplinary team decision-making for adjuvant breast cancer drug therapies: a machine learning approach.

PubMed

Lin, Frank P Y; Pokorny, Adrian; Teng, Christina; Dear, Rachel; Epstein, Richard J

2016-12-01

Multidisciplinary team (MDT) meetings are used to optimise expert decision-making about treatment options, but such expertise is not digitally transferable between centres. To help standardise medical decision-making, we developed a machine learning model designed to predict MDT decisions about adjuvant breast cancer treatments. We analysed MDT decisions regarding adjuvant systemic therapy for 1065 breast cancer cases over eight years. Machine learning classifiers with and without bootstrap aggregation were correlated with MDT decisions (recommended, not recommended, or discussable) regarding adjuvant cytotoxic, endocrine and biologic/targeted therapies, then tested for predictability using stratified ten-fold cross-validations. The predictions so derived were duly compared with those based on published (ESMO and NCCN) cancer guidelines. Machine learning more accurately predicted adjuvant chemotherapy MDT decisions than did simple application of guidelines. No differences were found between MDT- vs. ESMO/NCCN- based decisions to prescribe either adjuvant endocrine (97%, p = 0.44/0.74) or biologic/targeted therapies (98%, p = 0.82/0.59). In contrast, significant discrepancies were evident between MDT- and guideline-based decisions to prescribe chemotherapy (87%, p < 0.01, representing 43% and 53% variations from ESMO/NCCN guidelines, respectively). Using ten-fold cross-validation, the best classifiers achieved areas under the receiver operating characteristic curve (AUC) of 0.940 for chemotherapy (95% C.I., 0.922-0.958), 0.899 for the endocrine therapy (95% C.I., 0.880-0.918), and 0.977 for trastuzumab therapy (95% C.I., 0.955-0.999) respectively. Overall, bootstrap aggregated classifiers performed better among all evaluated machine learning models. A machine learning approach based on clinicopathologic characteristics can predict MDT decisions about adjuvant breast cancer drug therapies. The discrepancy between MDT- and guideline-based decisions regarding adjuvant chemotherapy implies that certain non-clincopathologic criteria, such as patient preference and resource availability, are factored into clinical decision-making by local experts but not captured by guidelines.

Specifying pancreatic endocrine cell fates.

PubMed

Collombat, Patrick; Hecksher-Sørensen, Jacob; Serup, Palle; Mansouri, Ahmed

2006-07-01

Cell replacement therapy could represent an attractive alternative to insulin injections for the treatment of diabetes. However, this approach requires a thorough understanding of the molecular switches controlling the specification of the different pancreatic cell-types in vivo. These are derived from an apparently identical pool of cells originating from the early gut endoderm, which are successively specified towards the pancreatic, endocrine, and hormone-expressing cell lineages. Numerous studies have outlined the crucial roles exerted by transcription factors in promoting the cell destiny, defining the cell identity and maintaining a particular cell fate. This review focuses on the mechanisms regulating the morphogenesis of the pancreas with particular emphasis on recent findings concerning the transcription factor hierarchy orchestrating endocrine cell fate allocation.

Role of epigenetic modifications in luminal breast cancer

PubMed Central

Abdel-Hafiz, Hany A; Horwitz, Kathryn B

2015-01-01

Luminal breast cancers represent approximately 75% of cases. Explanations into the causes of endocrine resistance are complex and are generally ascribed to genomic mechanisms. Recently, attention has been drawn to the role of epigenetic modifications in hormone resistance. We review these here. Epigenetic modifications are reversible, heritable and include changes in DNA methylation patterns, modification of histones and altered microRNA expression levels that target the receptors or their signaling pathways. Large-scale analyses indicate distinct epigenomic profiles that distinguish breast cancers from normal and benign tissues. Taking advantage of the reversibility of epigenetic modifications, drugs that target epigenetic modifiers, given in combination with chemotherapies or endocrine therapies, may represent promising approaches to restoration of therapy responsiveness in these cases. PMID:25689414

Aging of the endocrine system and its potential impact on sarcopenia.

PubMed

Vitale, Giovanni; Cesari, Matteo; Mari, Daniela

2016-11-01

Sarcopenia, occurring as a primary consequence of aging, is a progressive generalized decline of skeletal muscle mass, strength and function. The pathophysiology of sarcopenia is complex and multifactorial. One major cause of muscle mass and strength loss with aging appears to be the alteration in hormonal networks involved in the inflammatory processes, muscle regeneration and protein synthesis. This review describes the recent findings concerning the role of the aging on the endocrine system in the development of sarcopenia. We also report the benefits and safety of hormone replacement therapy in elderly subjects and discuss future perspectives in the therapy and prevention of skeletal muscle aging. Copyright © 2016 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Randomized Phase III Placebo-Controlled Trial of Letrozole Plus Oral Temsirolimus As First-Line Endocrine Therapy in Postmenopausal Women With Locally Advanced or Metastatic Breast Cancer

PubMed Central

Wolff, Antonio C.; Lazar, Ann A.; Bondarenko, Igor; Garin, August M.; Brincat, Stephen; Chow, Louis; Sun, Yan; Neskovic-Konstantinovic, Zora; Guimaraes, Rodrigo C.; Fumoleau, Pierre; Chan, Arlene; Hachemi, Soulef; Strahs, Andrew; Cincotta, Maria; Berkenblit, Anna; Krygowski, Mizue; Kang, Lih Lisa; Moore, Laurence; Hayes, Daniel F.

2013-01-01

Purpose Recent data showed improvement in progression-free survival (PFS) when adding everolimus to exemestane in patients with advanced breast cancer experiencing recurrence/progression after nonsteroidal aromatase inhibitor (AI) therapy. Here, we report clinical outcomes of combining the mammalian target of rapamycin (mTOR) inhibitor temsirolimus with letrozole in AI-naive patients. Patients and Methods This phase III randomized placebo-controlled study tested efficacy/safety of first-line oral letrozole 2.5 mg daily/temsirolimus 30 mg daily (5 days every 2 weeks) versus letrozole/placebo in 1,112 patients with AI-naive, hormone receptor–positive advanced disease. An independent data monitoring committee recommended study termination for futility at the second preplanned interim analysis (382 PFS events). Results Patients were balanced (median age, 63 years; 10% stage III, 40% had received adjuvant endocrine therapy). Those on letrozole/temsirolimus experienced more grade 3 to 4 events (37% v 24%). There was no overall improvement in primary end point PFS (median, 9 months; hazard ratio [HR], 0.90; 95% CI, 0.76 to 1.07; P = .25) nor in the 40% patient subset with prior adjuvant endocrine therapy. An exploratory analysis showed improved PFS favoring letrozole/temsirolimus in patients ≤ age 65 years (9.0 v 5.6 months; HR, 0.75; 95% CI, 0.60 to 0.93; P = .009), which was separately examined by an exploratory analysis of 5-month PFS using subpopulation treatment effect pattern plot methodology (P = .003). Conclusion Adding temsirolimus to letrozole did not improve PFS as first-line therapy in patients with AI-naive advanced breast cancer. Exploratory analyses of benefit in younger postmenopausal patients require external confirmation. PMID:23233719

Bone health and adherence to vitamin D and calcium therapy in early breast cancer patients on endocrine therapy with aromatase inhibitors.

PubMed

Bošković, Lidija; Gašparić, Maja; Petković, Marija; Gugić, Damir; Lovasić, Ingrid Belac; Soldić, Željko; Miše, Branka Petrić; Dabelić, Nina; Vazdar, Ljubica; Vrdoljak, Eduard

2017-02-01

Randomized trials involving aromatase inhibitors (AIs) in the adjuvant treatment of breast cancer patients have reported increased osteoporosis risk. Bone loss can be reduced with appropriate life style, vitamin D and calcium supplements, and with bisphosphonate therapy. The aim of this analysis was to investigate adherence to vitamin D and calcium in postmenopausal breast cancer patients receiving adjuvant non-steroidal AIs, and oncologists' adherence to the bone health guidelines. This prospective study included 438 newly diagnosed patients and those who have already been receiving non-steroidal AIs for up to 3.5 years. Median endocrine therapy duration before recruitment in the study was 10.5 months (interquartile 4.8-26.6). Densitometry was performed on 142 patients (32.4%) before initiation of endocrine therapy, and on additional 38 (8.6%) patients at second study visit. Densitometry was not performed on 258 (59%) patients. Vitamin D and calcium were prescribed to 329/438 (75.1%) patients at some point during the study. Patients who took more than 80% of the prescribed dose were considered adherent. Self-reported adherence was 88.4%. Osteoporosis was diagnosed in 24 patients (5.5%) of the total study population, bearing in mind that 258/438 (59%) patients did not have densitometry. Bisphosphonates were prescribed to 54/438 (12.3%) patients, whilst only 19 (35.2%) of those had osteoporosis. In this analysis, lack of oncologists' adherence to the bone health guidelines was observed. In addition, a significant proportion of the patients did not adhere to the vitamin D and calcium. Copyright © 2016 Elsevier Ltd. All rights reserved.

Hypopituitarism in pediatric survivors of inflicted traumatic brain injury.

PubMed

Auble, Bethany A; Bollepalli, Sureka; Makoroff, Kathi; Weis, Tammy; Khoury, Jane; Colliers, Tracy; Rose, Susan R

2014-02-15

Endocrine dysfunction is common after accidental traumatic brain injury (TBI). Prevalence of endocrine dysfunction after inflicted traumatic brain injury (iTBI) is not known. The aim of this study was to examine endocrinopathy in children after moderate-to-severe iTBI. Children with previous iTBI (n=14) were evaluated for growth/endocrine dysfunction, including anthropometric measurements and hormonal evaluation (nocturnal growth hormone [GH], thyrotropin surge, morning and low-dose adrenocorticotropin stimulated cortisol, insulin-like growth factor 1, IGF-binding protein 3, free thyroxine, prolactin [PRL], and serum/urine osmolality). Analysis used Fisher's exact test and Wilcoxon's rank-sum test, as appropriate. Eighty-six percent of subjects had endocrine dysfunction with at least one abnormality, whereas 50% had two or more abnormalities, significantly increased compared to an estimated 2.5% with endocrine abnormality in the general population (p<0.001). Elevated prolactin was common (64%), followed by abnormal thyroid function (33%), short stature (29%), and low GH peak (17%). High prolactin was common in subjects with other endocrine abnormalities. Two were treated with thyroid hormone and 2 may require GH therapy. In conclusion, children with a history of iTBI show high risk for endocrine dysfunction, including elevated PRL and growth abnormalities. This effect of iTBI has not been well described in the literature. Larger, multi-center, prospective studies would provide more data to determine the extent of endocrine dysfunction in iTBI. We recommend that any child with a history of iTBI be followed closely for growth velocity and pubertal changes. If growth velocity is slow, PRL level and a full endocrine evaluation should be performed.

Upfront immunohistochemistry improves specificity of Helicobacter pylori diagnosis. A French pathology laboratory point of view.

PubMed

Ginestet, Florent; Guibourg, Briac; Doucet, Laurent; Théreaux, Jérémie; Robaszkiewicz, Michel; Marcorelles, Pascale; Uguen, Arnaud

2017-10-01

There is no consensus about the histopathologic methods to detect Helicobacter pylori in gastric biopsies to date. We aimed to question about the value of upfront anti-H. pylori immunohistochemistry in this field. We led a retrospective study about the rate of H. pylori-positive gastric biopsies before and after the implementation of upfront immunohistochemistry, the inter-rater and intermethods agreements in H. pylori identification about Hematoxylin-Eosin Saffron (HES), Giemsa, and immunohistochemistry stains and the histopathologic features associated with low amounts of H. pylori. First, the rate of H. pylori-positive gastric biopsies significantly diminished after the implementation of upfront immunohistochemistry (from 21.15% to 12.56%, P<.0001), suggesting potential overdiagnosis of H. pylori infection before the use of immunohistochemistry. Secondly, immunohistochemistry was the most reproducible and performing stain (kappa values >0.80), but HES and Giemsa stains also presented good-to-very good agreements. Finally, less than 1% of gastric biopsies with inconspicuous H. pylori infection showed no mucosal injury pointing out that any HES-detected mucosal injury could help to preselect the gastric biopsies requiring ancillary stains for the detection of H. pylori. Albeit being considered as a gold standard in the detection of H. pylori, the interest of using immunohistochemistry as an upfront stain on gastric biopsies is still debated. In our opinion, its use in second line in case of ambiguous HE/HES-Giemsa result is more appropriate. Further effort is needed to optimize the inexpensive but feasible HE/HES-based detection of H. pylori. © 2017 John Wiley & Sons Ltd.

Deferred radiotherapy and upfront procarbazine–ACNU–vincristine administration for 1p19q codeleted oligodendroglial tumors are associated with favorable outcome without compromising patient performance, regardless of WHO grade

PubMed Central

Hata, Nobuhiro; Yoshimoto, Koji; Hatae, Ryusuke; Kuga, Daisuke; Akagi, Yojiro; Suzuki, Satoshi O; Iwaki, Toru; Shono, Tadahisa; Mizoguchi, Masahiro; Iihara, Koji

2016-01-01

Recently updated phase III trials revealed the favorable effect of add-on procarbazine-lomustine-vincristine chemotherapy (CT) to radiotherapy (RT) in treating anaplastic oligodendrogliomas with 1p19q codeletion (codel). However, the underlying rationality of deferring RT and upfront CT administration for these tumors is yet to be elucidated. Here, we retrospectively analyzed the long-term outcome of our case series with oligodendroglial tumors treated with deferred RT and upfront procarbazine+nimustine+vincristine (PAV) in the introduction administration. We enrolled 36 patients with newly diagnosed oligodendroglial tumors (17, grade II and 19, grade III) treated during 1999–2012 and followed up for a median period of 69.0 months. Their clinical and genetic prognostic factors were analyzed, and progression-free survival, overall survival (OS), and deterioration-free survival (DFS) were evaluated. Regardless of the WHO grade, the 25 patients with 1p19q codel tumors never received RT initially, and of these 25, 23 received PAV treatment upfront. The 75% OS of patients with 1p19q codel tumor was 135.3 months (did not reach the median OS), indicating a favorable outcome. Multivariate analysis revealed that IDH mutation and 1p19q, not WHO grade, are independent prognostic factors; furthermore, IDH and 1p19q status stratified the cohort into 3 groups with significantly different OS. The DFS explained the prolonged survival without declining performance in patients with both grade II and III 1p19q codel tumors. Deferred RT and upfront PAV treatment for 1p19q codel oligodendrogliomas were associated with favorable outcomes without compromising performance status, regardless of WHO grade. PMID:27895504

Upfront boost Gamma Knife "leading-edge" radiosurgery to FLAIR MRI-defined tumor migration pathways in 174 patients with glioblastoma multiforme: a 15-year assessment of a novel therapy.

PubMed

Duma, Christopher M; Kim, Brian S; Chen, Peter V; Plunkett, Marianne E; Mackintosh, Ralph; Mathews, Marlon S; Casserly, Ryan M; Mendez, Gustavo A; Furman, Daniel J; Smith, Garrett; Oh, Nathan; Caraway, Chad A; Sanathara, Ami R; Dillman, Robert O; Riley, Azzurra-Sky; Weiland, David; Stemler, Lian; Cannell, Ruslana; Abrams, Daniela Alexandru; Smith, Alexa; Owen, Christopher M; Eisenberg, Burton; Brant-Zawadzki, Michael

2016-12-01

OBJECTIVE Glioblastoma multiforme (GBM) is composed of cells that migrate through the brain along predictable white matter pathways. Targeting white matter pathways adjacent to, and leading away from, the original contrast-enhancing tumor site (termed leading-edge radiosurgery [LERS]) with single-fraction stereotactic radiosurgery as a boost to standard therapy could limit the spread of glioma cells and improve clinical outcomes. METHODS Between December 2000 and May 2016, after an initial diagnosis of GBM and prior to or during standard radiation therapy and carmustine or temozolomide chemotherapy, 174 patients treated with radiosurgery to the leading edge (LE) of tumor cell migration were reviewed. The LE was defined as a region outside the contrast-enhancing tumor nidus, defined by FLAIR MRI. The median age of patients was 59 years (range 22-87 years). Patients underwent LERS a median of 18 days from original diagnosis. The median target volume of 48.5 cm 3 (range 2.5-220.0 cm 3 ) of LE tissue was targeted using a median dose of 8 Gy (range 6-14 Gy) at the 50% isodose line. RESULTS The median overall survival was 23 months (mean 43 months) from diagnosis. The 2-, 3-, 5-, 7-, and 10-year actual overall survival rates after LERS were 39%, 26%, 16%, 10%, and 4%, respectively. Nine percent of patients developed treatment-related imaging-documented changes due to LERS. Nineteen percent of patients were hospitalized for management of edema, 22% for resection of a tumor cyst or new tumor bulk, and 2% for shunting to treat hydrocephalus throughout the course of their disease. Of the patients still alive, Karnofsky Performance Scale scores remained stable in 90% of patients and decreased by 1-3 grades in 10% due to symptomatic treatment-related imaging changes. CONCLUSIONS LERS is a safe and effective upfront adjunctive therapy for patients with newly diagnosed GBM. Limitations of this study include a single-center experience and single-institution determination of the LE tumor target. Use of a leading-edge calculation algorithm will be described to achieve a consistent approach to defining the LE target for general use. A multicenter trial will further elucidate its value in the treatment of GBM.

Screening for secondary endocrine hypertension in young patients.

PubMed

Trifanescu, Raluca; Carsote, Mara; Caragheorgheopol, Andra; Hortopan, Dan; Dumitrascu, Anda; Dobrescu, Mariana; Poiana, Catalina

2013-06-01

Secondary endocrine hypertension accounts for 5-12% of hypertension's causes. In selected patients (type 2 diabetes mellitus, sleep apnea syndrome with resistant hypertension, sudden deterioration in hypertension control), prevalence could be higher. To present etiology of endocrine secondary hypertension in a series of patients younger than 40 years at hypertension's onset. Medical records of 80 patients (39M/41F), aged 30.1 ± 8.2 years (range: 12-40 years), with maximum systolic blood pressure=190.4 ± 29.2 mm Hg, range: 145-300 mm Hg, maximum diastolic blood pressure=107.7 ± 16.9 mm Hg, range: 80-170 mm Hg) referred by cardiologists for endocrine hypertension screening were retrospectively reviewed. Cardiac and renal causes of secondary hypertension were previously excluded. In all patients, plasma catecholamines were measured by ELISA and plasma cortisol by immunochemiluminescence. Orthostatic aldosterone (ELISA) and direct renin (chemiluminescence) were measured in 48 patients. Secondary endocrine hypertension was confirmed in 16 out of 80 patients (20%). Primary hyperaldosteronism was diagnosed in 7 (4M/3F) out of 48 screened patients (14.6%). i.e. 8.75% from whole group: 5 patients with adrenal tumors (3 left/2 right), 2 patients with bilateral adrenal hyperplasia; all patients were hypokalemic at diagnostic (average nadir K+ levels = 2.5 ± 0.5 mmol/L); four patients were hypokalaemic on diuretic therapy (indapamidum); other 3 patients were hypokalaemic in the absence of diuretic therapy. Cushing's syndrome was diagnosed in 6 patients (7.5%): subclinical Cushing due to 4 cm right adrenal tumour - n = 1, overt ACTH-independent Cushing's syndrome due to: macronodular adrenal hyperplasia associated with primary hyperparathyroidism - n = 1; due to adrenal carcinoma - n = 1; due to adrenal adenomas - n = 2; Cushing's disease - n = 1). Pheochromocytomas were diagnosed in 3 patients (3.75%). Primary hyperaldosteronism was the most frequent cause of secondary endocrine hypertension in our series, followed by Cushing's syndrome and pheochromocytomas. Screening of young hypertensive patients for secondary causes, especially primary hyperaldosteronism, is mandatory.

Upfront Genotyping of DPYD*2A to Individualize Fluoropyrimidine Therapy: A Safety and Cost Analysis.

PubMed

Deenen, Maarten J; Meulendijks, Didier; Cats, Annemieke; Sechterberger, Marjolein K; Severens, Johan L; Boot, Henk; Smits, Paul H; Rosing, Hilde; Mandigers, Caroline M P W; Soesan, Marcel; Beijnen, Jos H; Schellens, Jan H M

2016-01-20

Fluoropyrimidines are frequently prescribed anticancer drugs. A polymorphism in the fluoropyrimidine metabolizing enzyme dihydropyrimidine dehydrogenase (DPD; ie, DPYD*2A) is strongly associated with fluoropyrimidine-induced severe and life-threatening toxicity. This study determined the feasibility, safety, and cost of DPYD*2A genotype-guided dosing. Patients intended to be treated with fluoropyrimidine-based chemotherapy were prospectively genotyped for DPYD*2A before start of therapy. Variant allele carriers received an initial dose reduction of ≥ 50% followed by dose titration based on tolerance. Toxicity was the primary end point and was compared with historical controls (ie, DPYD*2A variant allele carriers receiving standard dose described in literature) and with DPYD*2A wild-type patients treated with the standard dose in this study. Secondary end points included a model-based cost analysis, as well as pharmacokinetic and DPD enzyme activity analyses. A total of 2,038 patients were prospectively screened for DPYD*2A, of whom 22 (1.1%) were heterozygous polymorphic. DPYD*2A variant allele carriers were treated with a median dose-intensity of 48% (range, 17% to 91%). The risk of grade ≥ 3 toxicity was thereby significantly reduced from 73% (95% CI, 58% to 85%) in historical controls (n = 48) to 28% (95% CI, 10% to 53%) by genotype-guided dosing (P < .001); drug-induced death was reduced from 10% to 0%. Adequate treatment of genotype-guided dosing was further demonstrated by a similar incidence of grade ≥ 3 toxicity compared with wild-type patients receiving the standard dose (23%; P = .64) and by similar systemic fluorouracil (active drug) exposure. Furthermore, average total treatment cost per patient was lower for screening (€2,772 [$3,767]) than for nonscreening (€2,817 [$3,828]), outweighing screening costs. DPYD*2A is strongly associated with fluoropyrimidine-induced severe and life-threatening toxicity. DPYD*2A genotype-guided dosing results in adequate systemic drug exposure and significantly improves safety of fluoropyrimidine therapy for the individual patient. On a population level, upfront genotyping seemed cost saving. © 2015 by American Society of Clinical Oncology.

Embryonic transcription factor SOX9 drives breast cancer endocrine resistance.

PubMed

Jeselsohn, Rinath; Cornwell, MacIntosh; Pun, Matthew; Buchwalter, Gilles; Nguyen, Mai; Bango, Clyde; Huang, Ying; Kuang, Yanan; Paweletz, Cloud; Fu, Xiaoyong; Nardone, Agostina; De Angelis, Carmine; Detre, Simone; Dodson, Andrew; Mohammed, Hisham; Carroll, Jason S; Bowden, Michaela; Rao, Prakash; Long, Henry W; Li, Fugen; Dowsett, Mitchell; Schiff, Rachel; Brown, Myles

2017-05-30

The estrogen receptor (ER) drives the growth of most luminal breast cancers and is the primary target of endocrine therapy. Although ER blockade with drugs such as tamoxifen is very effective, a major clinical limitation is the development of endocrine resistance especially in the setting of metastatic disease. Preclinical and clinical observations suggest that even following the development of endocrine resistance, ER signaling continues to exert a pivotal role in tumor progression in the majority of cases. Through the analysis of the ER cistrome in tamoxifen-resistant breast cancer cells, we have uncovered a role for an RUNX2-ER complex that stimulates the transcription of a set of genes, including most notably the stem cell factor SOX9, that promote proliferation and a metastatic phenotype. We show that up-regulation of SOX9 is sufficient to cause relative endocrine resistance. The gain of SOX9 as an ER-regulated gene associated with tamoxifen resistance was validated in a unique set of clinical samples supporting the need for the development of improved ER antagonists.

Embryonic transcription factor SOX9 drives breast cancer endocrine resistance

PubMed Central

Jeselsohn, Rinath; Cornwell, MacIntosh; Pun, Matthew; Buchwalter, Gilles; Nguyen, Mai; Bango, Clyde; Huang, Ying; Kuang, Yanan; Paweletz, Cloud; Fu, Xiaoyong; Nardone, Agostina; De Angelis, Carmine; Detre, Simone; Dodson, Andrew; Mohammed, Hisham; Carroll, Jason S.; Bowden, Michaela; Rao, Prakash; Long, Henry W.; Li, Fugen; Dowsett, Mitchell; Schiff, Rachel; Brown, Myles

2017-01-01

The estrogen receptor (ER) drives the growth of most luminal breast cancers and is the primary target of endocrine therapy. Although ER blockade with drugs such as tamoxifen is very effective, a major clinical limitation is the development of endocrine resistance especially in the setting of metastatic disease. Preclinical and clinical observations suggest that even following the development of endocrine resistance, ER signaling continues to exert a pivotal role in tumor progression in the majority of cases. Through the analysis of the ER cistrome in tamoxifen-resistant breast cancer cells, we have uncovered a role for an RUNX2–ER complex that stimulates the transcription of a set of genes, including most notably the stem cell factor SOX9, that promote proliferation and a metastatic phenotype. We show that up-regulation of SOX9 is sufficient to cause relative endocrine resistance. The gain of SOX9 as an ER-regulated gene associated with tamoxifen resistance was validated in a unique set of clinical samples supporting the need for the development of improved ER antagonists. PMID:28507152

Impact of Upfront Cellular Enrichment by Laser Capture Microdissection on Protein and Phosphoprotein Drug Target Signaling Activation Measurements in Human Lung Cancer: Implications for Personalized Medicine

PubMed Central

Elisa, Baldelli; B., Haura Eric; Lucio, Crinò; Douglas, Cress W.; Vienna, Ludovini; B., Schabath Matthew; A., Liotta Lance; F., Petricoin Emanuel; Mariaelena, Pierobon

2015-01-01

Purpose The aim of this study was to evaluate whether upfront cellular enrichment via laser capture microdissection is necessary for accurately quantifying predictive biomarkers in non-small cell lung cancer tumors. Experimental design Fifteen snap frozen surgical biopsies were analyzed. Whole tissue lysate and matched highly enriched tumor epithelium via laser capture microdissection (LCM) were obtained for each patient. The expression and activation/phosphorylation levels of 26 proteins were measured by reverse phase protein microarray. Differences in signaling architecture of dissected and undissected matched pairs were visualized using unsupervised clustering analysis, bar graphs, and scatter plots. Results Overall patient matched LCM and undissected material displayed very distinct and differing signaling architectures with 93% of the matched pairs clustering separately. These differences were seen regardless of the amount of starting tumor epithelial content present in the specimen. Conclusions and clinical relevance These results indicate that LCM driven upfront cellular enrichment is necessary to accurately determine the expression/activation levels of predictive protein signaling markers although results should be evaluated in larger clinical settings. Upfront cellular enrichment of the target cell appears to be an important part of the workflow needed for the accurate quantification of predictive protein signaling biomarkers. Larger independent studies are warranted. PMID:25676683

Targeting chromatin binding regulation of constitutively active AR variants to overcome prostate cancer resistance to endocrine-based therapies

PubMed Central

Chan, Siu Chiu; Selth, Luke A.; Li, Yingming; Nyquist, Michael D.; Miao, Lu; Bradner, James E.; Raj, Ganesh V.; Tilley, Wayne D.; Dehm, Scott M.

2015-01-01

Androgen receptor (AR) variants (AR-Vs) expressed in prostate cancer (PCa) lack the AR ligand binding domain (LBD) and function as constitutively active transcription factors. AR-V expression in patient tissues or circulating tumor cells is associated with resistance to AR-targeting endocrine therapies and poor outcomes. Here, we investigated the mechanisms governing chromatin binding of AR-Vs with the goal of identifying therapeutic vulnerabilities. By chromatin immunoprecipitation and sequencing (ChIP-seq) and complementary biochemical experiments, we show that AR-Vs display a binding preference for the same canonical high-affinity androgen response elements (AREs) that are preferentially engaged by AR, albeit with lower affinity. Dimerization was an absolute requirement for constitutive AR-V DNA binding and transcriptional activation. Treatment with the bromodomain and extraterminal (BET) inhibitor JQ1 resulted in inhibition of AR-V chromatin binding and impaired AR-V driven PCa cell growth in vitro and in vivo. Importantly, this was associated with a novel JQ1 action of down-regulating AR-V transcript and protein expression. Overall, this study demonstrates that AR-Vs broadly restore AR chromatin binding events that are otherwise suppressed during endocrine therapy, and provides pre-clinical rationale for BET inhibition as a strategy for inhibiting expression and chromatin binding of AR-Vs in PCa. PMID:25908785

Increasing rates of people identifying as transgender presenting to Endocrine Services in the Wellington region.

PubMed

Delahunt, John W; Denison, Hayley J; Sim, Dalice A; Bullock, Jemima J; Krebs, Jeremy D

2018-01-19

Overseas clinics specialising in management of transgender people have noted a marked increase in the numbers of people requesting therapy in the last few years. No data has been presented for New Zealand. We therefore reviewed the number of transgender people seen in the Wellington Endocrine Service to assess if the pattern was similar and assess any potential problems for service delivery. Using hospital records, we reviewed the new appointments of people who were referred for advice on gender reassignment and seen in the Wellington Endocrine Service from 1990 to 2016. In total, 438 people who identified as transgender attended the clinic at least once in this period. There has been a progressive increase in number of people identifying as transgender presenting to the clinic, particularly since 2010. In addition to increasing overall numbers, there has been in particular increase in referrals for people under age 30, as well as an increasing proportion of people requesting female-to-male (FtM) therapy so that it is now approaching the number of people requesting male-to-female therapy (MtF). The pattern observed is comparable to changes reported overseas. These changes have practical consequences for the delivery of both secondary and primary level healthcare, requiring an increased focus on clinical coordination between the relevant medical services and their links to the primary services sector.

Prospective Study of Fertility Concerns and Preservation Strategies in Young Women With Breast Cancer

PubMed Central

Ruddy, Kathryn J.; Gelber, Shari I.; Tamimi, Rulla M.; Ginsburg, Elizabeth S.; Schapira, Lidia; Come, Steven E.; Borges, Virginia F.; Meyer, Meghan E.; Partridge, Ann H.

2014-01-01

Purpose Most research regarding fertility in young women with breast cancer has focused on long-term survivors. Little is known about how fertility concerns affect treatment decisions or fertility preservation strategies at the time of initial cancer diagnosis. Patients and Methods As part of an ongoing prospective multicenter cohort study, we surveyed women with newly diagnosed early-stage breast cancer at age ≤ 40 years. The baseline survey included sociodemographic, medical, and treatment data as well as a modified Fertility Issues Survey, including fertility concern and preservation items. Univariable and multivariable modeling were used to investigate predictors of greater fertility concern. Results Among the first 620 eligible respondents included in this analysis, median age was 37 years (range, 17 to 40 years); 425 women (68%) discussed fertility issues with their physicians before starting therapy, and 319 (51%) were concerned about becoming infertile after treatment. Because of concerns about fertility, four women (1%) chose not to receive chemotherapy, 12 (2%) chose one chemotherapy regimen over another, six (1%) considered not receiving endocrine therapy, 19 (3%) decided not to receive endocrine therapy, and 71 (11%) considered receiving endocrine therapy for < 5 years; 65 (10%) used fertility preservation strategies. Greater concern about fertility was associated with younger age, nonwhite race, not having children, and receipt of chemotherapy. Conclusion Many young women with newly diagnosed breast cancer have concerns about fertility, and for some, these substantially affect their treatment decisions. Only a minority of women currently pursue available fertility preservation strategies in this setting. PMID:24567428

Management of hirsutism.

PubMed

Agrawal, N K

2013-10-01

Although hirsutism is a frequent and distressing disorder often signaling an underlying endocrine disorder, a systematic approach to evaluation and the use of combination therapy will provide satisfactory treatment for most patients.

Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial.

PubMed

Cristofanilli, Massimo; Turner, Nicholas C; Bondarenko, Igor; Ro, Jungsil; Im, Seock-Ah; Masuda, Norikazu; Colleoni, Marco; DeMichele, Angela; Loi, Sherene; Verma, Sunil; Iwata, Hiroji; Harbeck, Nadia; Zhang, Ke; Theall, Kathy Puyana; Jiang, Yuqiu; Bartlett, Cynthia Huang; Koehler, Maria; Slamon, Dennis

2016-04-01

In the PALOMA-3 study, the combination of the CDK4 and CDK6 inhibitor palbociclib and fulvestrant was associated with significant improvements in progression-free survival compared with fulvestrant plus placebo in patients with metastatic breast cancer. Identification of patients most suitable for the addition of palbociclib to endocrine therapy after tumour recurrence is crucial for treatment optimisation in metastatic breast cancer. We aimed to confirm our earlier findings with this extended follow-up and show our results for subgroup and biomarker analyses. In this multicentre, double-blind, randomised phase 3 study, women aged 18 years or older with hormone-receptor-positive, HER2-negative metastatic breast cancer that had progressed on previous endocrine therapy were stratified by sensitivity to previous hormonal therapy, menopausal status, and presence of visceral metastasis at 144 centres in 17 countries. Eligible patients-ie, any menopausal status, Eastern Cooperative Oncology Group performance status 0-1, measurable disease or bone disease only, and disease relapse or progression after previous endocrine therapy for advanced disease during treatment or within 12 months of completion of adjuvant therapy-were randomly assigned (2:1) via a centralised interactive web-based and voice-based randomisation system to receive oral palbociclib (125 mg daily for 3 weeks followed by a week off over 28-day cycles) plus 500 mg fulvestrant (intramuscular injection on days 1 and 15 of cycle 1; then on day 1 of subsequent 28-day cycles) or placebo plus fulvestrant. The primary endpoint was investigator-assessed progression-free survival. Analysis was by intention to treat. We also assessed endocrine therapy resistance by clinical parameters, quantitative hormone-receptor expression, and tumour PIK3CA mutational status in circulating DNA at baseline. This study is registered with ClinicalTrials.gov, NCT01942135. Between Oct 7, 2013, and Aug 26, 2014, 521 patients were randomly assigned, 347 to fulvestrant plus palbociclib and 174 to fulvestrant plus placebo. Study enrolment is closed and overall survival follow-up is in progress. By March 16, 2015, 259 progression-free-survival events had occurred (145 in the fulvestrant plus palbociclib group and 114 in the fulvestrant plus placebo group); median follow-up was 8·9 months (IQR 8·7-9·2). Median progression-free survival was 9·5 months (95% CI 9·2-11·0) in the fulvestrant plus palbociclib group and 4·6 months (3·5-5·6) in the fulvestrant plus placebo group (hazard ratio 0·46, 95% CI 0·36-0·59, p<0·0001). Grade 3 or 4 adverse events occurred in 251 (73%) of 345 patients in the fulvestrant plus palbociclib group and 38 (22%) of 172 patients in the fulvestrant plus placebo group. The most common grade 3 or 4 adverse events were neutropenia (223 [65%] in the fulvestrant plus palbociclib group and one [1%] in the fulvestrant plus placebo group), anaemia (ten [3%] and three [2%]), and leucopenia (95 [28%] and two [1%]). Serious adverse events (all causalities) occurred in 44 patients (13%) of 345 in the fulvestrant plus palbociclib group and 30 (17%) of 172 patients in the fulvestrant plus placebo group. PIK3CA mutation was detected in the plasma DNA of 129 (33%) of 395 patients for whom these data were available. Neither PIK3CA status nor hormone-receptor expression level significantly affected treatment response. Fulvestrant plus palbociclib was associated with significant and consistent improvement in progression-free survival compared with fulvestrant plus placebo, irrespective of the degree of endocrine resistance, hormone-receptor expression level, and PIK3CA mutational status. The combination could be considered as a therapeutic option for patients with recurrent hormone-receptor-positive, HER2-negative metastatic breast cancer that has progressed on previous endocrine therapy. Pfizer. Copyright © 2016 Elsevier Ltd. All rights reserved.

Paving the road ahead for CD19 CAR T-cell therapy.

PubMed

Nellan, Anandani; Lee, Daniel W

2015-11-01

Modern immunotherapies, most notably in the form of anti-CD19 chimeric antigen receptor (CAR) T cells, have produced significant clinical responses in otherwise refractory pre-B-cell acute lymphoblastic leukemia patients. Several groups have simultaneously reported robust response rates in children and adults alike. These early studies indicate an impending shift in paradigm for the treatment of acute lymphoblastic leukemia. Incorporating CD19 CAR T-cell therapy into upfront or salvage regimens has its challenges and opportunities. Most CD19 CAR T-cell products in trial today are excellent at inducing minimal residual disease negative remissions, and most responding patients experience cytokine release syndrome and/or neurotoxicity. The challenges facing the CAR community involve how best to minimize the severity of cytokine release syndrome and neurotoxicity while maximizing antitumor efficacy, determining what role this therapy will play for the prophylaxis and treatment of central nervous system leukemia, and its implications on subsequent hematopoietic stem cell transplant given the emergence of CD19-negative relapses. CD19 CAR T-cell therapy is a powerful new tool in the oncologist's arsenal. How it is incorporated into standard practice and how it will shift survival curves are the exciting questions that are waiting to be answered.

Hematopoietic stem cell transplantation for non-Hodgkin lymphoma.

PubMed

Bhatt, Vijaya Raj; Vose, Julie M

2014-12-01

Up-front rituximab-based chemotherapy has improved outcomes in non-Hodgkin lymphoma (NHL); refractory or relapsed NHL still accounts for approximately 18,000 deaths in the United States. Autologous hematopoietic stem cell transplantation (SCT) can improve survival in primary refractory or relapsed aggressive NHL and mantle cell lymphoma and in relapsed follicular or peripheral T-cell lymphoma. Autologous SCT as a consolidation therapy after first complete or partial remission in high-risk aggressive NHL, mantle cell lymphoma, and peripheral T-cell lymphoma may improve progression-free survival. Allogeneic SCT offers a lower relapse rate but a higher nonrelapse mortality resulting in overall survival similar to autologous SCT. Copyright © 2014 Elsevier Inc. All rights reserved.

Electrolytes Test

MedlinePlus

... online at http://www.merck.com/mrkshared/mm_geriatrics/sec8/ch59.jsp. (1995-2004). Acid-Base Metabolism. The Merck Manual of Diagnosis and Therapy, Section 2. Endocrine And Metabolic Disorders, Chapter 12. ...

Functional Hypothalamic Amenorrhea: An Endocrine Society Clinical Practice Guideline.

PubMed

Gordon, Catherine M; Ackerman, Kathryn E; Berga, Sarah L; Kaplan, Jay R; Mastorakos, George; Misra, Madhusmita; Murad, M Hassan; Santoro, Nanette F; Warren, Michelle P

2017-05-01

The American Society for Reproductive Medicine, the European Society of Endocrinology, and the Pediatric Endocrine Society. This guideline was funded by the Endocrine Society. To formulate clinical practice guidelines for the diagnosis and treatment of functional hypothalamic amenorrhea (FHA). The participants include an Endocrine Society-appointed task force of eight experts, a methodologist, and a medical writer. This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation approach to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies. One group meeting, several conference calls, and e-mail communications enabled consensus. Endocrine Society committees and members and cosponsoring organizations reviewed and commented on preliminary drafts of this guideline. FHA is a form of chronic anovulation, not due to identifiable organic causes, but often associated with stress, weight loss, excessive exercise, or a combination thereof. Investigations should include assessment of systemic and endocrinologic etiologies, as FHA is a diagnosis of exclusion. A multidisciplinary treatment approach is necessary, including medical, dietary, and mental health support. Medical complications include, among others, bone loss and infertility, and appropriate therapies are under debate and investigation. Copyright © 2017 Endocrine Society

Long Range Plan for Embedded Computer Systems Support. Volume II

DTIC Science & Technology

1981-10-01

interface (pilot displays and controls plus visual system), and data collection (CMAC data, bus data and simulation data). Non-real time functions include...unless adequate upfront planning is implemented, the command will be controlled by the dynamics rather than controll - ing them. The upfront planning should...or should they be called manually? What amount and type of data should the various tools pass between each other? Under what conditions and controls

Impact of Research and Development, Analysis, and Standardization on PV Project Financing Costs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Feldman, David J; Margolis, Robert M; Jones-Albertus, Rebecca

The technical report discusses how R and D efforts focused on removing perceived risk from cash flows to investors have the potential to lower the cost of capital and increase the amount of leverage in a solar project. It also discusses how creating business efficiencies that allow financing transactions to occur more quickly with less effort can reduce the upfront costs associated with arranging financing for a solar project or group of projects. The paper then assesses the impact that these R and D activities might have on the volatility of PV asset cash flows and asset value, as wellmore » as the upfront costs of arranging a financial transaction. Finally, we insert these assumptions into financial models to analyze their impacts on the cost of capital for equity and debt investors, project leverage, and upfront financial transaction costs.« less

Cupping regulates local immunomodulation to activate neural-endocrine-immune worknet.

PubMed

Guo, Yang; Chen, Bo; Wang, Dong-Qiang; Li, Ming-Yue; Lim, Calista Hui-Min; Guo, Yi; Chen, Zelin

2017-08-01

Research on cupping therapy is lacking at home and abroad. However, cupping and acupuncture therapy are both surface stimulation therapies. This paper suggests the mechanism of cupping therapy and proposes that the same mechanism underlies both cupping and acupuncture therapy. The microenvironment is changed when stimulating the surface of the skin, and physical signals transform into biological signals, which also interact with each other in the body. These signalling cascades activate the neuroendocrine-immune system, which produces the therapeutic effect. Copyright © 2017 Elsevier Ltd. All rights reserved.

Surgical Resection of Brain Metastases and the Risk of Leptomeningeal Recurrence in Patients Treated With Stereotactic Radiosurgery

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johnson, Matthew D., E-mail: Matthewjohnson@beaumont.edu; Avkshtol, Vladimir; Baschnagel, Andrew M.

Purpose: Recent prospective data have shown that patients with solitary or oligometastatic disease to the brain may be treated with upfront stereotactic radiosurgery (SRS) with deferral of whole-brain radiation therapy (WBRT). This has been extrapolated to the treatment of patients with resected lesions. The aim of this study was to assess the risk of leptomeningeal disease (LMD) in patients treated with SRS to the postsurgical resection cavity for brain metastases compared with patients treated with SRS to intact metastases. Methods and Materials: Four hundred sixty-five patients treated with SRS without upfront WBRT at a single institution were identified; 330 ofmore » these with at least 3 months' follow-up were included in this analysis. One hundred twelve patients had undergone surgical resection of at least 1 lesion before SRS compared with 218 treated for intact metastases. Time to LMD and overall survival (OS) time were estimated from date of radiosurgery, and LMD was analyzed by the use of cumulative incidence method with death as a competing risk. Univariate and multivariate analyses were performed with competing risk regression to determine whether various clinical factors predicted for LMD. Results: With a median follow-up time of 9.0 months, 39 patients (12%) experienced LMD at a median of 6.0 months after SRS. At 1 year, the cumulative incidence of LMD, with death as a competing risk, was 5.2% for the patients without surgical resection versus 16.9% for those treated with surgery (Gray test, P<.01). On multivariate analysis, prior surgical resection (P<.01) and breast cancer primary (P=.03) were significant predictors of LMD development. The median OS times for patients undergoing surgery compared with SRS alone were 12.9 and 10.6 months, respectively (log-rank P=.06). Conclusions: In patients undergoing SRS with deferral of upfront WBRT for intracranial metastatic disease, prior surgical resection and breast cancer primary are associated with an increased risk for the development of LMD.« less

Results of Upfront Therapy for Marginal Zone Lymphoma.

PubMed

Ortega, José L; Cabanillas, Fernando; Rivera, Noridza; Tirado-Gomez, Maribel; Hallman, Deana; Pardo, Wandaly I; Bruno, Margarita

2017-12-01

Marginal zone lymphomas (MZLs) are indolent disorders composed of 3 subtypes: extranodal marginal zone lymphoma (MALT), splenic marginal zone lymphoma (SMZL), and nodal marginal zone lymphoma (NMZL). Early-stage MALT is treated with radiotherapy or antibiotics, and advanced MALT and NMZL are managed with either watch and wait or chemotherapy. SMZLs are treated with splenectomy or rituximab. However, because these approaches have failed to cure patients with SMZL and NMZL, we have systematically used upfront chemotherapy for them, as well as for advanced MALT. We report the outcomes of this approach. A total of 44 patients with MZL were identified from our database and divided into 2 groups. Group 1 (22 with early-stage MALT) patients received either radiotherapy (n = 17) or antibiotics with or without surgery (n = 5). Group 2 included 9 patients with advanced MALT, 9 with SMZL, and 4 with NMZL. Group 2 was treated with FND-R (fludarabine 25 mg/m 2 on days 1 to 3, mitoxantrone 10 mg/m 2 on day 1, dexamethasone 20 mg on days 1 to 5, and rituximab 375 mg/m 2 on day 1; n = 14) or CHOP-R (cyclophosphamide 750 mg/m 2 on day 1, doxorubicin 50 mg/m 2 on day 1, vincristine 2 mg intravenous push on day 1, prednisone 100 mg/m 2 orally on days 1 to 5, rituximab 375 mg/m 2 on day 1; n = 8), followed by maintenance rituximab for 70%. All patients achieved complete remission, and only 2 patients in group 1 had developed a relapse at 70 and 75 months. Both relapses were stage I MALT that had initially been treated with radiotherapy. Both were salvaged with FND-R and remained free of disease at 27 and 39 months after the relapse. At 10 years, the failure-free survival for the 44 patients was 80% and the overall survival was 100%. None of the patients in group 2 developed a relapse. The long-term toxicities have been acceptable. The excellent responses using upfront chemotherapy for MZL suggests that this disorder is curable. Our results should be confirmed in a prospective trial. Copyright © 2017 Elsevier Inc. All rights reserved.

[Evaluation and classification of drug therapy for breast cancer with bone-only metastasis].

PubMed

Meng, X Y; Song, S T

2017-03-23

Skeleton is one of the most common metastatic organs for breast cancer, which has a better prognosis than visceral metastases. Bone-only metastasis was defined"non-measurable" in the RECIST (Response Evaluation Criteria in Solid Tumors) criteria, and was excluded by clinical trials. However, patients with bone-only metastasis are also in need of effective treatment to prolong survival. Endocrine therapy is the most important treatment for bone metastatic patients. Tumor response of bone metastases can be determined objectively by bone-window CT. Effective treatment should be continued if the symptoms are relieved or osteogenesis is observed. Osteoblastic change in bone-window CT is a sign of improvement after treatment. Endocrine therapy is proper for ER-positive patients. The patients with initial osteoblastic metastasis should not be treated with salvage chemotherapy or anti-HER2 treatment, only if osteolytic metastasis or visceral metastasis is observed. Bishosphonates are just auxiliary drugs in bone metastasis, which should not be abused.

Tamoxifen enhances stemness and promotes metastasis of ERα36+ breast cancer by upregulating ALDH1A1 in cancer cells

PubMed Central

Wang, Qiang; Jiang, Jun; Ying, Guoguang; Xie, Xiao-Qing; Zhang, Xia; Xu, Wei; Zhang, Xuemin; Song, Erwei; Bu, Hong; Ping, Yi-Fang; Yao, Xiao-Hong; Wang, Bin; Xu, Shilei; Yan, Ze-Xuan; Tai, Yanhong; Hu, Baoquan; Qi, Xiaowei; Wang, Yan-Xia; He, Zhi-Cheng; Wang, Yan; Wang, Ji Ming; Cui, You-Hong; Chen, Feng; Meng, Kun; Wang, Zhaoyi; Bian, Xiu-Wu

2018-01-01

The 66 kDa estrogen receptor alpha (ERα66) is the main molecular target for endocrine therapy such as tamoxifen treatment. However, many patients develop resistance with unclear mechanisms. In a large cohort study of breast cancer patients who underwent surgery followed by tamoxifen treatment, we demonstrate that ERα36, a variant of ERα66, correlates with poor prognosis. Mechanistically, tamoxifen directly binds and activates ERα36 to enhance the stemness and metastasis of breast cancer cells via transcriptional stimulation of aldehyde dehydrogenase 1A1 (ALDH1A1). Consistently, the tamoxifen-induced stemness and metastasis can be attenuated by either ALDH1 inhibitors or a specific ERα36 antibody. Thus, tamoxifen acts as an agonist on ERα36 in breast cancer cells, which accounts for hormone therapy resistance and metastasis of breast cancer. Our study not only reveals ERα36 as a stratifying marker for endocrine therapy but also provides a promising therapeutic avenue for tamoxifen-resistant breast cancer. PMID:29393296

Management of hirsutism

PubMed Central

Agrawal, N. K.

2013-01-01

Although hirsutism is a frequent and distressing disorder often signaling an underlying endocrine disorder, a systematic approach to evaluation and the use of combination therapy will provide satisfactory treatment for most patients. PMID:24251227

Endocrine and reproductive dysfunction in men associated with occupational inorganic lead intoxication

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cullen, M.R.; Kayne, R.D.; Robins, J.M.

In an attempt to define a postulated effect of lead on male endocrine function, seven men with symptomatic occupational lead intoxication (maximum whole blood lead levels 66-139 ..mu..g/dl) underwent in-patient endocrine evaluation at the time of diagnosis. Defects in thyroid function probably of central origin, were present in three patients. Six patients had subnormal glucocorticoid production measured by 24-hr urinary 17-hydroxy-corticosteroids and plasma cortisol responses to vasopressin- and/or insulin-induced hypoglycemia. Although serum testosterone concentration was normal in six patients, five had defects in spermatogenesis, including two with ologospermia and two with azoospermia. Repeat examinations after chelation therapy showed only partialmore » improvement. It is concluded that heavy occupational exposure to lead, sufficient to cause clinical poisoning, may be associated with diffuse disturbances of endocrine and reproductive functions in men which are not rapidly reversible with standard treatment. Since men without overt poisoning have not been studied, these results cannot yet be included as sequelae of low-dose exposures.« less

Survival of melanoma patients treated with targeted therapy and immunotherapy after systematic upfront control of brain metastases by radiosurgery.

PubMed

Gaudy-Marqueste, C; Dussouil, A S; Carron, R; Troin, L; Malissen, N; Loundou, A; Monestier, S; Mallet, S; Richard, M A; Régis, J M; Grob, J J

2017-10-01

Targeted therapy (TT) and immunotherapies (ITs) have dramatically improved survival in metastatic melanoma (MM). However, their efficacy on brain metastasis (BM) remains limited and poorly documented. Retrospective cohort of consecutive MM patients (pts) with BMs, all systematically upfront treated by Gamma-Knife (GK) at first BM and retreated in case of new BMs, from 2010 to 2015 at the time when ipilimumab BRAF ± MEK inhibitors and anti-PD1 were introduced in practice. Survival after 1st GK (OS GK1 ) according to prognostic factors and treatment. Among 179 consecutive pts treated by GK, 109 received IT and/or TT after the 1st GK. Median OS GK1 was 10.95 months and 1- and 2-year survival rates were 49.5% and 27.4%, respectively, versus a median overall survival (OS) of 2.29 months (p < .001) in those who did not receive IT or TT. In pts who initially had a single BM, median OS and 1- and 2-year survival rates were 14.46 months, 66.7% and 43.4%, respectively; in pts with 2-3 BMs: 8.85 months, 46.4% and 31%, respectively; in pts with >3 BMs: 7.25 months, 37.2% and 11.9%, respectively. Multivariate analysis for OS GK1 confirmed that IT and TT were significantly and highly protective. Best OS GK1 was observed in BRAF-wild-type pts receiving anti-PD1 or in BRAF-mutated pts receiving BRAF-inhibitors and anti-PD1 (12.26 and 14.82 months, respectively). In real-life MM pts with BMs, a strategy aiming at controlling BM with GK together with TT and/or TT seems to achieve unprecedented survival rates. Copyright © 2017 Elsevier Ltd. All rights reserved.

The prognostic role of CD68 and FoxP3 expression in patients with primary central nervous system lymphoma.

PubMed

Cho, Hyunsoo; Kim, Se Hoon; Kim, Soo-Jeong; Chang, Jong Hee; Yang, Woo Ick; Suh, Chang-Ok; Cheong, June-Won; Kim, Yu Ri; Lee, Jung Yeon; Jang, Ji Eun; Kim, Yundeok; Min, Yoo Hong; Kim, Jin Seok

2017-07-01

The prognostic role of CD68 and FoxP3 in primary central nervous system lymphoma (PCNSL) has not been evaluated. Thus, we examined the prognostic significance of CD68 and FoxP3 expression in tumor samples of 76 newly diagnosed immunocompetent PCNSL patients. All patients were treated initially with high-dose methotrexate (HD-MTX)-based chemotherapy, and 16 (21.1%) patients received upfront autologous stem cell transplantation (ASCT) consolidation. High expression of CD68 (>55 cells/high-power field) or FoxP3 (>15 cells/high-power field) was observed in 10 patients, respectively. High CD68 expression was associated with inferior overall survival (OS) and progression-free survival (PFS) in multivariate analysis (P = 0.023 and P = 0.021, respectively). In addition, we performed subgroup analysis based on upfront ASCT. High CD68 expression was also associated with inferior OS and PFS in multivariate analysis (P = 0.013 and P < 0.001, respectively) among patients who did not receive upfront ASCT (n = 60), but not in patients who received upfront ASCT. The expression of FoxP3 was not significantly associated with survival. Therefore, we identified a prognostic significance of high CD68 expression in PCNSL, which suggests a need for further clinical trials and biological studies on the role of PCNSL tumor microenvironment.

Neural-endocrine-immune complex in the central modulation of tumorigenesis: facts, assumptions, and hypotheses.

PubMed

Mravec, Boris; Gidron, Yori; Kukanova, Barbara; Bizik, Jozef; Kiss, Alexander; Hulin, Ivan

2006-11-01

For the precise coordination of systemic functions, the nervous system uses a variety of peripherally and centrally localized receptors, which transmit information from internal and external environments to the central nervous system. Tight interconnections between the immune, nervous, and endocrine systems provide a base for monitoring and consequent modulation of immune system functions by the brain and vice versa. The immune system plays an important role in tumorigenesis. On the basis of rich interconnections between the immune, nervous and endocrine systems, the possibility that the brain may be informed about tumorigenesis is discussed in this review article. Moreover, the eventual modulation of tumorigenesis by central nervous system is also considered. Prospective consequences of the interactions between tumor and brain for diagnosis and therapy of cancer are emphasized.

Treatment of patients with pancreatic endocrine tumours using a new long-acting somatostatin analogue symptomatic and peptide responses.

PubMed Central

Wood, S M; Kraenzlin, M E; Adrian, T E; Bloom, S R

1985-01-01

Seven patients with gut and pancreatic endocrine tumours have been treated with a long acting somatostatin analogue (SMS 201-995), given as a twice daily subcutaneous injection. This produced dramatic improvement in their endocrine related symptoms, in association with a fall in circulating tumour peptides. One of these patients has now been treated for seven months with this analogue which has controlled his previously life threatening diarrhoea caused by a malignant VIP secreting tumour. He gives his own injections twice daily, and has returned to a full and active life. This is a promising agent both for acute treatment of peptide hypersecretion, and for the long term management of some patients who are unresponsive to other available therapy. PMID:2860052

Treatment of patients with pancreatic endocrine tumours using a new long-acting somatostatin analogue symptomatic and peptide responses.

PubMed

Wood, S M; Kraenzlin, M E; Adrian, T E; Bloom, S R

1985-05-01

Seven patients with gut and pancreatic endocrine tumours have been treated with a long acting somatostatin analogue (SMS 201-995), given as a twice daily subcutaneous injection. This produced dramatic improvement in their endocrine related symptoms, in association with a fall in circulating tumour peptides. One of these patients has now been treated for seven months with this analogue which has controlled his previously life threatening diarrhoea caused by a malignant VIP secreting tumour. He gives his own injections twice daily, and has returned to a full and active life. This is a promising agent both for acute treatment of peptide hypersecretion, and for the long term management of some patients who are unresponsive to other available therapy.

Pituitary Tumors

MedlinePlus

... hormones in your body. This can cause endocrine diseases such as Cushing's syndrome and hyperthyroidism. Symptoms of pituitary tumors include Headaches Vision problems Nausea and vomiting Problems caused ... the tumor. Other options include medicines, radiation therapy, and chemotherapy.

Treatment options in HR⁺/HER2⁻ advanced breast cancer patients pretreated with nonsteroidal aromatase inhibitors: what does current evidence tell us?

PubMed

De Placido, Sabino; Pronzato, Paolo

2015-01-01

Many postmenopausal women with advanced or metastatic breast cancer (BC) receive nonsteroidal aromatase inhibitors (NSAIs). Virtually all of them experience progression, but may still gain benefit from a different endocrine or targeted agent. We indirectly compare the results of trials on endocrine or targeted treatment in HR(+)/HER2(-) mBC patients who progressed after a prior NSAI therapy. Although with the limitations of any indirect comparison, evidence suggests that only the combination of everolimus and exemestane is associated with a prolonged progression-free survival and a more evident clinical benefit than its comparators. We speculate that prior NSAI therapy can 'per se' individuate patients eligible to everolimus. More robust data from head-to-head trials will provide more grounded evidence on this issue.

Genomic profiling of ER+ breast cancers after short-term estrogen suppression reveals alterations associated with endocrine resistance.

PubMed

Giltnane, Jennifer M; Hutchinson, Katherine E; Stricker, Thomas P; Formisano, Luigi; Young, Christian D; Estrada, Monica V; Nixon, Mellissa J; Du, Liping; Sanchez, Violeta; Ericsson, Paula Gonzalez; Kuba, Maria G; Sanders, Melinda E; Mu, Xinmeng J; Van Allen, Eliezer M; Wagle, Nikhil; Mayer, Ingrid A; Abramson, Vandana; Gόmez, Henry; Rizzo, Monica; Toy, Weiyi; Chandarlapaty, Sarat; Mayer, Erica L; Christiansen, Jason; Murphy, Danielle; Fitzgerald, Kerry; Wang, Kai; Ross, Jeffrey S; Miller, Vincent A; Stephens, Phillip J; Yelensky, Roman; Garraway, Levi; Shyr, Yu; Meszoely, Ingrid; Balko, Justin M; Arteaga, Carlos L

2017-08-09

Inhibition of proliferation in estrogen receptor-positive (ER + ) breast cancers after short-term antiestrogen therapy correlates with long-term patient outcome. We profiled 155 ER + /human epidermal growth factor receptor 2-negative (HER2 - ) early breast cancers from 143 patients treated with the aromatase inhibitor letrozole for 10 to 21 days before surgery. Twenty-one percent of tumors remained highly proliferative, suggesting that these tumors harbor alterations associated with intrinsic endocrine therapy resistance. Whole-exome sequencing revealed a correlation between 8p11-12 and 11q13 gene amplifications, including FGFR1 and CCND1 , respectively, and high Ki67. We corroborated these findings in a separate cohort of serial pretreatment, postneoadjuvant chemotherapy, and recurrent ER + tumors. Combined inhibition of FGFR1 and CDK4/6 reversed antiestrogen resistance in ER + FGFR1 / CCND1 coamplified CAMA1 breast cancer cells. RNA sequencing of letrozole-treated tumors revealed the existence of intrachromosomal ESR1 fusion transcripts and increased expression of gene signatures indicative of enhanced E2F-mediated transcription and cell cycle processes in cancers with high Ki67. These data suggest that short-term preoperative estrogen deprivation followed by genomic profiling can be used to identify druggable alterations that may cause intrinsic endocrine therapy resistance. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Cyclin-Dependent Kinase Inhibitors for the Treatment of Breast Cancer: Past, Present, and Future.

PubMed

DiPippo, Adam J; Patel, Neelam K; Barnett, Chad M

2016-06-01

Treatment of metastatic breast cancer (MBC) that is resistant to endocrine therapy presents a significant clinical challenge. The well-known role of cell cycle dysregulation in these patients is partly mediated by cyclin-dependent kinase (CDK) activity. Specific cyclin and CDK complexes regulate cell cycle progression by managing the transition through the cell cycle, and inhibition of CDKs represents an important target for novel agents. First-generation CDK inhibitors (e.g., flavopiridol) were relatively nonselective and had an unacceptable toxicity profile in early trials. Second-generation CDK inhibitors were designed to target the CDK4 and CDK6 (CDK4/6) pathway and have shown promising clinical activity with an acceptable toxicity profile in patients with MBC. Palbociclib is a first-in-class CDK4/6 inhibitor that was granted accelerated U.S. Food and Drug Administration approval in combination with letrozole for the treatment of MBC in the first-line setting (February 2015) as well as in combination with fulvestrant for MBC that had progressed on previous endocrine therapy (February 2016). Other CDK4/6 inhibitors, including ribociclib and abemaciclib, are under investigation as monotherapy and in combination with endocrine or anti-human epidermal growth receptor 2 therapy for the treatment of MBC. Ongoing clinical trials should provide additional information to guide the appropriate use of these agents and identify patient populations that could derive the most benefit. © 2016 Pharmacotherapy Publications, Inc.

Oncology providers' perspectives on endocrine therapy prescribing and management.

PubMed

Wheeler, Stephanie B; Roberts, Megan C; Bloom, Diane; Reeder-Hayes, Katherine E; Espada, Maya; Peppercorn, Jeffrey; Golin, Carol E; Earp, Jo Anne

2016-01-01

Adjuvant endocrine therapy (ET) can reduce the risk of recurrence among females with hormone receptor-positive breast cancer. Overall, initiation and adherence to ET are suboptimal, though reasons are not well described. The study's objective was to better understand ET decision making, prescribing, and patient management from oncology providers' perspectives. Using purposive sampling, we recruited oncology providers who saw five or more breast cancer patients per week (n=20). We conducted 30-45-minute telephone interviews, using a semistructured guide to elicit perspectives on ET use. We used thematic content analysis to systematically identify categories of meaning and double-coded transcripts using Atlas.ti. Providers recommend ET to all eligible patients except those with contraindications or other risk factors. Providers base their ET prescribing decisions on the patient's menopausal status, side effects, and comorbidities. ET is typically discussed multiple times: at the onset of breast cancer treatment and in more detail after other treatment completion. Providers felt that the associated recurrence risk reduction is the most compelling argument for patients during ET decision making. While providers rarely perceived noninitiation as a problem, nonadherence was prevalent, often due to unresolvable side effects. From the clinicians' perspectives, side effects from ET are the dominant factor in nonadherence. Efforts to improve adherence should focus on strategies to minimize side effects and ensure clinicians and patients are well informed regarding optimal side effect management. This finding has important implications for novel endocrine regimens that offer improved outcomes through longer duration or more intensive therapy.

Survival benefit of zoledronic Acid in postmenopausal breast cancer patients receiving aromatase inhibitors.

PubMed

Ahn, Sung Gwe; Kim, Sung Hyun; Lee, Hak Min; Lee, Seung Ah; Jeong, Joon

2014-12-01

A growing body of evidence indicates that zoledronic acid (ZA) can improve the clinical outcome in patients with breast cancer and low estrogen levels. In the present study, we aimed to investigate the survival benefit of ZA administration in postmenopausal Korean women with breast cancer who were also receiving aromatase inhibitors. Between January 2004 and December 2010, 235 postmenopausal breast cancer patients undergoing aromatase inhibitor therapy were investigated. All patients were postmenopausal, as confirmed by laboratory tests. Of these patients, 77 received adjuvant upfront ZA for at least 1 year in addition to conventional adjuvant treatment. The remaining 158 patients never received ZA and were treated according to the St. Gallen guidelines. The baseline characteristics for ZA treatment were not different between the two groups. The median follow-up time was 62 months, and the patients who received ZA in addition to aromatase inhibitors showed a better recurrence-free survival compared to those who received aromatase inhibitors alone (p=0.035). On multivariate analysis, the patients who received ZA showed a better recurrence-free survival independent of the tumor size, nodal status, progesterone receptor, and histological grade. For this model, Harrell c index was 0.743. The hazard ratio of ZA use for recurrence-free survival was 0.12 (95% confidence interval, 0.01-0.99). Our findings suggest that upfront use of ZA as part of adjuvant treatment can offer a survival benefit to postmenopausal breast cancer patients receiving aromatase inhibitor treatment.

Loss of steroid hormone receptors is common in malignant pleural and peritoneal effusions of breast cancer patients treated with endocrine therapy

PubMed Central

Schrijver, Willemijne A.M.E.; Schuurman, Karianne; van Rossum, Annelot; Peeters, Ton; Ter Hoeve, Natalie

2017-01-01

Discordance in estrogen receptor alpha (ERα), progesterone receptor (PR), androgen receptor (AR) and human epidermal growth factor receptor 2 (HER2) status between primary breast cancers and solid distant metastases (“conversion”) has been reported previously. Even though metastatic spread to the peritoneal and pleural cavities occurs frequently and is associated with high mortality, the rate of receptor conversion and the prognostic implications thereof remain elusive. We therefore determined receptor conversion in 91 effusion metastases (78 pleural, 13 peritoneal effusions) of 69 patients by immunohistochemistry (IHC) and in situ hybridization. Data were coupled to clinical variables and treatment history. ERα, PR and AR receptor status converted from positive in the primary tumor to negative in the effusion metastases or vice versa in 25-30%, 30-35% and 46-51% of cases for the 1% and 10% thresholds for positivity, respectively. 19-25% of patients converted clinically relevant from “ERα+ or PR+” to ERα-/PR- and 3-4% from ERα-/PR- to “ERα+ or PR+”. For HER2, conversion was observed in 6% of cases. Importantly, receptor conversion for ERα (p = 0.058) and AR (p < 0.001) was more often seen in patients adjuvantly treated with endocrine therapy. Analogous to this observation, HER2-loss was more frequent in patients adjuvantly treated with trastuzumab (p < 0.001). Alike solid distant metastases, receptor conversion for ERα, PR, AR and HER2 is a frequent phenomenon in peritoneal and pleural effusion metastases. Adjuvant endocrine and trastuzumab therapy imposes an evolutionary selection pressure on the tumor, leading to receptor loss in effusion metastases. Determination of receptor status in malignant effusion specimens will facilitate endocrine treatment decision-making at this lethal state of the disease, and is hence recommended whenever possible. PMID:28903441

Annual Research Progress Report, FY 1991

DTIC Science & Technology

1991-09-30

59 86/114 0 Natural History of HTLV-III Infection and Disease in a United States Military Community (PR) ............... . ............ 60 86/120 0...Malignant Lymphomas ..................... 142 90/147 0 SWOG 8819 Central Lymphoma Repository Tissue Procurement Protocol ........................... 143 90...Adjuvant Chemo- therapy with or without Endocrine Therapy in High- Risk, Node Negative Breast Cancer Patients and a Natural History Followup Study in Low

Endoscopic Therapies for Chronic Pancreatitis.

PubMed

Adler, Jeffrey M; Gardner, Timothy B

2017-07-01

Chronic pancreatitis is a fibroinflammatory disease of the pancreas leading to varying degrees of endocrine and exocrine dysfunction. Treatment options are generally designed to control the pain of chronic pancreatitis, and endoscopic therapy is one of the main treatment modalities. Herein, we describe the endoscopic management of pancreatic duct calculi and strictures, entrapment of the intrapancreatic bile duct, celiac plexus interventions, and drainage of pancreatic pseudocysts.

New endocrine therapies for breast cancer.

PubMed

Howell, A; Downey, S; Anderson, E

1996-04-01

How do the new endocrine therapies stand up to the aims of modern endocrine therapy outlined in Table 1? We wish to see increased efficacy, decreased toxicity and improved general health in women taking a new agent. None of the new non-steroidal anti-oestrogens have shown unequivocal evidence of improved efficacy in the clinic to mirror their improved profiles over tamoxifen in preclinical studies. We know that toremifene is equivalent to tamoxifen, but we do not have any phase III data from the other four compounds in development. The specific steroidal antioestrogen, ICI 182,780, looks very promising, but is early in its developmental programme. The new aromatase inhibitors are likely to prove equal to tamoxifen or progestagens, but it is disappointing that improved oestrogen suppression has not led, to date, to improved efficacy. No comment can be made about adjuvant or preventative therapy for any of the new agents, although trials are planned for the new aromatase inhibitors in this clinical situation. Currently, the antiprogestins are disappointing and we will need to wait a considerable time for new agents in preclinical testing to reach the clinic. Many of the new agents are associated with decreased toxicity. It is likely that the NSAEs will be equitoxic with tamoxifen. The steroidal antioestrogen looks particularly non-toxic as do the new aromatase inhibitors, and thus we have an advance in terms of reduced toxicity. The effects of the new agents on the uterus, lipids and bone are in the early stages of testing. Raloxifene, ICI 182,780 and the new aromatase inhibitors are expected to have no proliferative effects on the endometrium, but only the new NSAEs are expected to have beneficial cardiovascular and skeletal effects. If the steroidal anti-oestrogens and new aromatase inhibitors become adjuvant therapies of choice, other agents to prevent osteoporosis and cardiovascular events may also have to be administered.

Screening for Secondary Endocrine Hypertension in Young Patients

PubMed Central

TRIFANESCU, Raluca; CARSOTE, Mara; CARAGHEORGHEOPOL, Andra; HORTOPAN, Dan; DUMITRASCU, Anda; DOBRESCU, Mariana; POIANA, Catalina

2013-01-01

ABSTRACT Background: Secondary endocrine hypertension accounts for 5-12% of hypertension's causes. In selected patients (type 2 diabetes mellitus, sleep apnea syndrome with resistant hypertension, sudden deterioration in hypertension control), prevalence could be higher. Objectives: To present etiology of endocrine secondary hypertension in a series of patients younger than 40 years at hypertension's onset. Material and methods: Medical records of 80 patients (39M/41F), aged 30.1 ± 8.2 years (range: 12-40 years), with maximum systolic blood pressure=190.4 ± 29.2 mm Hg, range: 145-300 mm Hg, maximum diastolic blood pressure=107.7 ± 16.9 mm Hg, range: 80-170 mm Hg) referred by cardiologists for endocrine hypertension screening were retrospectively reviewed. Cardiac and renal causes of secondary hypertension were previously excluded. In all patients, plasma catecholamines were measured by ELISA and plasma cortisol by immunochemiluminescence. Orthostatic aldosterone (ELISA) and direct renin (chemiluminescence) were measured in 48 patients. Results: Secondary endocrine hypertension was confirmed in 16 out of 80 patients (20%). Primary hyperaldosteronism was diagnosed in 7 (4M/3F) out of 48 screened patients (14.6%). i.e. 8.75% from whole group: 5 patients with adrenal tumors (3 left/2 right), 2 patients with bilateral adrenal hyperplasia; all patients were hypokalemic at diagnostic (average nadir K+ levels = 2.5 ± 0.5 mmol/L); four patients were hypokalaemic on diuretic therapy (indapamidum); other 3 patients were hypokalaemic in the absence of diuretic therapy. Cushing's syndrome was diagnosed in 6 patients (7.5%): subclinical Cushing due to 4 cm right adrenal tumour – n = 1, overt ACTH-independent Cushing's syndrome due to: macronodular adrenal hyperplasia associated with primary hyperparathyroidism – n = 1; due to adrenal carcinoma – n = 1; due to adrenal adenomas – n = 2; Cushing's disease – n = 1). Pheochromocytomas were diagnosed in 3 patients (3.75%). Conclusion: Primary hyperaldosteronism was the most frequent cause of secondary endocrine hypertension in our series, followed by Cushing's syndrome and pheochromocytomas. Screening of young hypertensive patients for secondary causes, especially primary hyperaldosteronism, is mandatory. PMID:24371473

Advances in cardiovascular research. 15th Annual Meeting of the European Council for Cardiovascular Research (ECCR). La Colle sur Loup, France, 8–10 October 2010.

PubMed

Steckelings, U Muscha; De Mey, Jo G R; Pinto-Sietsma, Sara-Joan; Henrion, Daniel; Unger, Thomas

2011-01-01

The 15th Annual Meeting of the European Council of Cardiovascular Research brought together basic and clinical scientists working in the cardiovascular field in La Colle sur Loup, France. Upfront basic and clinical research addressing the mechanisms of disease, identification of biomarkers or development of new treatments was communicated in 101 presentations, 35 of them as a part of five on-topic oral sessions and three workshops. Three keynote lectures reviewed current knowledge and the latest data about mechanosensitive channels in pressure regulation, cell therapy in cardiovascular disease and mechanisms of cardiovascular risk associated with diabetic nephropathy. This article summarizes highlights of the oral sessions, workshops and keynote lectures.

Outcome after intensive reinduction therapy and allogeneic stem cell transplant in paediatric relapsed acute myeloid leukaemia.

PubMed

Karlsson, Lene; Forestier, Erik; Hasle, Henrik; Jahnukainen, Kirsi; Jónsson, Ólafur G; Lausen, Birgitte; Norén Nyström, Ulrika; Palle, Josefine; Tierens, Anne; Zeller, Bernward; Abrahamsson, Jonas

2017-08-01

Given that 30-40% of children with acute myeloid leukaemia (AML) relapse after primary therapy it is important to define prognostic factors and identify optimal therapy. From 1993 to 2012, 543 children from the Nordic countries were treated according to two consecutive protocols: 208 children relapsed. The influence of disease characteristics, first line treatment, relapse therapy and duration of first remission on outcome was analysed. Second complete remission (CR2) was achieved in 146 (70%) patients. Estimated 5-year overall survival (OS 5y ) was 39 ± 4% for the whole group and 43 ± 4% for the 190 patients given re-induction therapy, of whom 76% received regimens that included fludarabine, cytarabine (FLA) ± anthracyclines, 18% received Nordic Society for Paediatric Haematology and Oncology (NOPHO) upfront blocks and 5% received other regimens. Late relapse ≥1 year from diagnosis, no allogeneic stem cell transplantation (SCT) in first remission and core binding factor AML were independent favourable prognostic factors for survival. For the 128 children (124 in CR2) that received SCT as consolidation therapy after relapse, OS 5y was 61 ± 5%. Four of 19 children (21%) survived without receiving SCT as part of relapse therapy. Our data show that intensive re-induction followed by SCT can give cure rates of 40% in children with relapsed AML. © 2017 John Wiley & Sons Ltd.

Evaluation and Treatment of Hypertriglyceridemia: An Endocrine Society Clinical Practice Guideline

PubMed Central

Berglund, Lars; Brunzell, John D.; Goldberg, Anne C.; Goldberg, Ira J.; Sacks, Frank; Murad, Mohammad Hassan; Stalenhoef, Anton F. H.

2012-01-01

Objective: The aim was to develop clinical practice guidelines on hypertriglyceridemia. Participants: The Task Force included a chair selected by The Endocrine Society Clinical Guidelines Subcommittee (CGS), five additional experts in the field, and a methodologist. The authors received no corporate funding or remuneration. Consensus Process: Consensus was guided by systematic reviews of evidence, e-mail discussion, conference calls, and one in-person meeting. The guidelines were reviewed and approved sequentially by The Endocrine Society's CGS and Clinical Affairs Core Committee, members responding to a web posting, and The Endocrine Society Council. At each stage, the Task Force incorporated changes in response to written comments. Conclusions: The Task Force recommends that the diagnosis of hypertriglyceridemia be based on fasting levels, that mild and moderate hypertriglyceridemia (triglycerides of 150–999 mg/dl) be diagnosed to aid in the evaluation of cardiovascular risk, and that severe and very severe hypertriglyceridemia (triglycerides of > 1000 mg/dl) be considered a risk for pancreatitis. The Task Force also recommends that patients with hypertriglyceridemia be evaluated for secondary causes of hyperlipidemia and that subjects with primary hypertriglyceridemia be evaluated for family history of dyslipidemia and cardiovascular disease. The Task Force recommends that the treatment goal in patients with moderate hypertriglyceridemia be a non-high-density lipoprotein cholesterol level in agreement with National Cholesterol Education Program Adult Treatment Panel guidelines. The initial treatment should be lifestyle therapy; a combination of diet modification and drug therapy may also be considered. In patients with severe or very severe hypertriglyceridemia, a fibrate should be used as a first-line agent. PMID:22962670

Gastroenteropancreatic (neuro)endocrine neoplasms: the histology report.

PubMed

Rindi, Guido; Bordi, C; La Rosa, S; Solcia, E; Delle Fave, Gianfranco

2011-03-01

Based on the year 2000 World Health Organization (WHO) classification and the European Neuroendocrine Tumor Society (ENETS) grading and staging proposals, we here define the minimal guidelines for pathology reporting of (neuro)endocrine neoplasms. The macroscopical description is recommended according to standard procedures and the microscopical description according to recognized architectural and cytological features for endocrine lesions. Minimal diagnostic immunohistochemistry entails the use of chromogranin A, synaptophysin and Ki67. Other potentially useful tests are those for CD56 N-CAM, PGP 9.5 and hormones for diagnosis, the somatostatin receptor subtype 2 for potential radiodiagnostics and therapy, and transcription factors like TTF1 and CDX2, for site of origin. Grading definition is always mandatory as well as TNM staging for surgical specimens. Copyright © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd.. All rights reserved.

Proton Beam Therapy Versus Conformal Photon Radiation Therapy for Childhood Craniopharyngioma: Multi-institutional Analysis of Outcomes, Cyst Dynamics, and Toxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bishop, Andrew J.; Greenfield, Brad; Mahajan, Anita

2014-10-01

Purpose: We compared proton beam therapy (PBT) with intensity modulated radiation therapy (IMRT) for pediatric craniopharyngioma in terms of disease control, cyst dynamics, and toxicity. Methods and Materials: We reviewed records from 52 children treated with PBT (n=21) or IMRT (n=31) at 2 institutions from 1996-2012. Endpoints were overall survival (OS), disease control, cyst dynamics, and toxicity. Results: At 59.6 months' median follow-up (PBT 33 mo vs IMRT 106 mo; P<.001), the 3-year outcomes were 96% for OS, 95% for nodular failure-free survival and 76% for cystic failure-free survival. Neither OS nor disease control differed between treatment groups (OS P=.742;more » nodular failure-free survival P=.546; cystic failure-free survival P=.994). During therapy, 40% of patients had cyst growth (20% requiring intervention); immediately after therapy, 17 patients (33%) had cyst growth (transient in 14), more commonly in the IMRT group (42% vs 19% PBT; P=.082); and 27% experienced late cyst growth (32% IMRT, 19% PBT; P=.353), with intervention required in 40%. Toxicity did not differ between groups. On multivariate analysis, cyst growth was related to visual and hypothalamic toxicity (P=.009 and .04, respectively). Patients given radiation as salvage therapy (for recurrence) rather than adjuvant therapy had higher rates of visual and endocrine (P=.017 and .024, respectively) dysfunction. Conclusions: Survival and disease-control outcomes were equivalent for PBT and IMRT. Cyst growth is common, unpredictable, and should be followed during and after therapy, because it contributes to late toxicity. Delaying radiation therapy until recurrence may result in worse visual and endocrine function.« less

The impact of endocrine supplementation on adverse events in septic shock.

PubMed

Bissell, Brittany D; Erdman, Michael J; Smotherman, Carmen; Kraemer, Dale F; Ferreira, Jason A

2015-12-01

The objective of this study was to compare the incidence of severe adverse events of vasopressin vs hydrocortisone for endocrine support therapy in patients with septic shock. This was a retrospective, propensity-matched cohort of patients admitted to the medical intensive care unit with septic shock between February 2012 and February 2015. Patients were included if vasopressin or hydrocortisone was administered for hemodynamic support secondary to norepinephrine. In the unmatched cohort of 124 patients, vasopressin was associated with a significant decrease in the number of severe adverse events (P=.03). In the matched cohort, severe adverse events occurred 3 times as often in patients receiving hydrocortisone; however, this difference was not statistically significant. (odds ratio, 3.33; 95% confidence interval, 0.92-12.11; P=.06). In the matched cohort, vasopressin was associated with a faster time to hemodynamic stability (P<.05) and discontinuation of hemodynamic support (P<.01) with an increased requirement for third-line therapy (P<.01). No statistical differences were seen in length of stay (intensive care unit and hospital), length of mechanical ventilation, and in-hospital mortality. Given the lower incidence of adverse events and faster time to hemodynamic stability, vasopressin appears to be the most advantageous endocrine agent for hemodynamic support in septic shock. Copyright © 2015 Elsevier Inc. All rights reserved.

Epigenetic Mechanisms of Tamoxifen Resistance in Luminal Breast Cancer.

PubMed

Abdel-Hafiz, Hany A

2017-07-06

Breast cancer is one of the most common cancers and the second leading cause of cancer death in the United States. Estrogen receptor (ER)-positive cancer is the most frequent subtype representing more than 70% of breast cancers. These tumors respond to endocrine therapy targeting the ER pathway including selective ER modulators (SERMs), selective ER downregulators (SERDs) and aromatase inhibitors (AIs). However, resistance to endocrine therapy associated with disease progression remains a significant therapeutic challenge. The precise mechanisms of endocrine resistance remain unclear. This is partly due to the complexity of the signaling pathways that influence the estrogen-mediated regulation in breast cancer. Mechanisms include ER modifications, alteration of coregulatory function and modification of growth factor signaling pathways. In this review, we provide an overview of epigenetic mechanisms of tamoxifen resistance in ER-positive luminal breast cancer. We highlight the effect of epigenetic changes on some of the key mechanisms involved in tamoxifen resistance, such as tumor-cell heterogeneity, ER signaling pathway and cancer stem cells (CSCs). It became increasingly recognized that CSCs are playing an important role in driving metastasis and tamoxifen resistance. Understanding the mechanism of tamoxifen resistance will provide insight into the design of novel strategies to overcome the resistance and make further improvements in breast cancer therapeutics.

Myo-inositol vs. D-chiro inositol in PCOS treatment.

PubMed

Formuso, C; Stracquadanio, M; Ciotta, L

2015-08-01

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women in fertile age. It is an endocrine and metabolic disorder characterized by oligo-anovulation, hyperandrogenism and insulin-resistance. Various therapeutic approaches have been attempted in PCOS, including diet and the use of pharmacological agents such as oral contraceptives (OCs) or anti-androgens. Recently, the introduction of inositol in the treatment plan has proved to be as reasonable as useful in countering the endocrine-metabolic disorders of this syndrome. The aim of our study was to compare the clinical, endocrine and metabolic response after 6 months of therapy in 137 PCOS women characterized by oligomenorrhea and/or acne and/or mild hirsutism and insulin-resistance. The patients were treated with myo-inositol or with D-chiro-inositol or with placebo. Our study showed that both myo-inositol (MI-PG) and D-chiro inositol (DCI-PG) treatments are able to significantly improve the regularity of the menstrual cycle, the Acne Score, the endocrine and metabolic parameters and the insulin-resistence in young, overweight, PCOS patients. Definitely, we assumed that both treatments with myo-inositol and with D-chiro inositol could be proposed as a potential valid therapeutic approach for the treatment of patients with PCOS. Additionally, further examination and for a longer period of treatment are needed.

Commentary: Launch of a quality improvement network for evidence-based management of uncommon pediatric endocrine disorders: Turner syndrome as a prototype.

PubMed

Rosenfield, Robert L; DiMeglio, Linda A; Mauras, Nelly; Ross, Judith; Shaw, Natalie D; Greeley, Siri A W; Haymond, Morey; Rubin, Karen; Rhodes, Erinn T

2015-04-01

Traditional, hypothesis-oriented research approaches have thus far failed to generate sufficient evidence to achieve consensus about the management of children with many endocrine disorders, partly because of the rarity of these disorders and because of regulatory burdens unique to research in children. The Pediatric Endocrine Society is launching a quality improvement network in spring 2015 for the management of pediatric endocrine disorders that are relatively uncommon in any single practice and/or for which there is no consensus on management. The first of the quality improvement programs to be implemented seeks to improve the care of 11- to 17-year-old girls with Turner syndrome who require initiation of estrogen replacement therapy by providing a standardized clinical assessment and management plan (SCAMP) for transdermal estradiol treatment to induce pubertal development. The SCAMP algorithm represents a starting point within current best practice that is meant to undergo refinement through an iterative process of analysis of deidentified data collected in the course of clinical care by a network of pediatric endocrinologists. It is anticipated that this program will not only improve care, but will also result in actionable data that will generate new research hypotheses and changes in management of pediatric endocrine disorders.

Cost effectiveness of letrozole versus anastrozole in postmenopausal women with HR+ early-stage breast cancer.

PubMed

Lipsitz, Michael; Delea, Thomas E; Guo, Amy

2010-10-01

The Breast International Group (BIG) 1-98 and Arimidex, Tamoxifen Alone or in Combination (ATAC) trials demonstrated that, in postmenopausal women with hormone receptor positive (HR+) early-stage breast cancer, 5 years of initial adjuvant endocrine therapy with letrozole or anastrozole is superior to tamoxifen. With expected generic availability of anastrozole in July 2010 and letrozole in June 2011, there may be financial pressures prior to letrozole's generic availability to start treatment-naïve patients on anastrozole vs. letrozole or to switch patients already receiving letrozole to anastrozole. A Markov model was used to estimate cost per quality-adjusted life-year (QALY) gained with letrozole vs. anastrozole from the US healthcare system perspective. Cost effectiveness was examined separately in treatment-naïve patients and in patients already receiving letrozole. For the latter, cost effectiveness of continued letrozole vs. therapeutic substitution (TS) to generic anastrozole was evaluated separately in cohorts defined on years of endocrine therapy remaining. TS to generic anastrozole was assumed to result in an additional 5% of patients discontinuing endocrine therapy. Probabilities of distant recurrence and death were taken from reports of BIG 1-98, ATAC, the Early Breast Cancer Trialists' Collaborative Group meta-analysis of tamoxifen, and other published sources. Carry-over effects of aromatase inhibitors were assumed to be proportional to treatment duration. Costs of aromatase inhibitors were assumed to decline by 75% with generic availability. In treatment-naïve patients, total expected lifetime costs are $3916 greater with letrozole vs. anastrozole. However, initiation of treatment with letrozole results in a gain of 0.15 QALYs. Cost per QALY gained with letrozole vs. anastrozole is $25,846. In patients already receiving letrozole, the increase in total expected lifetime costs with continued letrozole vs. TS to anastrozole is between $4200 and $4500 in all cohorts. QALYs gained with letrozole range from 0.21 in those with 4 years of endocrine therapy remaining to 0.13 in those with 1 year of therapy remaining. Cost per QALY gained ranges from $20,276 to $34,356. For postmenopausal women with HR+ early-stage breast cancer, letrozole is more likely to be cost effective vs. anastrozole in treatment-naïve patients and in patients already receiving letrozole. Limitations of the study include a lack of direct evidence comparing letrozole and anastrozole and lack of data on rates of discontinuation due to therapeutic substitution with aromatase inhibitors.

Testosterone therapy in adult men with androgen deficiency syndromes: an endocrine society clinical practice guideline.

PubMed

Bhasin, Shalender; Cunningham, Glenn R; Hayes, Frances J; Matsumoto, Alvin M; Snyder, Peter J; Swerdloff, Ronald S; Montori, Victor M

2006-06-01

The objective was to provide guidelines for the evaluation and treatment of androgen deficiency syndromes in adult men. The Task Force was composed of a chair, selected by the Clinical Guidelines Subcommittee of The Endocrine Society, five additional experts, a methodologist, and a professional writer. The Task Force received no corporate funding or remuneration. The Task Force used systematic reviews of available evidence to inform its key recommendations. The Task Force used consistent language and graphical descriptions of both the strength of recommendation and the quality of evidence, using the recommendations of the Grading of Recommendations, Assessment, Development, and Evaluation group. Consensus was guided by systematic reviews of evidence and discussions during three group meetings, several conference calls, and e-mail communications. The drafts prepared by the panelists with the help of a professional writer were reviewed successively by The Endocrine Society's Clinical Guidelines Subcommittee, Clinical Affairs Committee, and Council. The version approved by the Council was placed on The Endocrine Society's web site for comments by members. At each stage of review, the Task Force received written comments and incorporated needed changes. We recommend making a diagnosis of androgen deficiency only in men with consistent symptoms and signs and unequivocally low serum testosterone levels. We suggest the measurement of morning total testosterone level by a reliable assay as the initial diagnostic test. We recommend confirmation of the diagnosis by repeating the measurement of morning total testosterone and in some patients by measurement of free or bioavailable testosterone level, using accurate assays. We recommend testosterone therapy for symptomatic men with androgen deficiency, who have low testosterone levels, to induce and maintain secondary sex characteristics and to improve their sexual function, sense of well-being, muscle mass and strength, and bone mineral density. We recommend against starting testosterone therapy in patients with breast or prostate cancer, a palpable prostate nodule or induration or prostate-specific antigen greater than 3 ng/ml without further urological evaluation, erythrocytosis (hematocrit > 50%), hyperviscosity, untreated obstructive sleep apnea, severe lower urinary tract symptoms with International Prostate Symptom Score (IPSS) greater than 19, or class III or IV heart failure. When testosterone therapy is instituted, we suggest aiming at achieving testosterone levels during treatment in the mid-normal range with any of the approved formulations, chosen on the basis of the patient's preference, consideration of pharmacokinetics, treatment burden, and cost. Men receiving testosterone therapy should be monitored using a standardized plan.

Impact of body mass index on the efficacy of endocrine therapy in patients with metastatic breast cancer - A retrospective two-center cohort study.

PubMed

Zewenghiel, Luwam; Lindman, Henrik; Valachis, Antonis

2018-05-18

The aim of this study was to investigate the impact of body mass index (BMI) on the efficacy of endocrine therapy in postmenopausal women with metastatic hormone receptor breast cancer (HR+BC) as well as to identify if the potential difference in efficacy was associated with Fulvestrant only or both aromatase inhibitors (AIs) and Fulvestrant. A consecutive cohort of postmenopausal women with HR+metastatic breast cancer that have received endocrine therapy including Fulvestrant as a metastatic treatment strategy at the Departments of Oncology in Eskilstuna and Uppsala, Sweden, between 2008 and 2016 were identified. The primary outcome of the study was time to disease progression (TTP) during the treatment with Fulvestrant in overweight and obese women compared to patient with normal BMI. In total, 173 patients were enrolled in the study cohort, amongst these, 141 patients received both Fulvestrant and AIs and 32 received only Fulvestrant. No statistical significant association was observed between the three BMI categories and TTP, during Fulvestrant treatment (p = 0.136). The rates of objective response and clinical benefit due to Fulvestrant were similar among patients with normal weight, overweight and obesity, respectively. No difference in treatment efficacy was seen between normal, overweight and obese women with metastatic HR+BC, when treated with Fulvestrant. Until further research with prospective studies is available, there is no evidence to support any modification in how Fulvestrant treatment is used in patients with metastatic breast cancer in regard to BMI. Copyright © 2018 Elsevier Ltd. All rights reserved.

20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years.

PubMed

Pan, Hongchao; Gray, Richard; Braybrooke, Jeremy; Davies, Christina; Taylor, Carolyn; McGale, Paul; Peto, Richard; Pritchard, Kathleen I; Bergh, Jonas; Dowsett, Mitch; Hayes, Daniel F

2017-11-09

The administration of endocrine therapy for 5 years substantially reduces recurrence rates during and after treatment in women with early-stage, estrogen-receptor (ER)-positive breast cancer. Extending such therapy beyond 5 years offers further protection but has additional side effects. Obtaining data on the absolute risk of subsequent distant recurrence if therapy stops at 5 years could help determine whether to extend treatment. In this meta-analysis of the results of 88 trials involving 62,923 women with ER-positive breast cancer who were disease-free after 5 years of scheduled endocrine therapy, we used Kaplan-Meier and Cox regression analyses, stratified according to trial and treatment, to assess the associations of tumor diameter and nodal status (TN), tumor grade, and other factors with patients' outcomes during the period from 5 to 20 years. Breast-cancer recurrences occurred at a steady rate throughout the study period from 5 to 20 years. The risk of distant recurrence was strongly correlated with the original TN status. Among the patients with stage T1 disease, the risk of distant recurrence was 13% with no nodal involvement (T1N0), 20% with one to three nodes involved (T1N1-3), and 34% with four to nine nodes involved (T1N4-9); among those with stage T2 disease, the risks were 19% with T2N0, 26% with T2N1-3, and 41% with T2N4-9. The risk of death from breast cancer was similarly dependent on TN status, but the risk of contralateral breast cancer was not. Given the TN status, the factors of tumor grade (available in 43,590 patients) and Ki-67 status (available in 7692 patients), which are strongly correlated with each other, were of only moderate independent predictive value for distant recurrence, but the status regarding the progesterone receptor (in 54,115 patients) and human epidermal growth factor receptor type 2 (HER2) (in 15,418 patients in trials with no use of trastuzumab) was not predictive. During the study period from 5 to 20 years, the absolute risk of distant recurrence among patients with T1N0 breast cancer was 10% for low-grade disease, 13% for moderate-grade disease, and 17% for high-grade disease; the corresponding risks of any recurrence or a contralateral breast cancer were 17%, 22%, and 26%, respectively. After 5 years of adjuvant endocrine therapy, breast-cancer recurrences continued to occur steadily throughout the study period from 5 to 20 years. The risk of distant recurrence was strongly correlated with the original TN status, with risks ranging from 10 to 41%, depending on TN status and tumor grade. (Funded by Cancer Research UK and others.).

Biotypology, endocrinology, and sterilization: the practice of eugenics in the treatment of Argentinian women during the 1930s.

PubMed

Eraso, Yolanda

2007-01-01

This article looks at medical approaches to women's fertility in Argentina in the 1930s and explores the ways in which eugenics encouraged the reproduction of the fit and attempted to avoid the reproduction of the unfit. The analysis concentrates on three main aspects: biotypology (the scientific classification of bodies), endocrine therapy, and sterilization. The article concludes by suggesting that a eugenically oriented obstetrical and gynecological practice encouraged both endocrine treatments (to achieve the ideal fertile woman) and sterilization, which, in spite of being legally banned, found a subtle application.

[SPECIFIC CLINICAL FEATURES OF TYPE 1 AUTOIMMUNE POLYGLANDULAR SYNDROME].

PubMed

Mikhina, M S; Molashenko, N V; Troshina, E A; Orlova, E M; Sozaeva, L S; Eystein, S H; Breivik, S

2015-01-01

Autoimmune polyglandular syndrome is a primary autoimmune disorder affecting two or more peripheral endocrine glands and responsible for their incompetence. It is frequently combined with various organ-specific non-endocrine diseases. Patients with this pathology need life-long replacement therapy and dynamic observation by endocrinologists and other specialists to monitor the effectiveness of the treatment and detect new components of the disease. We report a variant of type 1 autoimmune polyglandular syndrome. Special emphasis is laid on the importance of succession of actions of endocrinologists and specialists in related medical disciplines dealing with children and adult patients.

European Heart Rhythm Association (EHRA) position paper on arrhythmia management and device therapies in endocrine disorders, endorsed by Asia Pacific Heart Rhythm Society (APHRS) and Latin American Heart Rhythm Society (LAHRS).

PubMed

Gorenek, Bulent; Boriani, Giuseppe; Dan, Gheorge-Andrei; Fauchier, Laurent; Fenelon, Guilherme; Huang, He; Kudaiberdieva, Gulmira; Lip, Gregory Y H; Mahajan, Rajiv; Potpara, Tatjana; Ramirez, Juan David; Vos, Marc A; Marin, Francisco

2018-03-16

Endocrine disorders are associated with various tachyarrhythmias, including atrial fibrillation (AF), ventricular tachycardia (VT), ventricular fibrillation (VF), and bradyarrhythmias. Along with underlying arrhythmia substrate, electrolyte disturbances, glucose, and hormone levels, accompanying endocrine disorders contribute to development of arrhythmia. Arrhythmias may be life-threatening, facilitate cardiogenic shock development and increase mortality. The knowledge on the incidence of tachy- and bradyarrhythmias, clinical and prognostic significance as well as their management is limited; it is represented in observational studies and mostly in case reports on management of challenging cases. It should be also emphasized, that the topic is not covered in detail in current guidelines. Therefore, cardiologists and multidisciplinary teams participating in care of such patients do need the evidence-based, or in case of limited evidence expert-opinion based recommendations, how to treat arrhythmias using contemporary approaches, prevent their complications and recurrence in patients with endocrine disorders. In recognizing this close relationship between endocrine disorders and arrhythmias, the European Heart Rhythm Association (EHRA) convened a Task Force, with representation from Asia-Pacific Heart Rhythm Society (APHRS) and Sociedad Latinoamericana de Estimulación Cardíaca y Electrofisiología (SOLAECE), with the remit of comprehensively reviewing the available evidence and publishing a joint consensus document on endocrine disorders and cardiac arrhythmias, and providing up-to-date consensus recommendations for use in clinical practice.

[Disorders of endocrine function after brain tumor therapy in childhood].

PubMed

Marx, M; Langer, T; Beck, J D; Dörr, H G

1999-07-01

Advances in the therapy of malignant brain tumors in children have led to a significant improvement in survival rates over the last few decades. As a result, the recognition and treatment of late effects have become more important. In addition to secondary tumors and deficiencies in cognitive and intellectual skills, the resulting endocrine disturbances play an important role. Own data and literature review. Deviations from the normal growth hormone secretion are usually recognized first and are most common, and have already been observed after conventional whole brain irradiation with 18 Gy. With some delay, other hypothalamo-pituitary deficiencies may occur, including panhypopituitarism. Puberty may come too early or too late or may not appear at all. Girls in particular, frequently experience an early and rapid pubertal development after brain tumor therapy, which may lead to further reduction in height due to an accelerated bone maturation. Functional disturbances of the thyroid and adrenal glands due to hypothalamic or pituitary deficiency are less common, and usually seen only after a radiation dose of over 40 Gy. Survivors of childhood brain tumors must be considered as long-term survivors, in whom the first therapy-induced long-term side effects appear almost immediately after the end of therapy. Maximum quality of life for the individual patient can only be achieved by long-term care and close cooperation of specialists in the different medical disciplines involved.

Tamoxifen induces a pluripotency signature in breast cancer cells and human tumors.

PubMed

Notas, George; Pelekanou, Vassiliki; Kampa, Marilena; Alexakis, Konstantinos; Sfakianakis, Stelios; Laliotis, Aggelos; Askoxilakis, John; Tsentelierou, Eleftheria; Tzardi, Maria; Tsapis, Andreas; Castanas, Elias

2015-11-01

Tamoxifen is the treatment of choice in estrogen receptor alpha breast cancer patients that are eligible for adjuvant endocrine therapy. However, ∼50% of ERα-positive tumors exhibit intrinsic or rapidly acquire resistance to endocrine treatment. Unfortunately, prediction of de novo resistance to endocrine therapy and/or assessment of relapse likelihood remain difficult. While several mechanisms regulating the acquisition and the maintenance of endocrine resistance have been reported, there are several aspects of this phenomenon that need to be further elucidated. Altered metabolic fate of tamoxifen within patients and emergence of tamoxifen-resistant clones, driven by evolution of the disease phenotype during treatment, appear as the most compelling hypotheses so far. In addition, tamoxifen was reported to induce pluripotency in breast cancer cell lines, in vitro. In this context, we have performed a whole transcriptome analysis of an ERα-positive (T47D) and a triple-negative breast cancer cell line (MDA-MB-231), exposed to tamoxifen for a short time frame (hours), in order to identify how early pluripotency-related effects of tamoxifen may occur. Our ultimate goal was to identify whether the transcriptional actions of tamoxifen related to induction of pluripotency are mediated through specific ER-dependent or independent mechanisms. We report that even as early as 3 hours after the exposure of breast cancer cells to tamoxifen, a subset of ERα-dependent genes associated with developmental processes and pluripotency are induced and this is accompanied by specific phenotypic changes (expression of pluripotency-related proteins). Furthermore we report an association between the increased expression of pluripotency-related genes in ERα-positive breast cancer tissues samples and disease relapse after tamoxifen therapy. Finally we describe that in a small group of ERα-positive breast cancer patients, with disease relapse after surgery and tamoxifen treatment, ALDH1A1 (a marker of pluripotency in epithelial cancers which is absent in normal breast tissue) is increased in relapsing tumors, with a concurrent modification of its intra-cellular localization. Our data could be of value in the discrimination of patients susceptible to develop tamoxifen resistance and in the selection of optimized patient-tailored therapies. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

In situ aromatase expression in primary tumor is associated with estrogen receptor expression but is not predictive of response to endocrine therapy in advanced breast cancer

PubMed Central

2009-01-01

Background New, third-generation aromatase inhibitors (AIs) have proven comparable or superior to the anti-estrogen tamoxifen for treatment of estrogen receptor (ER) and/or progesterone receptor (PR) positive breast cancer. AIs suppress total body and intratumoral estrogen levels. It is unclear whether in situ carcinoma cell aromatization is the primary source of estrogen production for tumor growth and whether the aromatase expression is predictive of response to endocrine therapy. Due to methodological difficulties in the determination of the aromatase protein, COX-2, an enzyme involved in the synthesis of aromatase, has been suggested as a surrogate marker for aromatase expression. Methods Primary tumor material was retrospectively collected from 88 patients who participated in a randomized clinical trial comparing the AI letrozole to the anti-estrogen tamoxifen for first-line treatment of advanced breast cancer. Semi-quantitative immunohistochemical (IHC) analysis was performed for ER, PR, COX-2 and aromatase using Tissue Microarrays (TMAs). Aromatase was also analyzed using whole sections (WS). Kappa analysis was applied to compare association of protein expression levels. Univariate Wilcoxon analysis and the Cox-analysis were performed to evaluate time to progression (TTP) in relation to marker expression. Results Aromatase expression was associated with ER, but not with PR or COX-2 expression in carcinoma cells. Measurements of aromatase in WS were not comparable to results from TMAs. Expression of COX-2 and aromatase did not predict response to endocrine therapy. Aromatase in combination with high PR expression may select letrozole treated patients with a longer TTP. Conclusion TMAs are not suitable for IHC analysis of in situ aromatase expression and we did not find COX-2 expression in carcinoma cells to be a surrogate marker for aromatase. In situ aromatase expression in tumor cells is associated with ER expression and may thus point towards good prognosis. Aromatase expression in cancer cells is not predictive of response to endocrine therapy, indicating that in situ estrogen synthesis may not be the major source of intratumoral estrogen. However, aromatase expression in combination with high PR expression may select letrozole treated patients with longer TTP. Trial registration Sub-study of trial P025 for advanced breast cancer. PMID:19531212

Cardiovascular Disease After Aromatase Inhibitor Use.

PubMed

Haque, Reina; Shi, Jiaxiao; Schottinger, Joanne E; Chung, Joanie; Avila, Chantal; Amundsen, Britta; Xu, Xiaoqing; Barac, Ana; Chlebowski, Rowan T

2016-12-01

Cardiovascular disease (CVD) is an important cause of death in older patients with breast cancer. However, limited information exists on the long-term effect of aromatase inhibitor (AI) use on CVD risk in breast cancer survivors. To this point, no other population-based studies have been able to adjust for CVD risk factors or cardiovascular medications. To determine the long-term influence of adjuvant endocrine therapies on CVD in a cohort of postmenopausal breast cancer survivors in analyses that accounted for major CVD risk factors, medication use, chemotherapy, and radiotherapy. A retrospective cohort of postmenopausal women with breast cancer diagnosed from January 1, 1991, to December 31, 2010, and followed up through December 31, 2011 (maximum, 21 years [72 886 person-years]), was evaluated using records from a managed care organization with nearly 20 community hospitals in California. A total of 13 273 postmenopausal women with hormone receptor-positive breast cancer without prior CVD were included. Cardiovascular disease incidence was compared across endocrine therapy categories. Information on demographics, comorbidity, medication, use, and CVD risk was captured from electronic health records. Multivariate Cox proportional hazards models using time-dependent endocrine drug use variables and propensity scores were conducted. Data analysis was conducted from September 15, 2014, to February 1, 2016. Women were grouped by endocrine therapy status (tamoxifen citrate only, AI only, both, or neither). Person-year rates of CVD for each therapy group. During 72 886 person-years in 13 273 women (mean [SD] age, 66.8 [8.1] years) with follow-up through 2011, we observed 3711 CVD events. In multivariable analyses (reported as hazard ratio [95% CI]), AI-only users had a similar risk of cardiac ischemia (myocardial infarction and angina) (adjusted, 0.97 [0.78-1.22]) and stroke (adjusted, 0.97 [0.70-1.33]) as tamoxifen-only users (reference). However, we found an increased risk of other CVD (dysrhythmia, valvular dysfunction, and pericarditis) (adjusted, 1.29 [1.11-1.50]) in women who used AIs only or sequentially after tamoxifen (1.26 [1.09-1.45]) vs tamoxifen (reference) as well nonhormone users (1.18 [1.02-1.35]). The risk of the most serious cardiovascular events (cardiac ischemia or stroke) was not elevated in AI-only users compared with tamoxifen users. The finding that other CVD events combined were greater in AI users requires further study.

Multi-modal management of acromegaly: a value perspective.

PubMed

Kimmell, Kristopher T; Weil, Robert J; Marko, Nicholas F

2015-10-01

The Acromegaly Consensus Group recently released updated guidelines for medical management of acromegaly patients. We subjected these guidelines to a cost analysis. We conducted a cost analysis of the recommendations based on published efficacy rates as well as publicly available cost data. The results were compared to findings from a previously reported comparative effectiveness analysis of acromegaly treatments. Using decision tree software, two models were created based on the Acromegaly Consensus Group's recommendations and the comparative effectiveness analysis. The decision tree for the Consensus Group's recommendations was subjected to multi-way tornado analysis to identify variables that most impacted the value analysis of the decision tree. The value analysis confirmed the Consensus Group's recommendations of somatostatin analogs as first line therapy for medical management. Our model also demonstrated significant value in using dopamine agonist agents as upfront therapy as well. Sensitivity analysis identified the cost of somatostatin analogs and growth hormone receptor antagonists as having the most significant impact on the cost effectiveness of medical therapies. Our analysis confirmed the value of surgery as first-line therapy for patients with surgically accessible lesions. Surgery provides the greatest value for management of patients with acromegaly. However, in accordance with the Acromegaly Consensus Group's recent recommendations, somatostatin analogs provide the greatest value and should be used as first-line therapy for patients who cannot be managed surgically. At present, the substantial cost is the most significant negative factor in the value of medical therapies for acromegaly.

Treatment algorithm in 2014 for advanced non-small cell lung cancer: therapy selection by tumour histology and molecular biology.

PubMed

Manegold, Christian

2014-09-01

The availability of antineoplastic monoclonal antibodies, small molecules and newer cytotoxics such as pemetrexed, the EGFR-tyrosine kinase inhibitors erlotinib, gefitinib, afatinib as well as the anti-angiogenic bevacizumab and the ALK-inhibitor crizotinib has recently changes the treatment algorithm of advanced non-small cell lung cancer. Decision making in 2014 is characterized by customizing therapy, by selecting a specific therapeutic regimen based on the histotype and the genotype of the tumour. This refers to first-line induction therapy and maintenance therapy as well, but also to subsequent lines of therapy since anti-neoplastic drugs and regimens used upfront clinically influence the selection of agents/regimes considered for second-/third-line treatment. Consequently, therapy customization through tumour histology and molecular markers has significantly influenced the work of pathologists around the globe and the process of obtaining an extended therapeutically relevant tumour diagnosis. Not only histological sub-typing became standard but molecular information is also considered of increasing importance for treatment selection. Routine molecular testing in certified laboratories must be established, and the diagnostic process should ideally be performed under the guidance of evidence based recommendation. The process of investigating and implementing medical targeting in lung cancer therefore, requires advanced diagnostic techniques and expertise and because of its large dimension is costly and influenced by the limitation of financial and clinical resources. Copyright © 2014. Published by Elsevier Urban & Partner Sp. z o.o.

Major clinical research advances in gynecologic cancer in 2015

PubMed Central

2016-01-01

In 2015, fourteen topics were selected as major research advances in gynecologic oncology. For ovarian cancer, high-level evidence for annual screening with multimodal strategy which could reduce ovarian cancer deaths was reported. The best preventive strategies with current status of evidence level were also summarized. Final report of chemotherapy or upfront surgery (CHORUS) trial of neoadjuvant chemotherapy in advanced stage ovarian cancer and individualized therapy based on gene characteristics followed. There was no sign of abating in great interest in immunotherapy as well as targeted therapies in various gynecologic cancers. The fifth Ovarian Cancer Consensus Conference which was held in November 7–9 in Tokyo was briefly introduced. For cervical cancer, update of human papillomavirus vaccines regarding two-dose regimen, 9-valent vaccine, and therapeutic vaccine was reviewed. For corpus cancer, the safety concern of power morcellation in presumed fibroids was explored again with regard to age and prevalence of corpus malignancy. Hormone therapy and endometrial cancer risk, trabectedin as an option for leiomyosarcoma, endometrial cancer and Lynch syndrome, and the radiation therapy guidelines were also discussed. In addition, adjuvant therapy in vulvar cancer and the updated of targeted therapy in gynecologic cancer were addressed. For breast cancer, palbociclib in hormone-receptor-positive advanced disease, oncotype DX Recurrence Score in low-risk patients, regional nodal irradiation to internal mammary, supraclavicular, and axillary lymph nodes, and cavity shave margins were summarized as the last topics covered in this review. PMID:27775259

Major clinical research advances in gynecologic cancer in 2015.

PubMed

Suh, Dong Hoon; Kim, Miseon; Kim, Hak Jae; Lee, Kyung Hun; Kim, Jae Weon

2016-11-01

In 2015, fourteen topics were selected as major research advances in gynecologic oncology. For ovarian cancer, high-level evidence for annual screening with multimodal strategy which could reduce ovarian cancer deaths was reported. The best preventive strategies with current status of evidence level were also summarized. Final report of chemotherapy or upfront surgery (CHORUS) trial of neoadjuvant chemotherapy in advanced stage ovarian cancer and individualized therapy based on gene characteristics followed. There was no sign of abating in great interest in immunotherapy as well as targeted therapies in various gynecologic cancers. The fifth Ovarian Cancer Consensus Conference which was held in November 7-9 in Tokyo was briefly introduced. For cervical cancer, update of human papillomavirus vaccines regarding two-dose regimen, 9-valent vaccine, and therapeutic vaccine was reviewed. For corpus cancer, the safety concern of power morcellation in presumed fibroids was explored again with regard to age and prevalence of corpus malignancy. Hormone therapy and endometrial cancer risk, trabectedin as an option for leiomyosarcoma, endometrial cancer and Lynch syndrome, and the radiation therapy guidelines were also discussed. In addition, adjuvant therapy in vulvar cancer and the updated of targeted therapy in gynecologic cancer were addressed. For breast cancer, palbociclib in hormone-receptor-positive advanced disease, oncotype DX Recurrence Score in low-risk patients, regional nodal irradiation to internal mammary, supraclavicular, and axillary lymph nodes, and cavity shave margins were summarized as the last topics covered in this review.

Molecular Action and Clinical Relevance of Aromatase Inhibitors.

PubMed

Murphy

1998-01-01

BREAST CANCER: HIGH PREVALENCE AND RISING INCIDENCE: Breast cancer is the most common form of cancer among women in Europe, North and South America and Australasia; approximately 1 in 10 women in Western countries will develop breast cancer during their lifetime. It is estimated that the disease will affect five million women worldwide over the next decade, and the incidence of breast cancer is increasing on average by about 1% per year in industrialized countries and at a greater rate in developing countries. COMPLEX ETIOLOGY: Although the specific etiology of breast cancer remains unknown, a number of factors are recognized which increase a woman's risk of developing the disease. Genetic predisposition, or family history of breast cancer, is known to be responsible for 5% of all cases. However, the variation in incidence throughout populations, and changes relating to population migration and adoption of altered lifestyles, all point to the critical importance of nongenetic determinants. Such factors include early menarche, late menopause, late age at birth of first child or nulliparity, a history of benign breast disease, and diet. There is also evidence that hormones play a major role in the etiology of breast cancer, with the risk of developing malignancies related to the cumulative exposure of the breast to estrogen and progesterone, which stimulate the growth of tumor cells. TREATMENT FOR EARLY BREAST CANCER: SURGERY -/+ ADJUVANT THERAPY: At the time of diagnosis, approximately 50% of patients will be diagnosed with early breast cancer. This proportion is increasing as a consequence of the introduction of early detection programs. Surgery remains the primary treatment for early breast cancer, and the frequency of radical mastectomy has been replaced by breast conserving surgery. After surgery, other therapeutic modalities such as radiation, chemotherapy or endocrine therapy may be given in the adjuvant setting. Surgical cure rates vary for patients with early breast cancer; the US figure is approximately 40%, and there are no definitive means to predict those who will be cured and those who will have recurrent disease. As a result, following primary surgical treatment, adjuvant therapy is usually recommended to destroy any remaining cancer cells at the primary site, to control micrometastases and to prolong disease-free survival, with the ultimate aim of providing an overall survival benefit. Upon disease recurrence in the remaining 60% of patients, endocrine therapy and chemotherapy represent the two general classes of treatment. One of the principle decisions to be taken in advanced breast cancer is which therapy to select in order to maximize patient benefit. The choice is largely dependent upon prognostic factors and whether the patient is pre- or postmenopausal. ENDOCRINE THERAPY OR CHEMOTHERAPY IN ADVANCED BREAST CANCER: Unlike chemotherapy, endocrine therapy is not cytotoxic and is therefore better tolerated by the patient. A recent study comparing therapy for prognostically different groups showed that patients benefiting most from the use of sequential endocrine agents are those regarded as low risk. The preferred sequence of treatment has been suggested to be tamoxifen followed by selective aromatase inhibitor and then a progestin. ENDOCRINES AND ENZYMES OFFER NEW TREATMENTS FOR ADVANCED BREAST CANCER: ESTROGEN-DRIVEN BREAST CANCER: Since 1896, when Sir George Beatson demonstrated that ovariectomy induced regression of mammary tumors in women, the aim of endocrine breast cancer therapy has been to selectively deprive the body of estrogen. Ovariectomy accomplished this by removing the gland that is the predominant source of estrogens in premenopausal women. Since the avoidance of such surgery is preferable, emphasis is devoted to the pharmacological inhibitors of estrogen production. ENDOCRINE PATHWAY REVEALS "ACHILLES' HEEL": Like other steroid hormones, the two circulating estrogens-estrone and estradiol-are produced from cholesterol. Inhibiting the enzymes that are involved at earlier steps in the branching pathway of steroidogenesis could have an undesirable impact on the production of other physiologically important hormones such as aldosterone and cortisol. Since aromatase catalyzes the last step in estrogen production, it makes an ideal target for the development of selective and potent inhibitors (Fig. 1). STRUCTURE OF AROMATASE REVEALS SECRETS OF SELECTIVE INHIBITION: Aromatase is a cytochrome P450 enzyme, with both an iron-containing and a steroid-binding site. The substrate, androstenedione, sits in the enzyme's steroid-binding site, that site which otherwise catalyzes the formation of estrogen. From this structural relationship, there are, therefore, two reasonable ways to inhibit aromatase: * by occupying the steroid-binding site of the enzyme with a compound such as formestane (Lentaron®), or * by binding the iron with nitrogen-containing compounds such as aminoglutethimide (Orimeten®), the oldest aromatase inhibitor. AROMATASE INHIBITORS: STEROIDAL AND NON-STEROIDAL: Formestane (Lentaron®) is the only commercially available steroidal compound which inhibits aromatase and must be administered parenterally. Other new aromatase inhibitors such as fadrozole (Afema®) and letrozole (Femara®) are orally active nitrogen-containing compounds that bind the heme iron of aromatase. AMINOGLUTETHIMIDE VERSUS LETROZOLE: OLD VERSUS NEW: Although aminoglutethimide has long been used to treat advanced breast cancer, its aromatase inhibition is not selective. Consequently, aminoglutethimide also binds to and thereby inhibits several other cytochrome P450 enzymes in the steroidogenesis pathway. An ideal aromatase inhibitor would fit the catalytic site of aromatase optimally and would thus interact only with aromatase. The affinity of letrozole (Femara®) for the heme group of aromatase makes it a selective and potent inhibitor (Fig. 2). In fact, studies show that Femara® has little effect on the other adrenal steroids, and is the most selective aromatase inhibitor available today.

Catching the missing million: experiences in enhancing TB & DR-TB detection by providing upfront Xpert MTB/RIF testing for people living with HIV in India.

PubMed

Raizada, Neeraj; Sachdeva, Kuldeep Singh; Sreenivas, Achuthan; Kulsange, Shubhangi; Gupta, Radhey Shyam; Thakur, Rahul; Dewan, Puneet; Boehme, Catharina; Paramsivan, Chinnambedu Nainarappan

2015-01-01

A critical challenge in providing TB care to People Living with HIV (PLHIV) is establishing an accurate bacteriological diagnosis. Xpert MTB/RIF, a highly sensitive and specific rapid tool, offers a promising solution in addressing these challenges. This study presents results from PLHIV taking part in a large demonstration study across India wherein upfront Xpert MTB/RIF testing was offered to all presumptive PTB cases in public health facilities. The study covered a population of 8.8 million across 18 sub-district level tuberculosis units (TU), with one Xpert MTB/RIF platform established at each TU. All HIV-infected patients suspected of TB (both TB and Drug Resistant TB (DR-TB)) accessing public health facilities in study area were prospectively enrolled and provided upfront Xpert MTB/RIF testing. 2,787 HIV-infected presumptive pulmonary TB cases were enrolled and 867 (31.1%, 95% Confidence Interval (CI) 29.4‒32.8) HIV-infected TB cases were diagnosed under the study. Overall 27.6% (CI 25.9-29.3) of HIV-infected presumptive PTB cases were positive by Xpert MTB/RIF, compared with 12.9% (CI 11.6-14.1) who had positive sputum smears. Upfront Xpert MTB/RIF testing of presumptive PTB and DR-TB cases resulted in diagnosis of 73 (9.5%, CI 7.6‒11.8) and 16 (11.2%, CI 6.7‒17.1) rifampicin resistance cases, respectively. Positive predictive value (PPV) for rifampicin resistance detection was high 97.7% (CI 89.3‒99.8), with no significant difference with or without prior history of TB treatment. The study results strongly demonstrate limitations of using smear microscopy for TB diagnosis in PLHIV, leading to low TB and DR-TB detection which can potentially lead to either delayed or sub-optimal TB treatment. Our findings demonstrate the usefulness and feasibility of addressing this diagnostic gap with upfront of Xpert MTB/RIF testing, leading to overall strengthening of care and support package for PLHIV.

Catching the Missing Million: Experiences in Enhancing TB & DR-TB Detection by Providing Upfront Xpert MTB/RIF Testing for People Living with HIV in India

PubMed Central

Raizada, Neeraj; Sachdeva, Kuldeep Singh; Sreenivas, Achuthan; Kulsange, Shubhangi; Gupta, Radhey Shyam; Thakur, Rahul; Dewan, Puneet; Boehme, Catharina; Paramsivan, Chinnambedu Nainarappan

2015-01-01

Background A critical challenge in providing TB care to People Living with HIV (PLHIV) is establishing an accurate bacteriological diagnosis. Xpert MTB/RIF, a highly sensitive and specific rapid tool, offers a promising solution in addressing these challenges. This study presents results from PLHIV taking part in a large demonstration study across India wherein upfront Xpert MTB/RIF testing was offered to all presumptive PTB cases in public health facilities. Method The study covered a population of 8.8 million across 18 sub-district level tuberculosis units (TU), with one Xpert MTB/RIF platform established at each TU. All HIV-infected patients suspected of TB (both TB and Drug Resistant TB (DR-TB)) accessing public health facilities in study area were prospectively enrolled and provided upfront Xpert MTB/RIF testing. Result 2,787 HIV-infected presumptive pulmonary TB cases were enrolled and 867 (31.1%, 95% Confidence Interval (CI) 29.4‒32.8) HIV-infected TB cases were diagnosed under the study. Overall 27.6% (CI 25.9–29.3) of HIV-infected presumptive PTB cases were positive by Xpert MTB/RIF, compared with 12.9% (CI 11.6–14.1) who had positive sputum smears. Upfront Xpert MTB/RIF testing of presumptive PTB and DR-TB cases resulted in diagnosis of 73 (9.5%, CI 7.6‒11.8) and 16 (11.2%, CI 6.7‒17.1) rifampicin resistance cases, respectively. Positive predictive value (PPV) for rifampicin resistance detection was high 97.7% (CI 89.3‒99.8), with no significant difference with or without prior history of TB treatment. Conclusion The study results strongly demonstrate limitations of using smear microscopy for TB diagnosis in PLHIV, leading to low TB and DR-TB detection which can potentially lead to either delayed or sub-optimal TB treatment. Our findings demonstrate the usefulness and feasibility of addressing this diagnostic gap with upfront of Xpert MTB/RIF testing, leading to overall strengthening of care and support package for PLHIV. PMID:25658091

Multiple endocrine neoplasia type 1

PubMed Central

Marini, Francesca; Falchetti, Alberto; Monte, Francesca Del; Sala, Silvia Carbonell; Gozzini, Alessia; Luzi, Ettore; Brandi, Maria Luisa

2006-01-01

Multiple Endocrine Neoplasia type 1 (MEN1) is a rare autosomal dominant hereditary cancer syndrome presented mostly by tumours of the parathyroids, endocrine pancreas and anterior pituitary, and characterised by a very high penetrance and an equal sex distribution. It occurs in approximately one in 30,000 individuals. Two different forms, sporadic and familial, have been described. The sporadic form presents with two of the three principal MEN1-related endocrine tumours (parathyroid adenomas, entero-pancreatic tumours and pituitary tumours) within a single patient, while the familial form consists of a MEN1 case with at least one first degree relative showing one of the endocrine characterising tumours. Other endocrine and non-endocrine lesions, such as adrenal cortical tumours, carcinoids of the bronchi, gastrointestinal tract and thymus, lipomas, angiofibromas, collagenomas have been described. The responsible gene, MEN1, maps on chromosome 11q13 and encodes a 610 aminoacid nuclear protein, menin, with no sequence homology to other known human proteins. MEN1 syndrome is caused by inactivating mutations of the MEN1 tumour suppressor gene. This gene is probably involved in the regulation of several cell functions such as DNA replication and repair and transcriptional machinery. The combination of clinical and genetic investigations, together with the improving of molecular genetics knowledge of the syndrome, helps in the clinical management of patients. Treatment consists of surgery and/or drug therapy, often in association with radiotherapy or chemotherapy. Currently, DNA testing allows the early identification of germline mutations in asymptomatic gene carriers, to whom routine surveillance (regular biochemical and/or radiological screenings to detect the development of MEN1-associated tumours and lesions) is recommended. PMID:17014705

Endocrine and metabolic emergencies in children: hypocalcemia, hypoglycemia, adrenal insufficiency, and metabolic acidosis including diabetic ketoacidosis

PubMed Central

2015-01-01

It is important to fast diagnosis and management of the pediatric patients of the endocrine metabolic emergencies because the signs and symptoms of these disorders are nonspecific. Delayed diagnosis and treatment may lead to serious consequences of the pediatric patients, for example, cerebral dysfunction leading to coma or death of the patients with hypoglycemia, hypocalcemia, adrenal insufficiency, or diabetic ketoacidosis. The index of suspicion of the endocrine metabolic emergencies should be preceded prior to the starting nonspecific treatment. Importantly, proper diagnosis depends on the collection of blood and urine specimen before nonspecific therapy (intravenous hydration, electrolytes, glucose or calcium injection). At the same time, the taking of precise history and searching for pathognomonic physical findings should be performed. This review was described for fast diagnosis and proper management of hypoglycemic emergencies, hypocalcemia, adrenal insufficiency, and metabolic acidosis including diabetic ketoacidosis. PMID:26817004

The hormonal control of ejaculation.

PubMed

Corona, Giovanni; Jannini, Emmanuele A; Vignozzi, Linda; Rastrelli, Giulia; Maggi, Mario

2012-09-01

Hormones regulate all aspects of male reproduction, from sperm production to sexual drive. Although emerging evidence from animal models and small clinical studies in humans clearly point to a role for several hormones in controlling the ejaculatory process, the exact endocrine mechanisms are unclear. Evidence shows that oxytocin is actively involved in regulating orgasm and ejaculation via peripheral, central and spinal mechanisms. Associations between delayed and premature ejaculation with hypothyroidism and hyperthyroidism, respectively, have also been extensively documented. Some models suggest that glucocorticoids are involved in the regulation of the ejaculatory reflex, but corresponding data from human studies are scant. Oestrogens regulate epididymal motility, whereas testosterone can affect the central and peripheral aspects of the ejaculatory process. Overall, the data of the endocrine system in regulating the ejaculatory reflex suggest that widely available endocrine therapies might be effective in treating sexual disorders in these men. Indeed, substantial evidence has documented that treatments of thyroid diseases are able to improve some ejaculatory difficulties.

Rationale for the Use of Upfront Whole Brain Irradiation in Patients with Brain Metastases from Breast Cancer

PubMed Central

Tallet, Agnes V.; Azria, David; Le Rhun, Emilie; Barlesi, Fabrice; Carpentier, Antoine F.; Gonçalves, Antony; Taillibert, Sophie; Dhermain, Frédéric; Spano, Jean-Philippe; Metellus, Philippe

2014-01-01

Breast cancer is the second most common cause of brain metastases and deserves particular attention in relation to current prolonged survival of patients with metastatic disease. Advances in both systemic therapies and brain local treatments (surgery and stereotactic radiosurgery) have led to a reappraisal of brain metastases management. With respect to this, the literature review presented here was conducted in an attempt to collect medical evidence-based data on the use of whole-brain radiotherapy for the treatment of brain metastases from breast cancer. In addition, this study discusses here the potential differences in outcomes between patients with brain metastases from breast cancer and those with brain metastases from other primary malignancies and the potential implications within a treatment strategy. PMID:24815073

Brain Metastases in Oncogene-Addicted Non-Small Cell Lung Cancer Patients: Incidence and Treatment

PubMed Central

Remon, J.; Besse, Benjamin

2018-01-01

Brain metastases (BM) are common in non-small cell lung cancer patients including in molecularly selected populations, such as EGFR-mutant and ALK-rearranged tumors. They are associated with a reduced quality of life, and are commonly the first site of progression for patients receiving tyrosine kinase inhibitors (TKIs). In this review, we summarize incidence of BM and intracranial efficacy with TKI agents according to oncogene driver mutations, focusing on important clinical issues, notably optimal first-line treatment in oncogene-addicted lung tumors with upfront BM (local therapies followed by TKI vs. TKI monotherapy). We also discuss the potential role of newly emerging late-generation TKIs as new standard treatment in oncogene-addicted lung cancer tumors compared with sequential strategies. PMID:29696132

Rationale for the use of upfront whole brain irradiation in patients with brain metastases from breast cancer.

PubMed

Tallet, Agnes V; Azria, David; Le Rhun, Emilie; Barlesi, Fabrice; Carpentier, Antoine F; Gonçalves, Antony; Taillibert, Sophie; Dhermain, Frédéric; Spano, Jean-Philippe; Metellus, Philippe

2014-05-08

Breast cancer is the second most common cause of brain metastases and deserves particular attention in relation to current prolonged survival of patients with metastatic disease. Advances in both systemic therapies and brain local treatments (surgery and stereotactic radiosurgery) have led to a reappraisal of brain metastases management. With respect to this, the literature review presented here was conducted in an attempt to collect medical evidence-based data on the use of whole-brain radiotherapy for the treatment of brain metastases from breast cancer. In addition, this study discusses here the potential differences in outcomes between patients with brain metastases from breast cancer and those with brain metastases from other primary malignancies and the potential implications within a treatment strategy.

Management of Wilms' tumor: NWTS vs SIOP

PubMed Central

Bhatnagar, Sushmita

2009-01-01

With the availability of several protocols in the management of Wilms' tumor, there is dilemma in the minds of the treating oncologists or pediatric onco-surgeons as to whether the child should receive upfront chemotherapy or should be operated upon primarily. It is necessary for us to understand why do we follow either of the protocols, NWTS which follows the upfront surgery principle or the SIOP which follows the upfront chemotherapy principle in all stages of the disease. While deciding which protocol to follow, it is imperative to know the pros and cons of the treatment strategies and also to study the outcome patterns in both the treatment regimes which is what this article highlights. In an attempt to compare all the differences in both the major protocols, it was realized that most of our patients in the Indian scenario present with advanced disease and thus poorer outcomes if intensive and appropriate treatment strategies are not utilized. Hence, it is imperative that we should study our own patients through the Indian Wilms' tumor study group and adopt the policies which improve the overall event free survival on a nationwide basis. PMID:20177436

Maturation and function of human embryonic stem cell-derived pancreatic progenitors in macroencapsulation devices following transplant into mice.

PubMed

Bruin, Jennifer E; Rezania, Alireza; Xu, Jean; Narayan, Kavitha; Fox, Jessica K; O'Neil, John J; Kieffer, Timothy J

2013-09-01

Islet transplantation is a promising cell therapy for patients with diabetes, but it is currently limited by the reliance upon cadaveric donor tissue. We previously demonstrated that human embryonic stem cell (hESC)-derived pancreatic progenitor cells matured under the kidney capsule in a mouse model of diabetes into glucose-responsive insulin-secreting cells capable of reversing diabetes. However, the formation of cells resembling bone and cartilage was a major limitation of that study. Therefore, we developed an improved differentiation protocol that aimed to prevent the formation of off-target mesoderm tissue following transplantation. We also examined how variation within the complex host environment influenced the development of pancreatic progenitors in vivo. The hESCs were differentiated for 14 days into pancreatic progenitor cells and transplanted either under the kidney capsule or within Theracyte (TheraCyte, Laguna Hills, CA, USA) devices into diabetic mice. Our revised differentiation protocol successfully eliminated the formation of non-endodermal cell populations in 99% of transplanted mice and generated grafts containing >80% endocrine cells. Progenitor cells developed efficiently into pancreatic endocrine tissue within macroencapsulation devices, despite lacking direct contact with the host environment, and reversed diabetes within 3 months. The preparation of cell aggregates pre-transplant was critical for the formation of insulin-producing cells in vivo and endocrine cell development was accelerated within a diabetic host environment compared with healthy mice. Neither insulin nor exendin-4 therapy post-transplant affected the maturation of macroencapsulated cells. Efficient differentiation of hESC-derived pancreatic endocrine cells can occur in a macroencapsulation device, yielding glucose-responsive insulin-producing cells capable of reversing diabetes.

Bruton tyrosine kinase inhibition in chronic lymphocytic leukemia.

PubMed

Maddocks, Kami; Jones, Jeffrey A

2016-04-01

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia and remains incurable outside of the setting of allogeneic stem cell transplant. While the standard therapy for both initial and relapsed CLL has traditionally included monoclonal antibody therapy in combination with chemotherapy, there are patients with high-risk disease features including unmutated IgVH, del(11q22) and del(17p13) that are associated with poor overall responses to these therapies with short time to relapse and shortened overall survival. Additionally, many of these therapies have a high rate of infectious toxicity in a population already at increased risk. Targeting the B-cell receptor (BCR) signaling pathway has emerged as a promising therapeutic advance in a variety of B-cell malignancies, including CLL. Bruton agammaglobulinemia tyrosine kinase (Btk) is a tyrosine kinase in the BCR pathway critical to the survival of both normal and malignant B cells and inhibition of this kinase has shown to block the progression of CLL. Ibrutinib, a first in class oral inhibitor of Btk, has shown promise as a very effective agent in the treatment of CLL-in both relapsed and upfront therapy, alone and in combination with other therapies, and in patients of all-risk disease-which has led to its approval in relapsed CLL and as frontline therapy in patients with the high-risk del(17p13) disease. Several studies are ongoing to evaluate the efficacy and safety of ibrutinib in combination with chemotherapy as frontline treatment for CLL and investigation into newer-generation Btk inhibitors is also underway. Copyright © 2016 Elsevier Inc. All rights reserved.

Glyceollin I reverses epithelial to mesenchymal transition in letrozole resistance

USDA-ARS?s Scientific Manuscript database

Although aromatase inhibitors, such as letrozole; are standard endocrine therapy for postmenopausal women with early stage metastatic estrogen-dependent breast cancer, the major limitation in managing this disease is the development of drug resistance; therefore, a better understanding of this proce...

[The relative analysis of clinical endocrine features and pathological types of pituitary microadenomas].

PubMed

Yan, Qing; Zhang, Hua-qiu; Wang, He-ping; Guo, Dong-sheng; Lei, Ting; Li, Ling

2010-06-15

To study the relationship between the clinical presentation, endocrinal findings and pathological types in patients with pituitary microadenomas, so as to improve the accuracy of clinical diagnosis and choose the best therapy strategy before the operation. From January 2007 to June 2009, the clinical data of 94 patients who were surgically removed pituitary microadenomas were obtained, including the clinical presentation, endocrinal findings and pathological diagnosis. The analysis was accomplished with Chi-square test. Hormonal symptoms were found in 86 patients (91.5%), it occurred more frequently in immunopositive patients (85/92, 92.4%) than in immunonegative patients (1/2, 50.0%) (P < 0.05). The coincidence of hormonal symptoms and immunohistochemistry diagnosis was 71.7%; 88.9% patients had the symptoms of amenorrhea, galactorrhea and sexual function diseases in prolactin (PRL) positive group and 28.1% patients had the symptoms of gigantism or acromegaly in growth hormone (GH) positive group. The coincidence of endocrinal findings and immunohistochemistry diagnosis was 69.0%; 87.7% patients had high level of blood PRL in PRL positive group and 21.9% patients had high level of blood GH in GH positive group. There is an obvious relationship between the clinical presentation, endocrinal findings and pathological diagnosis in patients with pituitary microadenomas, which may contribute to the clinical diagnosis and treatment of pituitary secreting microadenomas.

Endocrine and metabolic disorders associated with human immune deficiency virus infection.

PubMed

Unachukwu, C N; Uchenna, D I; Young, E E

2009-01-01

Many reports have described endocrine and metabolic disorders in the human immunodeficiency virus (HIV) infection. This article reviewed various reports in the literature in order to increase the awareness and thus the need for early intervention when necessary. Data were obtained from MEDLINE, Google search and otherjournals on 'HIV, Endocrinopathies/Metabolic Disorders' from 1985 till 2007. Studies related to HIV associated endocrinopathies and metabolic disorders in the last two decades were reviewed. Information on epidemiology, pathogenesis, diagnosis and treatment of the target organ endocrinopathies and metabolic disorders in HIV/AIDS were extracted from relevant literature. Endocrine and metabolic disturbances occur in the course of HIV infection. Pathogenesis includes direct infection of endocrine glands by HIV or opportunistic organisms, infiltration by neoplasms and side effects of drugs. Adrenal insufficiency is the commonest HIV endocrinopathy with cytomegalovirus adrenalitis occurring in 40-88% of cases. Thyroid dysfunction may occur as euthyroid sick syndrome or sub-clinical hypothyroidism. Hypogonadotrophic dysfunction accounts for 75% of HIV-associated hypogonadism, with prolonged amenorrhoea being three times more likely in the women. Pancreatic dysfunction may result in hypoglycaemia or diabetes mellitus (DM). Highly active antiretroviral therapy (HAART) especially protease inhibitors has been noted to result in insulin resistance and lipodystrophy. Virtually every endocrine organ is involved in the course of HIV infection. Detailed endocrinological and metabolic evaluation and appropriate treatment is necessary in the optimal management of patients with HIV infection in our environment.

Patient-reported Quality of Life and Treatment Satisfaction in Patients With HR+/HER2- Advanced/Metastatic Breast Cancer.

PubMed

Wood, Robert; Mitra, Debanjali; de Courcy, Jonathan; Iyer, Shrividya

2017-08-01

Globally, around 1.67 million new cases of breast cancer are diagnosed each year, with advanced breast cancer (ABC-Stage III) and metastatic breast cancer (MBC-Stage IV) together accounting for up to 22% of incident cases. Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR + /HER2 - ) breast cancer comprises 66% of ABC/MBC. Understanding disease-specific health-related quality of life and patient satisfaction with treatments currently available for HR + /HER2 - ABC/MBC in clinical practice is essential for assessing potential unmet need in this patient population. Data on treatment patterns in patients with HR + /HER2 - ABC/MBC were collected from oncology practices across the United States and Europe in a cross-sectional study in a clinical practice setting, the Adelphi Real World Advanced Breast Cancer Disease Specific Programme. A subset of patients included in the study completed several self-reported tools, including the Functional Assessment of Cancer Therapy-Breast and the Cancer Therapy Satisfaction Questionnaire. Analyses were conducted using data from the overall cohort and stratified by current treatment, metastatic sites, and number of prior therapy lines. Overall, 739 patients were recruited by 173 oncologists; 83% of patients had MBC, with the balance having ABC. The majority of patients with MBC had visceral metastases without bone metastases, and similar percentages of the total study population (≈40%) were receiving chemotherapy and endocrine therapy. Patients receiving only endocrine therapy had significantly better cancer-specific quality of life than did those receiving chemotherapy. Endocrine therapy also associated with fewer concerns about side effects and higher treatment satisfaction than chemotherapy. Statistically lower scores, indicating poorer well-being, were observed in patients with both bone and visceral metastases compared with those with either bone-only or visceral-only metastases for all but the Social/Family Well-Being and Functional Well-Being domains of the Functional Assessment of Cancer Therapy-Breast. Patients with bone and visceral metastases had significantly greater concerns about treatment side effects than those with metastases at other sites. Receipt of a greater number of prior lines of therapy was associated with poorer well-being scores. There was a significant negative association between number of lines of treatment and treatment expectations. Findings from this study from clinical practice suggest that treatment outcomes in HR + /HER2 - ABC/MBC could be optimized through improved understanding of the impact that components of patient care have on health-related quality of life and treatment satisfaction. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

Comparison of the effects of ovarian cauterization and gonadotropin-releasing hormone agonist and oral contraceptive therapy combination on endocrine changes in women with polycystic ovary disease.

PubMed

Taskin, O; Yalcinoglu, A I; Kafkasli, A; Burak, F; Ozekici, U

1996-06-01

To study the effects of laparoscopic ovarian cauterization and combination of long-acting GnRH agonist (GnRH-a) and oral contraceptive (OC) therapy on endocrine changes in women with clomiphene citrate (CC)- resistant polycystic ovary disease (PCOD). Prospective, randomized. University-based infertility clinic. Seventeen women with CC-resistant PCOD were included randomly in the study to either laparoscopic ovarian cautery or GnRH-a and OC therapy for 3 months. Serum concentrations of LH, FSH, androstenedione (A), T, and sex hormone-binding globulin (SHBG) were determined before each therapeutic approach and during the follicular phase of first menstrual cycle after the cessation of each treatment. The mean serum concentrations and the clinical profiles were similar in both groups. Both groups showed significant changes in LH, FSH, A, T, and SHBG compared with pretreatment levels. There were no significant differences in the final concentrations of LH, FSH, and A between the two study groups after each treatment, whereas T and SHBG levels were significantly different in the goserelin and OC group. The decrease in LH and increase in SHBG serum concentrations were greater in the goserelin and OC-treated women [-59% and + 5.9% versus - 70% and + 13.5%, respectively]. Although the SHBG concentration increased in both groups, the serum SHBG concentration of the goserelin and OC group was significantly higher than the other group. Both therapeutic modalities revealed similar effects on the endocrine profiles in women with CC-resistant PCOD. Considering the invasiveness, cost, and potential complications of laparoscopic ovarian cauterization, noninvasive medical treatment with GnRH-a and OC combination may be more effective in restoring the optimal follicular environment in women with PCOD.

Information needs and decision-making preferences of older women offered a choice between surgery and primary endocrine therapy for early breast cancer.

PubMed

Burton, Maria; Kilner, Karen; Wyld, Lynda; Lifford, Kate Joanna; Gordon, Frances; Allison, Annabel; Reed, Malcolm; Collins, Karen Anna

2017-12-01

To establish older women's (≥75 years) information preferences regarding 2 breast cancer treatment options: surgery plus adjuvant endocrine therapy versus primary endocrine therapy. To quantify women's preferences for the mode of information presentation and decision-making (DM) style. This was a UK multicentre survey of women, ≥75 years, who had been offered a choice between PET and surgery at diagnosis of breast cancer. A questionnaire was developed including 2 validated scales of decision regret and DM preferences. Questionnaires were sent to 247 women, and 101 were returned (response rate 41%). The median age of participants was 82 (range 75 to 99), with 58 having had surgery and 37 having PET. Practical details about the impact, safety, and efficacy of treatment were of most interest to participants. Of least interest were cosmetic outcomes after surgery. Information provided verbally by doctors and nurses, supported by booklets, was preferred. There was little interest in technology-based sources of information. There was equal preference for a patient- or doctor-centred DM style and lower preference for a shared DM style. The majority (74%) experienced their preferred DM style. Levels of decision regret were low (15.73, scale 0-100). Women strongly preferred face to face information. Written formats were also helpful but not computer-based resources. Information that was found helpful to women in the DM process was identified. The study demonstrates many women achieved their preferred DM style, with a preference for involvement, and expressed low levels of decision regret. Copyright © 2017 John Wiley & Sons, Ltd.

PALOMA-3: Phase III Trial of Fulvestrant With or Without Palbociclib in Premenopausal and Postmenopausal Women With Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer That Progressed on Prior Endocrine Therapy-Safety and Efficacy in Asian Patients.

PubMed

Iwata, Hiroji; Im, Seock-Ah; Masuda, Norikazu; Im, Young-Hyuck; Inoue, Kenichi; Rai, Yoshiaki; Nakamura, Rikiya; Kim, Jee Hyun; Hoffman, Justin T; Zhang, Ke; Giorgetti, Carla; Iyer, Shrividya; Schnell, Patrick T; Bartlett, Cynthia Huang; Ro, Jungsil

2017-08-01

To assess efficacy and safety of palbociclib plus fulvestrant in Asians with endocrine therapy-resistant metastatic breast cancer. The Palbociclib Ongoing Trials in the Management of Breast Cancer 3 (PALOMA-3) trial, a double-blind phase III study, included 521 patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer with disease progression on endocrine therapy. Patient-reported outcomes (PROs) were assessed on study treatment and at the end of treatment. This preplanned subgroup analysis of the PALOMA-3 study included premenopausal and postmenopausal Asians taking palbociclib plus fulvestrant (n = 71) or placebo plus fulvestrant (n = 31). Palbociclib plus fulvestrant improved progression-free survival (PFS) compared with fulvestrant alone. Median PFS was not reached with palbociclib plus fulvestrant (95% CI, 9.2 months to not reached) but was 5.8 months with placebo plus fulvestrant (95% CI, 3.5 to 9.2 months; hazard ratio, 0.485; 95% CI, 0.270 to 0.869; P = .0065). The most common all-cause grade 3 or 4 adverse events in the palbociclib arm were neutropenia (92%) and leukopenia (29%); febrile neutropenia occurred in 4.1% of patients. Within-patient mean trough concentration comparisons across subgroups indicated similar palbociclib exposure between Asians and non-Asians. Global quality of life was maintained; no statistically significant changes from baseline were observed for patient-reported outcome scores with palbociclib plus fulvestrant. This is the first report, to our knowledge, showing that palbociclib plus fulvestrant improves PFS in asian patients. Palbociclib plus fulvestrant was well tolerated in this study.

Targeting the cyclin D-cyclin-dependent kinase (CDK) 4/6-retinoblastoma pathway with selective CDK 4/6 inhibitors in hormone receptor-positive breast cancer: rationale, current status, and future directions.

PubMed

Spring, Laura; Bardia, Aditya; Modi, Shanu

2016-01-01

Dysregulation of the cyclin D-cyclin-dependent kinase (CDK) 4/6-INK4-retinoblastoma (Rb) pathway is an important contributor to endocrine therapy resistance. Recent clinical development of selective inhibitors of CDK4 and CDK6 kinases has led to renewed interest in cell cycle regulators, following experience with relatively non-selective pan-CDK inhibitors that often resulted in limited activity and poor safety profiles in the clinic. The highly selective oral CDK 4/6 inhibitors palbociclib (PD0332991), ribociclib (LEE011), and abemaciclib (LY2835219) are able to inhibit the proliferation of Rb-positive tumor cells and have demonstrated dose-dependent growth inhibition in ER+ breast cancer models. In metastatic breast cancer, all three agents are being explored in combination with endocrine therapy in Phase III studies. Results so far indicated promising efficacy and manageable safety profiles, and led to the FDA approval of palbociclib. Phase II-III studies of these agents, in combination with endocrine therapy, are also underway in early breast cancer in the neoadjuvant and adjuvant settings. Selective CDK 4/6 inhibitors are also being investigated with other targeted agents or chemotherapy in the advanced setting. This article reviews the rationale for targeting cyclin D-CDK 4/6 in hormone receptor-positive (HR+) breast cancer, provides an overview of the available preclinical and clinical data with CDK 4/6 inhibitors in breast cancer to date, and summarizes the main features of ongoing clinical trials of these new agents in breast cancer. Future trials evaluating further combination strategies with CDK 4/6 backbone and translational studies refining predictive biomarkers are needed to help personalize the optimal treatment regimen for individual patients with ER+ breast cancer.

Expanding the indications of pancreas transplantation alone.

PubMed

Mehrabi, Arianeb; Golriz, Mohammad; Adili-Aghdam, Fatemeh; Hafezi, Mohammadreza; Ashrafi, Maryam; Morath, Christian; Zeier, Martin; Hackert, Thilo; Schemmer, Peter

2014-11-01

Total pancreatectomy (TP) is associated with postoperative endocrine and exocrine insufficiency. Especially, insulin therapy reduces quality of life and may lead to long-term complications. We review the literature with regard to the potential option of pancreas transplantation alone (PTA) after TP in patients with chronic pancreatitis or benign tumors. A MEDLINE search (1958-2013) using the terminologies pancreas transplantation, pancreas transplantation alone, total pancreatectomy, morbidity, mortality, insulin therapy, and quality of life was performed. In addition, the current book and congress publications were reviewed. Total pancreatectomy after benign and borderline tumors as well as chronic pancreatitis is continuously increasing. Despite improvement of exogenous insulin therapy, more than 50% of these patients experience severe glucose control problems, which cause up to 50% long-term mortality. Pancreas transplantation alone can cure both endocrine and exocrine insufficiency and reduce the associated risks. The 3-year graft and patient survival rates after PTA are up to 73% and 100%, respectively. Pancreas transplantation alone after TP in patients with pancreatitis or benign tumors improves the recipient's quality of life and reduces long-term mortality. Considering the amount of available organs and potential candidates, PTA can be a treatment option for patients after TP with chronic pancreatitis or benign tumors.

Self-renewal of CD133(hi) cells by IL6/Notch3 signalling regulates endocrine resistance in metastatic breast cancer.

PubMed

Sansone, Pasquale; Ceccarelli, Claudio; Berishaj, Marjan; Chang, Qing; Rajasekhar, Vinagolu K; Perna, Fabiana; Bowman, Robert L; Vidone, Michele; Daly, Laura; Nnoli, Jennifer; Santini, Donatella; Taffurelli, Mario; Shih, Natalie N C; Feldman, Michael; Mao, Jun J; Colameco, Christopher; Chen, Jinbo; DeMichele, Angela; Fabbri, Nicola; Healey, John H; Cricca, Monica; Gasparre, Giuseppe; Lyden, David; Bonafé, Massimiliano; Bromberg, Jacqueline

2016-02-09

The mechanisms of metastatic progression from hormonal therapy (HT) are largely unknown in luminal breast cancer. Here we demonstrate the enrichment of CD133(hi)/ER(lo) cancer cells in clinical specimens following neoadjuvant endocrine therapy and in HT refractory metastatic disease. We develop experimental models of metastatic luminal breast cancer and demonstrate that HT can promote the generation of HT-resistant, self-renewing CD133(hi)/ER(lo)/IL6(hi) cancer stem cells (CSCs). HT initially abrogates oxidative phosphorylation (OXPHOS) generating self-renewal-deficient cancer cells, CD133(hi)/ER(lo)/OXPHOS(lo). These cells exit metabolic dormancy via an IL6-driven feed-forward ER(lo)-IL6(hi)-Notch(hi) loop, activating OXPHOS, in the absence of ER activity. The inhibition of IL6R/IL6-Notch pathways switches the self-renewal of CD133(hi) CSCs, from an IL6/Notch-dependent one to an ER-dependent one, through the re-expression of ER. Thus, HT induces an OXPHOS metabolic editing of luminal breast cancers, paradoxically establishing HT-driven self-renewal of dormant CD133(hi)/ER(lo) cells mediating metastatic progression, which is sensitive to dual targeted therapy.

The Impact of Endocrine Therapy on Cognitive Functions of Breast Cancer Patients: A Systematic Review.

PubMed

Bakoyiannis, Ioannis; Tsigka, Eleousa-Alexandra; Perrea, Despina; Pergialiotis, Vasilios

2016-02-01

The purpose of the present review was to study the impact of endocrine therapy (ET) on the cognitive outcomes of breast cancer patients. We systematically searched the literature using the MEDLINE (1966-2015), Scopus (2004-2015), ClinicalTrials.gov (2008-2015) and Cochrane Central Register (CENTRAL) databases, as well as the references of the electronically retrieved articles. Twelve studies were included in the present systematic review, which assessed the cognitive function of 2756 patients. Among these patients, 2381 received ET, whereas the remaining 375 served as controls (placebo or no therapy). The majority of patients were postmenopausal, and the minimum follow-up period was 3 months and the maximum 2 years. Treatment with ET seems to be accompanied by altered cognitive abilities, including verbal memory, verbal fluency, motor speed, attention and working memory. Tamoxifen seems to be related to decreased cognitive performances compared with treatment with an aromatase inhibitor. ET among breast cancer patients seems to negatively alter the cognitive outcomes of breast cancer patients. However, the methodological heterogeneity of the included studies, as well as the relatively small follow-up period, render imperative the conduct of further studies in the field.

[Management of endocrine dysfunctions after allogeneic hematopoietic stem cell transplantation: a report of the SFGM-TC on adrenal insufficiency and osteoporosis].

PubMed

Cornillon, J; Vantyghem, M-C; Couturier, M A; de Berranger, E; François, S; Hermete, E; Maillard, N; Marcais, A; Tabrizi, R; Decanter, C; Duléry, R; Bauters, F; Yakoub-Agha, I

2013-08-01

In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the third annual series of workshops which brought together practitioners from all member centers and took place in October 2012 in Lille. Here we report our results and recommendations regarding the management of short and long-term endocrine dysfunction following allogeneic stem cell transplantation. The key aim of this workshop was to give an overview on secondary adrenal insufficiency and osteoporosis post-transplant. Copyright © 2013. Published by Elsevier SAS.

Biotypology, Endocrinology, and Sterilization: The Practice of Eugenics in the Treatment of Argentinian Women during the 1930s

PubMed Central

ERASO, YOLANDA

2008-01-01

SUMMARY This article looks at medical approaches to women’s fertility in Argentina in the 1930s and explores the ways in which eugenics encouraged the reproduction of the fit and attempted to avoid the reproduction of the unfit. The analysis concentrates on three main aspects: biotypology (the scientific classification of bodies), endocrine therapy, and sterilization. The article concludes by suggesting that a eugenically oriented obstetrical and gynecological practice encouraged both endocrine treatments (to achieve the ideal fertile woman) and sterilization, which, in spite of being legally banned, found a subtle application. PMID:18084107

Efficacy and Safety of Dual Antiplatelet Therapy After Complex PCI.

PubMed

Giustino, Gennaro; Chieffo, Alaide; Palmerini, Tullio; Valgimigli, Marco; Feres, Fausto; Abizaid, Alexandre; Costa, Ricardo A; Hong, Myeong-Ki; Kim, Byeong-Keuk; Jang, Yangsoo; Kim, Hyo-Soo; Park, Kyung Woo; Gilard, Martine; Morice, Marie-Claude; Sawaya, Fadi; Sardella, Gennaro; Genereux, Philippe; Redfors, Bjorn; Leon, Martin B; Bhatt, Deepak L; Stone, Gregg W; Colombo, Antonio

2016-10-25

Optimal upfront dual antiplatelet therapy (DAPT) duration after complex percutaneous coronary intervention (PCI) with drug-eluting stents (DES) remains unclear. This study investigated the efficacy and safety of long-term (≥12 months) versus short-term (3 or 6 months) DAPT with aspirin and clopidogrel according to PCI complexity. The authors pooled patient-level data from 6 randomized controlled trials investigating DAPT durations after PCI. Complex PCI was defined as having at least 1 of the following features: 3 vessels treated, ≥3 stents implanted, ≥3 lesions treated, bifurcation with 2 stents implanted, total stent length >60 mm, or chronic total occlusion. The primary efficacy endpoint was major adverse cardiac events (MACE), defined as the composite of cardiac death, myocardial infarction, or stent thrombosis. The primary safety endpoint was major bleeding. Intention-to-treat was the primary analytic approach. Of 9,577 patients included in the pooled dataset for whom procedural variables were available, 1,680 (17.5%) underwent complex PCI. Overall, 85% of patients received new-generation DES. At a median follow-up time of 392 days (interquartile range: 366 to 710 days), patients who underwent complex PCI had a higher risk of MACE (adjusted hazard ratio [HR]: 1.98; 95% confidence interval [CI]: 1.50 to 2.60; p < 0.0001). Compared with short-term DAPT, long-term DAPT yielded significant reductions in MACE in the complex PCI group (adjusted HR: 0.56; 95% CI: 0.35 to 0.89) versus the noncomplex PCI group (adjusted HR: 1.01; 95% CI: 0.75 to 1.35; p interaction  = 0.01). The magnitude of the benefit with long-term DAPT was progressively greater per increase in procedural complexity. Long-term DAPT was associated with increased risk for major bleeding, which was similar between groups (p interaction  = 0.96). Results were consistent by per-treatment landmark analysis. Alongside other established clinical risk factors, procedural complexity is an important parameter to take into account in tailoring upfront duration of DAPT. Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Psychosocial influences on HIV-1 disease progression: neural, endocrine, and virologic mechanisms.

PubMed

Cole, Steve W

2008-06-01

This review surveys empirical research pertinent to the hypothesis that activity of the hypothalamus-pituitary-adrenal (HPA) axis and/or the sympathetic nervous system (SNS) might mediate biobehavioral influences on HIV-1 pathogenesis and disease progression. Data are considered based on causal effects of neuroeffector molecules on HIV-1 replication, prospective relationships between neural/endocrine parameters and HIV-relevant biological or clinical markers, and correlational data consistent with in vivo neural/endocrine mediation in human or animal studies. Results show that HPA and SNS effector molecules can enhance HIV-1 replication in cellular models via effects on viral infectivity, viral gene expression, and the innate immune response to infection. Animal models and human clinical studies both provide evidence consistent with SNS regulation of viral replication, but data on HPA mediation are less clear. Regulation of leukocyte biology by neuroeffector molecules provides a plausible biological mechanism by which psychosocial factors might influence HIV-1 pathogenesis, even in the era of effective antiretroviral therapy. As such, neural and endocrine parameters might provide useful biomarkers for gauging the promise of behavioral interventions and suggest novel adjunctive strategies for controlling HIV-1 disease progression.

Therapy of older persons with acute myeloid leukaemia.

PubMed

Krug, Utz; Gale, Robert Peter; Berdel, Wolfgang E; Müller-Tidow, Carsten; Stelljes, Matthias; Metzeler, Klaus; Sauerland, M Cristina; Hiddemann, Wolfgang; Büchner, Thomas

2017-09-01

Most persons age≥60 y with acute myeloid leukaemia (AML) die from their disease. When interpreting clinical trials data from these persons one must be aware of substantial selection biases. Randomized trials of post-remission treatments can be performed upfront or after achieving defined landmarks. Both strategies have important limitations. Selection of the appropriate treatment is critical. Age, performance score, co-morbidities and frailty provide useful data to treatment selection. If an intensive remission induction therapy is appropriate, therapy with cytarabine and an anthracycline is the most common regimen. Non-intensive therapies consist of the hypo-methylating drugs azacitidine and decitabine, low-dose cytarabine and supportive care. Feasibility of doing an allotransplant in older persons with AML is increasing. However, only very few qualify. Results of cytogenetic testing are risk factor in young and old persons with AML. Adverse abnormalities are more frequent in older persons. Although data about the frequency of mutations in older persons with AML is increasing their prognostic impact is less clear than in younger subjects. Neither differences in the distribution of cytogenetic risk, mutations, nor differences in clinical risk factors between younger and older persons with AML completely explain the age-dependent outcome. Many drugs are in clinical development in older persons with AML. Their potential role in the treatment of older persons with AML remains to be defined. Copyright © 2017 Elsevier Ltd. All rights reserved.

Reconsidering the Gatekeeper Paradigm for Percutaneous Coronary Intervention in Stable Coronary Disease Management.

PubMed

Schulman-Marcus, Joshua; Weintraub, William S; Boden, William E

2017-10-15

Major randomized clinical trials over the last decade support the role of optimal medical therapy for the initial management approach for patients with stable coronary artery disease (CAD), whereas percutaneous coronary intervention (PCI) ought to be reserved for patients with persistent symptoms despite optimal medical therapy. Likewise, several studies have continued to demonstrate the superiority of coronary artery bypass grafting surgery over PCI in many patients with extensive multivessel CAD, especially those with diabetes. Nevertheless, the decision-making paradigm for patients with stable CAD often continues to propagate the upfront use of "ad hoc PCI" and disadvantages alternative therapeutic approaches. In our editorial, we discuss how multiple systemic and interpersonal factors continue to favor early revascularization with PCI in stable patients. We discuss whether the interventional cardiologist can be an unbiased "gatekeeper" for the use of PCI or whether other physicians should also be involved with the patient in decision-making. Finally, we offer suggestions that can redefine the gatekeeper role to facilitate an evidence-based approach that embraces shared decision-making. Copyright © 2017 Elsevier Inc. All rights reserved.

Contemporary strategies to improve the outcome in locally advanced pancreatic cancer.

PubMed

Schneider, Rick; Späth, Christoph; Nitsche, Ulrich; Erkan, Mert; Kleeff, Jörg

2017-10-01

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with an overall 5-year survival rate of less than 7%. After many years of basic and clinical research efforts, pancreatic cancer patients presenting with locally advanced, unresectable tumors remain a therapeutic challenge. Despite the lack of high quality randomized controlled trials, perioperative/neoadjuvant treatment strategies seem to be beneficial in these patients. At present the FOLFIRINOX regimen, which was established in the palliative setting, is increasingly recognized as the backbone of neoadjuvant therapy for locally advanced PDAC. Surgical resection follows the same principles and guidelines as upfront surgery specifically regarding the extent of resection including lymphadenectomy, vascular resections and multivisceral resections. Because of the limited diagnostic accuracy of restaging after neoadjuvant treatment, an adjusted intraoperative strategy is necessary to minimize the risk of debulking procedures and maximize the chance of a potential curative resection. Locally advanced PDAC requires a multidisciplinary and individualized treatment approach, and further research efforts for novel and innovative therapies. This article provides an updated overview on strategies to improve the outcome in locally advanced PDAC.

Does Specialty Bias Trump Evidence in the Management of High-risk Prostate Cancer?

PubMed

Kishan, Amar U; Duchesne, Gillian; Wang, Pin-Chieh; Rwigema, Jean-Claude M; Saigal, Christopher; Rettig, Matthew; Steinberg, Michael L; King, Christopher R

2018-06-01

The objective was to query how specialty influences treatment recommendations for high-risk prostate cancer in 3 clinical settings: upfront management, postoperative management, and management of biochemical recurrences (BCRs) after radiotherapy (RT). We hypothesized that specialty bias would manifest in all settings, trumping available evidence. A survey of practicing urologists and radiation oncologists was distributed through electronic mail. Questions pertained to upfront management, postoperative treatment, and local salvage for postradiation BCRs. The associations between 26 selected categorical responses and specialty were assessed using multivariate logistic regression. Training level/expertise, practice setting, percentage of consultation caseload consisting of prostate cancer, and nationality were set as effect modifiers. One thousand two hundred fifty-three physicians (846 radiation oncologists and 407 urologists) completed the survey. Radiation oncologists were more likely to recommend adjuvant RT and consider it to be underutilized, and more likely to recommend salvage RT at lower prostate-specific antigen thresholds (P<0.0001). Urologists were more likely to recommend salvage radical prostatectomy or cryoablation for local salvage after RT, whereas radiation oncologists were more likely to recommend RT-based modalities and more likely to report that local salvage was underutilized after RT (P<0.0001). Urologists were more likely to report that upfront radical prostatectomy was a better definitive treatment (P<0.0001), whereas radiation oncologists were more likely to report the opposite (P=0.005). Specialty biases permeate recommendations for upfront management and management in the postoperative and post-RT BCR setting, irrespective of available evidence. These data reveal the critical need for multidisciplinary clinics and cross-specialty training as potential solutions for overcoming specialty bias.

Can computerized tomography accurately stage childhood renal tumors?

PubMed

Abdelhalim, Ahmed; Helmy, Tamer E; Harraz, Ahmed M; Abou-El-Ghar, Mohamed E; Dawaba, Mohamed E; Hafez, Ashraf T

2014-07-01

Staging of childhood renal tumors is crucial for treatment planning and outcome prediction. We sought to identify whether computerized tomography could accurately predict the local stage of childhood renal tumors. We retrospectively reviewed our database for patients diagnosed with childhood renal tumors and treated surgically between 1990 and 2013. Inability to retrieve preoperative computerized tomography, intraoperative tumor spillage and nonWilms childhood renal tumors were exclusion criteria. Local computerized tomography stage was assigned by a single experienced pediatric radiologist blinded to the pathological stage, using a consensus similar to the Children's Oncology Group Wilms tumor staging system. Tumors were stratified into up-front surgery and preoperative chemotherapy groups. The radiological stage of each tumor was compared to the pathological stage. A total of 189 tumors in 179 patients met inclusion criteria. Computerized tomography staging matched pathological staging in 68% of up-front surgery (70 of 103), 31.8% of pre-chemotherapy (21 of 66) and 48.8% of post-chemotherapy scans (42 of 86). Computerized tomography over staged 21.4%, 65.2% and 46.5% of tumors in the up-front surgery, pre-chemotherapy and post-chemotherapy scans, respectively, and under staged 10.7%, 3% and 4.7%. Computerized tomography staging was more accurate in tumors managed by up-front surgery (p <0.001) and those without extracapsular extension (p <0.001). The validity of computerized tomography staging of childhood renal tumors remains doubtful. This staging is more accurate for tumors treated with up-front surgery and those without extracapsular extension. Preoperative computerized tomography can help to exclude capsular breach. Treatment strategy should be based on surgical and pathological staging to avoid the hazards of inaccurate staging. Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Differential epigenetic reprogramming in response to specific endocrine therapies promotes cholesterol biosynthesis and cellular invasion

PubMed Central

Nguyen, Van T. M.; Barozzi, Iros; Faronato, Monica; Lombardo, Ylenia; Steel, Jennifer H.; Patel, Naina; Darbre, Philippa; Castellano, Leandro; Győrffy, Balázs; Woodley, Laura; Meira, Alba; Patten, Darren K.; Vircillo, Valentina; Periyasamy, Manikandan; Ali, Simak; Frige, Gianmaria; Minucci, Saverio; Coombes, R. Charles; Magnani, Luca

2015-01-01

Endocrine therapies target the activation of the oestrogen receptor alpha (ERα) via distinct mechanisms, but it is not clear whether breast cancer cells can adapt to treatment using drug-specific mechanisms. Here we demonstrate that resistance emerges via drug-specific epigenetic reprogramming. Resistant cells display a spectrum of phenotypical changes with invasive phenotypes evolving in lines resistant to the aromatase inhibitor (AI). Orthogonal genomics analysis of reprogrammed regulatory regions identifies individual drug-induced epigenetic states involving large topologically associating domains (TADs) and the activation of super-enhancers. AI-resistant cells activate endogenous cholesterol biosynthesis (CB) through stable epigenetic activation in vitro and in vivo. Mechanistically, CB sparks the constitutive activation of oestrogen receptors alpha (ERα) in AI-resistant cells, partly via the biosynthesis of 27-hydroxycholesterol. By targeting CB using statins, ERα binding is reduced and cell invasion is prevented. Epigenomic-led stratification can predict resistance to AI in a subset of ERα-positive patients. PMID:26610607

High-dose fulvestrant as third-line endocrine therapy for breast cancer metastasis to the left kidney: A case report and literature review.

PubMed

Xia, Dandan; Wang, Huiyu; Wang, Runjie; Liu, Chaoying; Xu, Junying

2018-06-01

Endocrine therapy plays an important role in the treatment of patients with hormone receptor-positive breast cancer. Renal metastasis of breast cancer is rare in clinical practice. We present here a 54-year-old woman with breast cancer after first line chemotherapy and second line endocrinotherapy (i.e., toremifene & exemestane) failure. The patient was rarely diagnosed breast cancer metastasis to the kidney and a positive hormone status (ER and PR) but was negative for human epidermal factor receptor 2 (HER2). The patient was treated with a high dose of fulvestrant (SERD; 500 mg) by intramuscular injection once per month. The patient's condition significantly improved as measured by a decrease in the renal and pulmonary masses; symptoms including dry cough and blood phlegm also improved. Endocrinotherapy with high-dose fulvestrant may provide benefits for patients with HR+/HER2- advanced breast cancer with renal metastasis after SERMs failure.

Plasma ESR1 Mutations and the Treatment of Estrogen Receptor-Positive Advanced Breast Cancer.

PubMed

Fribbens, Charlotte; O'Leary, Ben; Kilburn, Lucy; Hrebien, Sarah; Garcia-Murillas, Isaac; Beaney, Matthew; Cristofanilli, Massimo; Andre, Fabrice; Loi, Sherene; Loibl, Sibylle; Jiang, John; Bartlett, Cynthia Huang; Koehler, Maria; Dowsett, Mitch; Bliss, Judith M; Johnston, Stephen R D; Turner, Nicholas C

2016-09-01

ESR1 mutations are selected by prior aromatase inhibitor (AI) therapy in advanced breast cancer. We assessed the impact of ESR1 mutations on sensitivity to standard therapies in two phase III randomized trials that represent the development of the current standard therapy for estrogen receptor-positive advanced breast cancer. In a prospective-retrospective analysis, we assessed ESR1 mutations in available archived baseline plasma from the SoFEA (Study of Faslodex Versus Exemestane With or Without Arimidex) trial, which compared exemestane with fulvestrant-containing regimens in patients with prior sensitivity to nonsteroidal AI and in baseline plasma from the PALOMA3 (Palbociclib Combined With Fulvestrant in Hormone Receptor-Positive HER2-Negative Metastatic Breast Cancer After Endocrine Failure) trial, which compared fulvestrant plus placebo with fulvestrant plus palbociclib in patients with progression after receiving prior endocrine therapy. ESR1 mutations were analyzed by multiplex digital polymerase chain reaction. In SoFEA, ESR1 mutations were found in 39.1% of patients (63 of 161), of whom 49.1% (27 of 55) were polyclonal, with rates of mutation detection unaffected by delays in processing of archival plasma. Patients with ESR1 mutations had improved progression-free survival (PFS) after taking fulvestrant (n = 45) compared with exemestane (n = 18; hazard ratio [HR], 0.52; 95% CI, 0.30 to 0.92; P = .02), whereas patients with wild-type ESR1 had similar PFS after receiving either treatment (HR, 1.07; 95% CI, 0.68 to 1.67; P = .77). In PALOMA3, ESR1 mutations were found in the plasma of 25.3% of patients (91 of 360), of whom 28.6% (26 of 91) were polyclonal, with mutations associated with acquired resistance to prior AI. Fulvestrant plus palbociclib improved PFS compared with fulvestrant plus placebo in both ESR1 mutant (HR, 0.43; 95% CI, 0.25 to 0.74; P = .002) and ESR1 wild-type patients (HR, 0.49; 95% CI, 0.35 to 0.70; P < .001). ESR1 mutation analysis in plasma after progression after prior AI therapy may help direct choice of further endocrine-based therapy. Additional confirmatory studies are required. © 2016 by American Society of Clinical Oncology.

Costs and Benefits of Extended Endocrine Strategies for Premenopausal Breast Cancer.

PubMed

Kwon, Janice S; Pansegrau, Gary; Nourmoussavi, Melica; Hammond, Geoffrey L; Carey, Mark S

2017-08-01

Background: After completing 5 years of adjuvant tamoxifen, women with estrogen receptor (ER)-positive breast cancer benefit from 5 more years of endocrine therapy, either with tamoxifen or an aromatase inhibitor (AI). For premenopausal women, ovarian ablation (OA) would be required before starting an AI (OA/AI). According to the SOFT/TEXT studies, OA/AI improves 5-year disease-free survival compared with tamoxifen alone, suggesting that OA/AI could be superior to tamoxifen as extended endocrine therapy. The long-term costs and consequences of premature menopause from OA are unknown, but could be estimated through a cost-effectiveness analysis. Methods: A Markov chain Monte Carlo simulation model estimated the costs and benefits of 3 extended endocrine strategies in a hypothetical cohort of premenopausal women with ER-positive early breast cancer: (1) no further treatment; (2) tamoxifen for 5 years (extended tamoxifen); or (3) OA/AI for 5 years. Effectiveness was measured in years of life expectancy gain. Sensitivity analyses accounted for uncertainty surrounding various parameters. Monte Carlo simulation estimated the number of adverse events and deaths from each strategy in the US population over a 40-year period. Results: Extended tamoxifen yielded a higher average life expectancy gain than OA/AI (17.31 vs 17.06 years) at lower average cost ($3,550 vs $14,312). For 18,000 premenopausal ER-positive women, the simulation estimated 13,236, 12,557, and 11,338 deaths with no further treatment, extended tamoxifen, and OA/AI, respectively, but an additional 1,897 deaths from OA, for a total of 13,235 deaths associated with OA/AI. After 24.6 years of follow-up, more women are expected to die from OA/AI than extended tamoxifen. Conclusions: For premenopausal women with ER-positive cancer who have completed adjuvant tamoxifen, another 5 years of tamoxifen is the preferable extended endocrine strategy. The potential long-term health consequences of OA could affect overall survival when it precedes the use of an AI. Copyright © 2017 by the National Comprehensive Cancer Network.

Developing a HER3 Vaccine to Prevent Resistance to Endocrine Therapy

DTIC Science & Technology

2013-10-01

linearized using digestion with Pme I, recombined into linearized (E1-,E2b-,E3-) serotype 5 pAd construct in BJ 5183 bacterial recombination-based system...activity Clinical activity was assessed according to Response Evalu- ation Criteria in Solid Tumors ( RECIST 1.0 criteria [22]) using computed tomography...tumors: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247 23. CTEP Cancer Therapy Evaluation Program. CTCAE and CTC Website (2010) http

Controversies in breast cancer: adjuvant and neoadjuvant therapy.

PubMed

Montemurro, Filippo; Redana, Stefania; Valabrega, Giorgio; Aglietta, Massimo

2005-06-01

Initial randomised studies of chemotherapy and endocrine therapy showed that systemic treatments had a substantial impact on the survival of women with early breast cancer. The original assumption was that the efficacy of these treatments was limited to those patients presenting with more adverse prognostic features. Subsequently, meta-analyses of randomised trials revealed that the benefits of chemotherapy and endocrine therapy are not mutually exclusive and extend to all the prognostic subgroups. However, the absolute benefit varies according to baseline characteristics such as tumour stage and other biological factors. Over the last 10 years, considerable progress has been made with the introduction of new drugs into the adjuvant and neoadjuvant treatment of women with breast cancer. Taxanes and third-generation aromatase inhibitors are providing proof of additional benefits compared with standard reference treatments. In parallel, research on the biology of breast cancer is establishing novel prognostic and predictive factors, which may allow better treatment tailoring. Currently, however, women with early breast cancer and their doctors face the difficult task of making therapeutic decisions often based on early results from positive studies. In a disease where follow up is crucial to fully assess the benefit and long-term toxicities of an intervention, current knowledge leaves unanswered questions that generate debate and controversy. This review will summarise recent results from randomised trials of adjuvant and neoadjuvant therapy in women with early breast cancer and focus on the current controversies.

Cytarabine and daunorubicin for the treatment of acute myeloid leukemia.

PubMed

Murphy, Tracy; Yee, Karen W L

2017-11-01

Acute myeloid leukemia (AML) is the most common acute forms of leukemia in adults. It has a poor long-term survival with a high relapse rate and at relapse, is commonly resistant to available therapies. The current combination of daunorubicin (DNR) for three days and cytarabine (Ara-C) as a continuous infusion for seven days, more commonly known as '3 + 7' has remained essentially unaltered over the last forty-four years and remains the standard induction regimen internationally. Areas covered: This paper will briefly review clinically important trials related to '3 + 7'. Somatic mutations in AML that are linked to chemoresistance to '3 + 7'will be discussed. Other topics covered include the novel ratiometric agent containing daunorubicin and cytarabine, CPX-351, and midostaurin in FLT3 mutated AML. Expert opinion: '3 + 7' continues to be the backbone of therapy for AML. However, genetic risk stratification should be used to determine patients who are unlikely to respond to standard intensive chemotherapy and hence, should be enrolled onto a clinical trial upfront. This will facilitate development of newer effective treatment strategies in AML. Patients with mutations that are associated with chemoresistance should be offered therapies which may circumvent or overcome these pathways.

Interferon alpha 2 maintenance therapy may enable high rates of treatment discontinuation in chronic myeloid leukemia.

PubMed

Burchert, A; Saussele, S; Eigendorff, E; Müller, M C; Sohlbach, K; Inselmann, S; Schütz, C; Metzelder, S K; Ziermann, J; Kostrewa, P; Hoffmann, J; Hehlmann, R; Neubauer, A; Hochhaus, A

2015-06-01

A minority of chronic myeloid leukemia (CML) patients is capable of successfully discontinuing imatinib. Treatment modalities to increase this proportion are currently unknown. Here, we assessed the role of interferon alpha 2a (IFN) on therapy discontinuation in a previously reported cohort of 20 chronic phase CML patients who were treated upfront with IFN alpha plus imatinib followed by IFN monotherapy to maintain cytogenetic or molecular remission (MR) after imatinib discontinuation. After a median follow-up of 7.9 years (range, 5.2-12.2), relapse-free survival was 73% (8/11 patients) and 84% (5/6 patients) for patients who discontinued imatinib in major MR (MMR) and MR4/MR4.5, respectively. Ten patients discontinued IFN after a median of 4.5 years (range, 0.24-9.3). After a median of 2.8 years (range, 0.7-5.1), nine of them remain in ongoing treatment-free remission with MR5 (n=6) and MR4.5 (n=3). The four patients who still administer IFN are in stable MR5, MR4.5, MR4, and MMR, respectively. In conclusion, an IFN/imatinib induction treatment followed by a temporary IFN maintenance therapy may enable a high rate of treatment discontinuation in CML patients in at least MMR when stopping imatinib.

A short history of pediatric endocrinology in North America.

PubMed

Fisher, Delbert A

2004-04-01

Pediatric endocrinology evolved as a subspecialty from the era of biochemical and metabolic clinical investigation led by John Howland, Edwards Park, and James Gamble at Johns Hopkins; Allan Butler at Boston University and Harvard University; Daniel Darrow at Yale University; and Irving McQuarrie at the University of Rochester and the University of Minnesota during the early 20th century. The father of the new subspecialty was Lawson Wilkins, a private pediatric practitioner in Baltimore, Maryland, who was invited by Dr. Edwards Park to establish an endocrine clinic at the Harriet Lane Home at Johns Hopkins in 1935. Dr. Wilkins managed his practice and the clinic until 1946, when, at the age of 52, he accepted a full-time position at the University. Dr. Nathan Talbot was invited to develop a pediatric endocrine clinic at Massachusetts General Hospital by Allan Butler in 1942. These units and their associated subspecialty training programs during the 1950s and 1960s provided the large majority of the second-generation pediatric endocrinologists who went on to establish endocrine subspecialty programs in university medical centers in North America as well as Europe and South America. Diabetes as a clinical pediatric discipline evolved in parallel from the early clinics of Elliott Joslin and Priscilla White in Boston, M.C. Hardin and Robert Jackson at the University of Iowa, George Guest at the University of Cincinnati Children's Hospital, and Alex Hartman at the St. Louis Children's Hospital. The Lawson Wilkins Pediatric Endocrine Society was founded in 1971, and the Council on Diabetes and Youth was established within the American Diabetes Association in 1980. Medical and economic factors led to increasing integration of pediatric diabetes and general endocrine care and training, and diabetes care now is a major activity within the subspecialty of pediatric endocrinology. The growth of pediatric endocrinology in North America has paralleled the growth of academic medicine during the past half-century. In 2002, there were 72 training programs in North America: 65 in the United States and seven in Canada. The endocrinology sub-board of the American Board of Pediatrics was established in 1978 to certify training and competence in endocrinology, including diabetes. By 2002, the board had certified 927 pediatric endocrinologists. Pediatric endocrine subspecialists during the past half-century have contributed major advances in our understanding of the ontogeny of endocrine systems and the diagnosis and treatment of fetal-perinatal endocrine disorders; newborn screening for endocrine and metabolic disorders; the physiology and therapies for disorders of sexual differentiation and pubertal maturation; the development of anthropometric standards for childhood growth and development; the characterization and physiology of hormone systems, including receptors and hormone actions; the molecular genetics of a number of congenital endocrine disorders and heritable endocrine diseases; development of pediatric endocrine diagnostics and reference standards; the pathophysiology and management of autoimmune endocrine disease; and development of a growing armamentarium of therapeutic agents for treatment of endocrine and metabolic diseases.

X-Box Binding Protein-1 in Breast Cancer

DTIC Science & Technology

2005-08-01

analysis of gene expression (SAGE) as previously described (13), using the "SAGE" software (Dr. Kinzler, Johns Hopkins University). Most genes...rationale for endocrine therapy in breast cancer. Best Pract. Res. Clin. Endocrinol. Metabol. 18, 1–32. Molinari, A. M., Bontempo, P., Schiavone , E. M

Aetiology, diagnosis, and management of hypopituitarism in adult life

PubMed Central

Prabhakar, V K B; Shalet, S M

2006-01-01

Hypopituitarism is a complex medical condition associated with increased morbidity and mortality, requires complicated treatment regimens, and necessitates lifelong follow up by the endocrinologist. The causes, clinical features, and the management of hypopituitarism including endocrine replacement therapy are considered in this review article. PMID:16597813

Beliefs about medicine and illness are associated with fear of cancer recurrence in women taking adjuvant endocrine therapy for breast cancer.

PubMed

Corter, Arden L; Findlay, Michael; Broom, Reuben; Porter, David; Petrie, Keith J

2013-02-01

Adjuvant endocrine therapy for early-stage breast cancer has greatly reduced the morbidity and mortality associated with breast cancer recurrence. Despite this, a significant proportion of women report fears of cancer recurrence. This study examined the associations between fear of cancer recurrence (FoR) and illness perceptions, medication beliefs, and treatment side effects in women taking adjuvant endocrine therapy following breast cancer. A total of 153 post-menopausal women with early-stage breast cancer completed a postal survey. Analyses were conducted to examine the association between FoR and illness perceptions, medication beliefs, treatment side effects, demographic factors, and emotional distress and to identify which of these factors would be most strongly associated with FoR in a regression model. All illness perceptions (apart from personal control) were associated with FoR, as were patient beliefs about endocrine therapy. Although treatment side effects, being unemployed, and higher levels of anxiety and depression were associated with FoR, only illness perceptions (identity, treatment control, timeline, and emotional representation) and medication necessity beliefs were significantly correlated with FoR in the final model. It appears that, in addition to directly targeting FoR, it may be worthwhile to address the illness and medication beliefs supporting the fear. Additionally, helping women to differentiate everyday symptoms from those indicative of breast cancer may help to reduce fear of recurrence. What is already known on this subject? A significant proportion of women report fear of cancer recurrence following breast cancer. The literature shows that illness perceptions, side effects of treatment, and beliefs about medicines are related to fear of recurrence among cancer patients. However, because these variables have often been looked at in isolation, it is not clear whether some perceptions or cues are more likely to relate to fear of recurrence than others. What does this study add? This study shows illness perceptions and medication beliefs are strongly related to fears of cancer recurrence. The results point to ways in which the self-regulatory model of illness may be used to reduce patients' fear of recurrence. The study results show that women with higher fear of recurrence may be balancing a tension between believing that they need to take the medication to protect their future health alongside concerns that the treatment may not be working. © 2012 The British Psychological Society.

Adjuvant chemotherapy for early female breast cancer: a systematic review of the evidence for the 2014 Cancer Care Ontario systemic therapy guideline

PubMed Central

Gandhi, S.; Fletcher, G.G.; Eisen, A.; Mates, M.; Freedman, O.C.; Dent, S.F.; Trudeau, M.E.

2015-01-01

Background The Program in Evidence-Based Care (pebc) of Cancer Care Ontario recently created an evidence-based consensus guideline on the systemic treatment of early breast cancer. The evidence for the guideline was compiled using a systematic review to answer the question “What is the optimal systemic therapy for patients with early-stage, operable breast cancer, when patient and disease factors are considered?” The question was addressed in three parts: cytotoxic chemotherapy, endocrine treatment, and human epidermal growth factor receptor 2 (her2)–directed therapy. Methods For the systematic review, the medline and embase databases were searched for the period January 2008 to May 2014. The Standards and Guidelines Evidence directory of cancer guidelines and the Web sites of major oncology guideline organizations were also searched. The basic search terms were “breast cancer” and “systemic therapy” (chemotherapy, endocrine therapy, targeted agents, ovarian suppression), and results were limited to randomized controlled trials (rcts), guidelines, systematic reviews, and meta-analyses. Results Several hundred documents that met the inclusion criteria were retrieved. The Early Breast Cancer Trialists’ Collaborative Group meta-analyses encompassed many of the rcts found. Several additional studies that met the inclusion criteria were retained, as were other guidelines and systematic reviews. Chemotherapy was reviewed mainly in three classes: anti-metabolite–based regimens (for example, cyclophosphamide–methotrexate–5-fluorouracil), anthracyclines, and taxane-based regimens. In general, single-agent chemotherapy is not recommended for the adjuvant treatment of breast cancer in any patient population. Anthracycline–taxane-based polychemotherapy regimens are, overall, considered superior to earlier-generation regimens and have the most significant impact on patient survival outcomes. Regimens with varying anthracycline and taxane doses and schedules are options; in general, paclitaxel given every 3 weeks is inferior. Evidence does not support the use of bevacizumab in the adjuvant setting; other systemic therapy agents such as metformin and vaccines remain investigatory. Adjuvant bisphosphonates for menopausal women will be discussed in later work. Conclusions The results of this systematic review constitute a comprehensive compilation of the high-level evidence that is the basis for the 2014 pebc guideline on systemic therapy for early breast cancer. Use of cytotoxic chemotherapy is presented here; the results addressing endocrine therapy and her2-targeted treatment, and the final clinical practice recommendations, are published separately in this supplement. PMID:25848343

The Historical Development of Immunoendocrine Concepts of Psychiatric Disorders and Their Therapy.

PubMed

Steinberg, Holger; Kirkby, Kenneth C; Himmerich, Hubertus

2015-12-04

Relationships between the central nervous, immune and endocrine systems are a focus of psychiatric research, particularly in depression and schizophrenia. The field has long antecedents. Observed phenomena attributable to these relationships date back to the Neolithic era. Immunoendocrine theories in the broadest sense are recorded in antiquity. In the 19th century, Kraepelin and Wagner-Jauregg reported pioneering clinical observations in psychiatric patients. Von Basedow, Addison and Cushing described psychiatric symptoms in patients suffering from endocrine diseases. The 20th century opened with the identification of hormones, the first, adrenaline, chemically isolated independently by Aldrich und Takamine in 1901. Berson and Yalow developed the radioimmunoassay (RIA) technique in 1959 making it possible to measure levels of hormones and cytokines. These developments have enabled great strides in psychoimmunoendocrinology. Contemporary research is investigating diagnostic and therapeutic applications of these concepts, for example by identifying biomarkers within the endocrine and immune systems and by synthesizing and testing drugs that modulate these systems and show antidepressant or antipsychotic properties.

Athletic amenorrhea: energy deficit or psychogenic challenge?

PubMed Central

Pauli, Samuel A.; Berga, Sarah L.

2010-01-01

Athletic women are at risk for developing ovulatory dysfunction, which presents variably as menstrual irregularity or absence. Initially characterized as an isolated disruption of hypothalamic gonadotropin releasing hormone (GnRH) release, athletic amenorrhea, a form of hypogonadotropic hypogonadism, is invariably accompanied by additional neuroendocrine aberrations, including activation of adrenal and suppression of thyroidal axes. Exercise may elicit intermittent or chronic metabolic stress due to increased energy expenditure and/or insufficient or imbalanced nutrient intake. In addition, athletic activities are motivated by or serve as psychogenic stressors. Prior studies dichotomized stressors as metabolic or psychogenic. Not only is this a false dichotomy because all stressors have both a metabolic and a psychogenic component, but also stressors act synergistically rather than in isolation to compromise GnRH drive and endocrine homeostasis. To ameliorate reproductive and endocrine consequences of stress, then, requires identification and amelioration of all relevant stressors. Formal psychosocial support helps individuals to develop better coping strategies and make appropriate lifestyle changes. Our research has shown that cognitive behavior therapy restores reproductive and endocrine balance. PMID:20840250

[Endocrine orbitopathy - the topic still alive].

PubMed

Fryšák, Zdeněk; Karásek, David; Halenka, Milan

Endocrine orbitopathy (EO) must be understood mainly as a result of oxidative stress. The pathological process finally affects both the appearance and vision of the patient. In the case of inappropriate or late treatment or lack of patient cooperation, it significantly influences the quality of life of those affected. In spite of the sophisticated dia-gnostic algorithms, in some cases it is difficult to confirm the diagnosis of EO. The range of laboratory methods, the essential part of the diagnostic process, has only recently been extended by the possibility of quantification of specific, stimulating immunoglobulins (TSI). A major shortcoming may be seen in an undervalued importance of orbital ultrasonography, in particular of the eye muscles (US).Key words: biological treatment - endocrine orbitopathy (EO) - Graves-Basedow disease (GB) - "hashitoxicosis" (HTX) - hyaluronan synthase 2 (HAS2) - thyroid-blocking immunoglobulins (TBI) - thyroid-stimulating immunoglobulins (TSI) - hyaluronic acid (HA) - lymphocytary, Hashimotos thyroiditis (HT) - pulse therapy - TSH-receptor - transcription factors FOXOs - orbital ultrasonography, mainly of the eye muscles (US).

The Historical Development of Immunoendocrine Concepts of Psychiatric Disorders and Their Therapy

PubMed Central

Steinberg, Holger; Kirkby, Kenneth C.; Himmerich, Hubertus

2015-01-01

Relationships between the central nervous, immune and endocrine systems are a focus of psychiatric research, particularly in depression and schizophrenia. The field has long antecedents. Observed phenomena attributable to these relationships date back to the Neolithic era. Immunoendocrine theories in the broadest sense are recorded in antiquity. In the 19th century, Kraepelin and Wagner-Jauregg reported pioneering clinical observations in psychiatric patients. Von Basedow, Addison and Cushing described psychiatric symptoms in patients suffering from endocrine diseases. The 20th century opened with the identification of hormones, the first, adrenaline, chemically isolated independently by Aldrich und Takamine in 1901. Berson and Yalow developed the radioimmunoassay (RIA) technique in 1959 making it possible to measure levels of hormones and cytokines. These developments have enabled great strides in psychoimmunoendocrinology. Contemporary research is investigating diagnostic and therapeutic applications of these concepts, for example by identifying biomarkers within the endocrine and immune systems and by synthesizing and testing drugs that modulate these systems and show antidepressant or antipsychotic properties. PMID:26690116

Acromegaly: an endocrine society clinical practice guideline.

PubMed

Katznelson, Laurence; Laws, Edward R; Melmed, Shlomo; Molitch, Mark E; Murad, Mohammad Hassan; Utz, Andrea; Wass, John A H

2014-11-01

The aim was to formulate clinical practice guidelines for acromegaly. The Task Force included a chair selected by the Endocrine Society Clinical Guidelines Subcommittee (CGS), five experts in the field, and a methodologist. The authors received no corporate funding or remuneration. This guideline is cosponsored by the European Society of Endocrinology. This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. The Task Force reviewed primary evidence and commissioned two additional systematic reviews. One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society and the European Society of Endocrinology reviewed drafts of the guidelines. Using an evidence-based approach, this acromegaly guideline addresses important clinical issues regarding the evaluation and management of acromegaly, including the appropriate biochemical assessment, a therapeutic algorithm, including use of medical monotherapy or combination therapy, and management during pregnancy.

Driving Toward Precision Medicine for Acute Leukemias: Are We There Yet?

PubMed

Chung, Clement; Ma, Hilary

2017-09-01

Despite recent progress in the understanding of the molecular basis of acute leukemias, treatment options for these diseases have not changed significantly over the last few decades. We present a nonexhaustive summary of the current cytogenetic and molecular changes associated with acute leukemias in disease prognostication and potential targeted therapies. An emerging paradigm is that many genetic or molecular alterations target similar signal transduction, transcriptional, and epigenetic pathways. Some of these targets may be used as predictive biomarkers for the development of novel targeted therapies that depart significantly from conventional chemotherapy, the current mainstay for the treatment of acute leukemias. Established leukemia-specific predictive biomarkers for precision medicine include those genetic lesions such as BCR-ABL1 for Philadelphia-positive acute lymphoblastic leukemia and PML-RARα for acute promyelocytic leukemia. Evidence indicates that targeted therapy for FLT-ITD gene mutations with small-molecule tyrosine kinase inhibitors can extend its use from relapsed disease to up-front induction therapy. Core-binding factor acute myeloid leukemia in adults predicts benefit with high-dose cytarabine in the absence of KIT mutation. Although risk-adapted therapy based on genetic abnormalities in acute leukemias has allowed the beginning of personalized treatment and selective use of hematopoietic stem cell transplantation, the prognostic and/or predictive value of many novel mutations of the acute leukemic genome is yet to be elucidated. Many challenges lie ahead in targeted therapies due to overlapping of chromosomal and molecular lesions as well as other limiting factors. Future work should focus on the understanding of pathogenetic changes that lead to leukemogenesis, which may guide the rational design of new targeted therapies and make the drive toward precision medicine for acute leukemias one step closer. © 2017 Pharmacotherapy Publications, Inc.

The impact of pancreaticoduodenectomy on endocrine and exocrine pancreatic function: A prospective cohort study based on pre- and postoperative function tests.

PubMed

Roeyen, Geert; Jansen, Miet; Hartman, Vera; Chapelle, Thiery; Bracke, Bart; Ysebaert, Dirk; De Block, Christophe

Studies reporting on function after pancreatic surgery are frequently based on diabetes history, fasting glycemia or random glycemia. The aim of this study was to investigate prospectively the evolution of pancreatic function in patients undergoing pancreaticoduodenectomy based on proper pre- and postoperative function tests. It was hypothesised that pancreatic function deteriorates after pancreaticoduodenectomy. Between 2013 and 2016, 78 patients undergoing pancreaticoduodenectomy for oncologic indications had a prospective evaluation of their endocrine and exocrine pancreatic function. Endocrine function was evaluated with the 75 g oral glucose tolerance test (OGTT) and the 1 mg intravenous glucagon test. Exocrine function was evaluated with a 13C-labelled mixed-triglyceride breath test. Tests were performed pre- and postoperatively. In 90.5% (19/21) of patients with preoperatively known diabetes, no change in endocrine function was observed. In contrast, endocrine function improved in 68.1% (15/22) of patients with newly diagnosed diabetes. 40% (14/35) of patients with a preoperative normal OGTT or prediabetes experienced deterioration in function. In multivariate analysis, improvement of newly diagnosed diabetes was correlated with preoperative bilirubin levels (p = 0.045), while progression towards diabetes was correlated with preoperative C-peptidogenic index T 30 (p = 0.037). A total of 20.5% (16/78) of patients had pancreatic exocrine insufficiency preoperatively. Another 51.3% (40/78) of patients deteriorated on exocrine level. In total, 64.1% (50/78) of patients required pancreatic enzyme-replacement therapy postoperatively. Although deterioration of endocrine function was expected after pancreatic resection, improvement is frequently observed in patients with newly diagnosed diabetes. Exocrine function deteriorates after pancreaticoduodenectomy. Copyright © 2017 IAP and EPC. Published by Elsevier B.V. All rights reserved.

Multi-institutional Nomogram Predicting Survival Free From Salvage Whole Brain Radiation After Radiosurgery in Patients With Brain Metastases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gorovets, Daniel; Department of Radiation Oncology, Perlmutter Cancer Center, NYU School of Medicine, New York, New York; Ayala-Peacock, Diandra

Purpose: Optimal patient selection for stereotactic radiosurgery (SRS) as the initial treatment for brain metastases is complicated and controversial. This study aimed to develop a nomogram that predicts survival without salvage whole brain radiation therapy (WBRT) after upfront SRS. Methods and Materials: Multi-institutional data were analyzed from 895 patients with 2095 lesions treated with SRS without prior or planned WBRT. Cox proportional hazards regression model was used to identify independent pre-SRS predictors of WBRT-free survival, which were integrated to build a nomogram that was subjected to bootstrap validation. Results: Median WBRT-free survival was 8 months (range, 0.1-139 months). Significant independent predictors formore » inferior WBRT-free survival were age (hazard ratio [HR] 1.1 for each 10-year increase), HER2(−) breast cancer (HR 1.6 relative to other histologic features), colorectal cancer (HR 1.4 relative to other histologic features), increasing number of brain metastases (HR 1.09, 1.32, 1.37, and 1.87 for 2, 3, 4, and 5+ lesions, respectively), presence of neurologic symptoms (HR 1.26), progressive systemic disease (HR 1.35), and increasing extracranial disease burden (HR 1.31 for oligometastatic and HR 1.56 for widespread). Additionally, HER2(+) breast cancer (HR 0.81) and melanoma (HR 1.11) trended toward significance. The independently weighted hazard ratios were used to create a nomogram to display estimated probabilities of 6-month and 12-month WBRT-free survival with a corrected Harrell's C concordance statistic of 0.62. Conclusions: Our nomogram can be used at initial evaluation to help select patients best suited for upfront SRS for brain metastases while reducing expense and morbidity in patients who derive minimal or no benefit.« less

Integrating Tenascin-C protein expression and 1q25 copy number status in pediatric intracranial ependymoma prognostication: A new model for risk stratification.

PubMed

Andreiuolo, Felipe; Le Teuff, Gwénaël; Bayar, Mohamed Amine; Kilday, John-Paul; Pietsch, Torsten; von Bueren, André O; Witt, Hendrik; Korshunov, Andrey; Modena, Piergiorgio; Pfister, Stefan M; Pagès, Mélanie; Castel, David; Giangaspero, Felice; Chimelli, Leila; Varlet, Pascale; Rutkowski, Stefan; Frappaz, Didier; Massimino, Maura; Grundy, Richard; Grill, Jacques

2017-01-01

Despite multimodal therapy, prognosis of pediatric intracranial ependymomas remains poor with a 5-year survival rate below 70% and frequent late deaths. This multicentric European study evaluated putative prognostic biomarkers. Tenascin-C (TNC) immunohistochemical expression and copy number status of 1q25 were retained for a pooled analysis of 5 independent cohorts. The prognostic value of TNC and 1q25 on the overall survival (OS) was assessed using a Cox model adjusted to age at diagnosis, tumor location, WHO grade, extent of resection, radiotherapy and stratified by cohort. Stratification on a predictor that did not satisfy the proportional hazards assumption was considered. Model performance was evaluated and an internal-external cross validation was performed. Among complete cases with 5-year median follow-up (n = 470; 131 deaths), TNC and 1q25 gain were significantly associated with age at diagnosis and posterior fossa tumor location. 1q25 status added independent prognostic value for death beyond the classical variables with a hazard ratio (HR) = 2.19 95%CI = [1.29; 3.76] (p = 0.004), while TNC prognostic relation was tumor location-dependent with HR = 2.19 95%CI = [1.29; 3.76] (p = 0.004) in posterior fossa and HR = 0.64 [0.28; 1.48] (p = 0.295) in supratentorial (interaction p value = 0.015). The derived prognostic score identified 3 different robust risk groups. The omission of upfront RT was not associated with OS for good and intermediate prognostic groups while the absence of upfront RT was negatively associated with OS in the poor risk group. Integrated TNC expression and 1q25 status are useful to better stratify patients and to eventually adapt treatment regimens in pediatric intracranial ependymoma.

β-D-glucan inhibits endocrine-resistant breast cancer cell proliferation and alters gene expression

PubMed Central

JAFAAR, ZAINAB M.T.; LITCHFIELD, LACEY M.; IVANOVA, MARGARITA M.; RADDE, BRANDIE N.; AL-RAYYAN, NUMAN; KLINGE, CAROLYN M.

2014-01-01

Endocrine therapies have been successfully used for breast cancer patients with estrogen receptor α (ERα) positive tumors, but ∼40% of patients relapse due to endocrine resistance. β-glucans are components of plant cell walls that have immunomodulatory and anticancer activity. The objective of this study was to examine the activity of β-D-glucan, purified from barley, in endocrine-sensitive MCF-7 versus endocrine-resistant LCC9 and LY2 breast cancer cells. β-D-glucan dissolved in DMSO but not water inhibited MCF-7 cell proliferation in a concentration-dependent manner as measured by BrdU incorporation with an IC50 of ∼164±12 μg/ml. β-D-glucan dissolved in DMSO inhibited tamoxifen/endocrine-resistant LCC9 and LY2 cell proliferation with IC50 values of 4.6±0.3 and 24.2±1.4 μg/ml, respectively. MCF-10A normal breast epithelial cells showed a higher IC50 ∼464 μg/ml and the proliferation of MDA-MB-231 triple negative breast cancer cells was not inhibited by β-D-glucan. Concentration-dependent increases in the BAX/BCL2 ratio and cell death with β-D-glucan were observed in MCF-7 and LCC9 cells. PCR array analysis revealed changes in gene expression in response to 24-h treatment with 10 or 50 μg/ml β-D-glucan that were different between MCF-7 and LCC9 cells as well as differences in basal gene expression between the two cell lines. Select results were confirmed by quantitative real-time PCR demonstrating that β-D-glucan increased RASSF1 expression in MCF-7 cells and IGFBP3, CTNNB1 and ERβ transcript expression in LCC9 cells. Our data indicate that β-D-glucan regulates breast cancer-relevant gene expression and may be useful for inhibiting endocrine-resistant breast cancer cell proliferation. PMID:24534923

Incidence of late endocrine dysfunction following irradiation for childhood medulloblastoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Abayomi, O.K.; Sadeghi-Nejad, A.

1986-06-01

A retrospective analysis of treatment in 20 patients who had received post-operative radiotherapy for medulloblastoma between 1969 and 1977 was completed. The patients were followed for a minimum of 60 months. Eleven patients survived for 5 or more years after treatment. The patients received 3600 cGy to the whole brain. The posterior fossa received 5600 cGY and the spinal axis 3600 cGY. Eight of eleven patients developed growth impairment; 6 of 7 patients had growth hormone deficiency. Since all endocrine gland failures are amenable to therapy, early attention to patients' growth rate and detection of hypothalamic-pituitary failure, would be ofmore » benefit to longterm survivors.« less

Genetic Analysis in Blood and Tumor Samples From Patients With Advanced or Metastatic Estrogen Receptor Positive and HER2 Negative Breast Cancer Receiving Palbociclib and Endocrine Therapy

ClinicalTrials.gov

2018-04-18

Estrogen Receptor Positive; HER2/Neu Negative; Recurrent Breast Carcinoma; Stage III Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer

Loss of PEDF: A Novel Mechanism of Antihormone Resistance in Breast Cancer

DTIC Science & Technology

2013-08-01

phosphorylated ERa, Akt, and RET in these tumors. Discussion Resistance to endocrine therapy presents a major chal- lenge in the management of ERa-positive... Drury S, Dowsett M, Martin LA, Isacke CM: Targeting the receptor tyrosine kinase RET sensitizes breast cancer cells to tamoxifen treatment and reveals

Hair Measurements of Cortisol, DHEA, and DHEA to Cortisol Ratio as Biomarkers of Chronic Stress among People Living with HIV in China: Known-Group Validation

PubMed Central

Li, Xiaoming; Zilioli, Samuele; Chen, Zheng; Deng, Huihua; Pan, Juxian

2017-01-01

Background Existing literature suggests that endocrine measures, including the steroid hormones of cortisol and Dehydroepiandrosterone (DHEA), as well as the DHEA to cortisol ratio in the human hair can be used as promising biomarkers of chronic stress among humans. However, data are limited regarding the validity of these measures as biomarkers of chronic stress among people living with HIV (PLWH), whose endocrine system or hypothalamic pituitary adrenal (HPA) axis may be affected by HIV infection and/or antiretroviral therapy (ART) medications. Method Using hair sample data and self-reported survey from 60 PLWH in China, we examined the validity of three endocrine measures among Chinese PLWH using a known-groups validation strategy. High-stress group (n = 30) and low-stress group (n = 30) of PLWH were recruited through individual assessment interviews by a local licensed psychologist. The endocrine measures in hair were extracted and assessed by LC-APCI-MS/MS method. Both bivariate and multivariate analyses were conducted to examine the associations between the endocrine measures and the stress level, and to investigate if the associations differ by ART status. Results The levels of endocrine measures among Chinese PLWH were consistent with existing studies among PLWH. Generally, this pilot study confirmed the association between endocrine measures and chronic stress. The high stress group showed higher level hair cortisol and lower DHEA to cortisol ratio. The higher stress group also reported higher scores of stressful life events, perceived stress, anxiety and depression. Hair cortisol level was positively related to anxiety; DHEA was negatively associated with stressful life events; and the DHEA to cortisol ratio was positively related to stressful life events and perceived stress. ART did not affect the associations between the endocrine measures and stress level. Conclusions Our findings suggest that hair cortisol and DHEA to cortisol ratio can be used as promising biomarkers of chronic stress among PLWH. Clarifying the role of steroid hormones in the psychoimmunology of PLWH may yield important implications for clinical practice and psychological intervention. PMID:28095431

In real life, one-quarter of patients with hormone receptor-positive metastatic breast cancer receive chemotherapy as initial palliative therapy: a study of the Southeast Netherlands Breast Cancer Consortium.

PubMed

Lobbezoo, D J A; van Kampen, R J W; Voogd, A C; Dercksen, M W; van den Berkmortel, F; Smilde, T J; van de Wouw, A J; Peters, F P J; van Riel, J M G H; Peters, N A J B; de Boer, M; Peer, P G M; Tjan-Heijnen, V C G

2016-02-01

The objective of this study was to present initial systemic treatment choices and the outcome of hormone receptor-positive (HR+) metastatic breast cancer. All the 815 consecutive patients diagnosed with metastatic breast cancer in 2007-2009 in eight participating hospitals were identified. From the 611 patients with HR+ disease, a total of 520 patients with HER2-negative (HER2-) breast cancer were included. Initial palliative systemic treatment was registered. Progression-free survival (PFS) and overall survival (OS) per initial palliative systemic therapy were obtained using the Kaplan-Meier method and compared using the log-rank test. From the total of 520 patients with HR+/HER2- metastatic breast cancer, 482 patients (93%) received any palliative systemic therapy. Patients that received initial chemotherapy (n = 116) were significantly younger, had less comorbidity, had received more prior adjuvant systemic therapy and were less likely to have bone metastasis only compared with patients that received initial endocrine therapy (n = 366). Median PFS of initial palliative chemotherapy was 5.3 months [95% confidence interval (CI) 4.2-6.2] and of initial endocrine therapy 13.3 months (95% CI 11.3-15.5), with a median OS of 16.1 and 36.9 months, respectively. Initial chemotherapy was also associated with worse outcome in terms of PFS and OS after adjustment for prognostic factors. A high percentage of patients with HR+ disease received initial palliative chemotherapy, which was associated with worse outcome, even after adjustment of relevant prognostic factors. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Effect of treatment with depot somatostatin analogue octreotide on primary hyperparathyroidism (PHP) in multiple endocrine neoplasia type 1 (MEN1) patients.

PubMed

Faggiano, Antongiulio; Tavares, Lidice Brandao; Tauchmanova, Libuse; Milone, Francesco; Mansueto, Gelsomina; Ramundo, Valeria; De Caro, Maria Laura Del Basso; Lombardi, Gaetano; De Rosa, Gaetano; Colao, Annamaria

2008-11-01

In patients with multiple endocrine neoplasia type 1 (MEN1), expression of somatostatin receptor (SST) in parathyroid adenomas and effectiveness of therapy with somatostatin analogues on primary hyperparathyroidism (PHP) have been scarcely investigated. To evaluate the effects of depot long acting octreotide (OCT-LAR) in patients with MEN1-related PHP. Eight patients with a genetically confirmed MEN1, presenting both PHP and duodeno-pancreatic neuroendocrine tumours (NET), were enrolled. The initial treatment was OCT-LAR 30 mg every 4 weeks. This therapy was established to stabilize the duodeno-pancreatic NET before to perform parathyroidectomy for PHP. Before OCT-LAR therapy, a SST scintigraphy was performed in all patients. SST subtype 2A immunohistochemistry was performed on parathyroid tumour samples from three patients undergone parathyroidectomy after OCT-LAR therapy. Serum concentrations of PTH, calcium and phosphorus as well as the 24-h urine calcium : creatinine ratio and the renal threshold phosphate concentration were evaluated before and after OCT-LAR. After OCT-LAR therapy, hypercalcaemia and hypercalciuria normalized in 75% and 62.5% of patients, respectively, and serum phosphorus and renal threshold phosphate significantly increased. Serum PTH concentrations significantly decreased in all patients and normalized in two of them. SST subtype 2A immunostaining was found in all parathyroid adenomas investigated, while SST scintigraphy showed a positive parathyroid tumour uptake in three of eight patients (37.5%). Six months of OCT-LAR therapy controlled hypercalcaemia and hypercalciuria in two-thirds of patients with MEN1-related PHP. Direct OCT-LAR effects mediated by binding to SST expression on parathyroid tumour cells are likely the main mechanism to explain the activity of this compound on calcium and phosphorus abnormalities in MEN1 PHP.

Integrating Comparative Effectiveness Design Elements and Endpoints Into a Phase III, Randomized Clinical Trial (SWOG S1007) Evaluating OncotypeDX-Guided Management for Women With Breast Cancer Involving Lymph Nodes

PubMed Central

Ramsey, Scott D.; Barlow, William E.; Gonzalez-Angulo, Ana M.; Tunis, Sean; Baker, Laurence; Crowley, John; Deverka, Patricia; Veenstra, David; Hortobagyi, Gabriel N.

2012-01-01

Women with breast cancer involving the lymph nodes are typically treated with cytotoxic chemotherapy. Retrospective evaluations of prior studies suggest that the 21-gene test (OncotypeDX®), may allow identification of those who can safely avoid chemotherapy. To better understand the performance of the 21-gene test, the RxPONDER (Rx for Positive Node, Endocrine Responsive breast cancer) study was designed, a multicenter Phase III trial randomizing women with hormone receptor-positive and HER2-negative breast cancer involving 1–3 lymph nodes and a 21-gene assay recurrence score (RS) of 25 or less to endocrine therapy alone versus chemotherapy followed by endocrine therapy. As one of the first large-scale comparative-effectiveness studies in oncology, RxPONDER utilized an external stakeholder group to help inform the design of the trial. Stakeholders met with representatives of SWOG over several months through a structured discussion process. The stakeholder engagement process resulted in several changes being made to the trial design. In addition, stakeholder representatives from the health insurance industry provided guidance regarding a mechanism whereby the costs of OncotypeDX® would be paid by the majority of health insurers as part of the trial. The process may serve as a template for future studies evaluating the comparative effectiveness of genomic tests in oncology, particularly those that are conducted within cooperative clinical trials groups. PMID:23000081

Gynaecomastia with hypergonadotrophic hypogonadism and Leydig cell insufficiency in recipients of high-dose chemotherapy or chemo-radiotherapy.

PubMed

Harris, E; Mahendra, P; McGarrigle, H H; Linch, D C; Chatterjee, R

2001-12-01

Late side-effects of stem cell transplantation include hypogonadism with infertility and sexual dysfunction, but gynaecomastia is less well recognised. We report five cases of gynaecomastia with features of hypergonadotrophic hypogonadism (primary testicular failure), who received either a TBI/cyclophosphamide conditioned allograft (n = 3) or a BEAM autograft (n = 2). Patients receiving an allograft had gynaecomastia, Leydig cell insufficiency (LCI) diminished libido and erectile dysfunction. Surgery was required in one case, while in two cases the gynaecomastia resolved spontaneously after 6 months. Two patients also had gynaecomastia and sexual dysfunction, severe hypogonadism, very low testosterone levels and marked hyperprolactinaemia following autoBMT. Both responded well to testosterone replacement therapy (TRT). As a group, all patients had primary testicular failure and all except one, had LCI (compensated or frank). However, there was no correlation between the severity of gynaecomastia and the degree of endocrine dysfunction. This preliminary study is the first to suggest that gynaecomastia, due to primary hypogonadism and LCI, may be a significant complication of myeloablative conditioning therapy. Therefore gynaecomastia in BMT recipients must always be treated as a pathological entity as it may be the external manifestation of a complex endocrine pathology. It is a potentially treatable condition. Although spontaneously reversible, some patients may require TRT or even surgery. We recommend comprehensive endocrine testing in conjunction with a reproductive endocrinologist and prompt intervention to alleviate embarrassment and anxiety in afflicted BMT recipients.

Plasma thymidine kinase-1 activity predicts outcome in patients with hormone receptor positive and HER2 negative metastatic breast cancer treated with endocrine therapy

PubMed Central

Bonechi, Martina; Galardi, Francesca; Biagioni, Chiara; De Luca, Francesca; Bergqvist, Mattias; Neumüller, Magnus; Guarducci, Cristina; Boccalini, Giulia; Gabellini, Stefano; Migliaccio, Ilenia; Di Leo, Angelo; Pestrin, Marta; Malorni, Luca

2018-01-01

The aim of this study was to investigate if thymidine kinase-1 (TK1), a well-known proliferation marker, could represent a valid circulating biomarker to identify hormone receptor positive (HR+)/HER2 negative (HER2neg) metastatic breast cancer (MBC) patients most likely to benefit from endocrine therapy (ET). We used the DiviTum™ assay to analyze TK1 activity in cell lysates of three HR+/HER2neg BC cell lines and in plasma of 31 HR+/HER2neg MBC patients receiving ET. Blood samples were collected at treatment initiation, after one month and at disease progression. CTCs count and ESR1/PIK3CA mutations in circulating tumor DNA were performed and correlated with TK1 activity. TK1 activity was reduced in the two endocrine-sensitive cell lines after 2 days of treatment. In patients, high baseline TK1 activity correlated with CTCs positivity (p-value=0.014). Patients with low baseline levels of TK1 activity had a significantly better PFS compared to those with high baseline TK1 activity (p-value=0.012). Patients with an early drop of TK1 activity after one month of treatment had a significantly better PFS compared to those who experienced an increase (p-value=0.0026). Our study suggests that TK1 could be a potential prognostic, predictive and monitoring marker of early ET response in HR+/HER2neg MBC patients. PMID:29662653

Plasma thymidine kinase-1 activity predicts outcome in patients with hormone receptor positive and HER2 negative metastatic breast cancer treated with endocrine therapy.

PubMed

Bonechi, Martina; Galardi, Francesca; Biagioni, Chiara; De Luca, Francesca; Bergqvist, Mattias; Neumüller, Magnus; Guarducci, Cristina; Boccalini, Giulia; Gabellini, Stefano; Migliaccio, Ilenia; Di Leo, Angelo; Pestrin, Marta; Malorni, Luca

2018-03-27

The aim of this study was to investigate if thymidine kinase-1 (TK1), a well-known proliferation marker, could represent a valid circulating biomarker to identify hormone receptor positive (HR+)/HER2 negative (HER2neg) metastatic breast cancer (MBC) patients most likely to benefit from endocrine therapy (ET). We used the DiviTum™ assay to analyze TK1 activity in cell lysates of three HR+/HER2neg BC cell lines and in plasma of 31 HR+/HER2neg MBC patients receiving ET. Blood samples were collected at treatment initiation, after one month and at disease progression. CTCs count and ESR1 / PIK3CA mutations in circulating tumor DNA were performed and correlated with TK1 activity. TK1 activity was reduced in the two endocrine-sensitive cell lines after 2 days of treatment. In patients, high baseline TK1 activity correlated with CTCs positivity (p-value=0.014). Patients with low baseline levels of TK1 activity had a significantly better PFS compared to those with high baseline TK1 activity (p-value=0.012). Patients with an early drop of TK1 activity after one month of treatment had a significantly better PFS compared to those who experienced an increase (p-value=0.0026). Our study suggests that TK1 could be a potential prognostic, predictive and monitoring marker of early ET response in HR+/HER2neg MBC patients.

Human bone marrow-derived mesenchymal cells differentiate and mature into endocrine pancreatic lineage in vivo.

PubMed

Phadnis, Smruti M; Joglekar, Mugdha V; Dalvi, Maithili P; Muthyala, Sudhakar; Nair, Prabha D; Ghaskadbi, Surendra M; Bhonde, Ramesh R; Hardikar, Anandwardhan A

2011-03-01

The scarcity of human islets for transplantation remains a major limitation of cell replacement therapy for diabetes. Bone marrow-derived progenitor cells are of interest because they can be isolated, expanded and offered for such therapy under autologous/allogeneic settings. We characterized and compared human bone marrow-derived mesenchymal cells (hBMC) obtained from (second trimester), young (1-24 years) and adult (34-81 years) donors. We propose a novel protocol that involves assessment of paracrine factors from regenerating pancreas in differentiation and maturation of hBMC into endocrine pancreatic lineage in vivo. We observed that donor age was inversely related to growth potential of hBMC. Following in vitro expansion and exposure to specific growth factors involved in pancreatic development, hBMC migrated and formed islet-like cell aggregates (ICA). ICA show increased abundance of pancreatic transcription factors (Ngn3, Brn4, Nkx6.1, Pax6 and Isl1). Although efficient differentiation was not achieved in vitro, we observed significant maturation and secretion of human c-peptide (insulin) upon transplantation into pancreactomized and Streptozotocin (STZ)-induced diabetic mice. Transplanted ICA responded to glucose and maintained normoglycemia in diabetic mice. Our data demonstrate that hBMC have tremendous in vitro expansion potential and can be differentiated into multiple lineages, including the endocrine pancreatic lineage. Paracrine factors secreted from regenerating pancreas help in efficient differentiation and maturation of hBMC, possibly via recruiting chromatin modulators, to generate glucose-responsive insulin-secreting cells.

Correlation of treatment-emergent adverse events and clinical response to endocrine therapy in early breast cancer: a retrospective analysis of the German cohort of TEAM.

PubMed

Hadji, P; Kieback, D G; Tams, J; Hasenburg, A; Ziller, M

2012-10-01

Previous studies have suggested a correlation between the occurrence of vasomotor or joint symptoms during tamoxifen or aromatase inhibitor treatment and improved clinical response. A retrospective analysis of the German cohort of the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial was carried out to assess disease-free survival (DFS) and overall survival (OS) in patients with and without arthralgia/myalgia and/or menopausal symptoms during adjuvant endocrine treatment. A total of 1502 patients were included; 739 patients received tamoxifen followed by exemestane and 763 received exemestane. Patients reporting arthralgia/myalgia and patients reporting menopausal symptoms during endocrine treatment had significantly longer OS and DFS than those not reporting these events. The effect on OS was irrespective of treatment. DFS was significantly improved in exemestane-treated patients reporting arthralgia/myalgia or those reporting menopausal symptoms versus those not reporting these events. This effect on DFS was not observed in patients receiving sequential treatment. A combined analysis of patients reporting either menopausal symptoms or arthralgia/myalgia showed that OS and DFS were significantly improved in patients reporting one of these symptoms versus those not reporting either symptom. The occurrence of arthralgia/myalgia or menopausal symptoms during endocrine treatment is associated with significantly improved OS.

High-sensitivity assay for monitoring ESR1 mutations in circulating cell-free DNA of breast cancer patients receiving endocrine therapy.

PubMed

Lupini, Laura; Moretti, Anna; Bassi, Cristian; Schirone, Alessio; Pedriali, Massimo; Querzoli, Patrizia; Roncarati, Roberta; Frassoldati, Antonio; Negrini, Massimo

2018-03-12

Approximately 70% of breast cancers (BCs) express estrogen receptor alpha (ERα) and are treated with endocrine therapy. However, the effectiveness of this therapy is limited by innate or acquired resistance in approximately one-third of patients. Activating mutations in the ESR1 gene that encodes ERα promote critical resistance mechanisms. Here, we developed a high sensitivity approach based on enhanced-ice-COLD-PCR for detecting ESR1 mutations. The method produced an enrichment up to 100-fold and allowed the unambiguous detection of ESR1 mutations even when they consisted of only 0.01% of the total ESR1 allelic fraction. After COLD-PCR enrichment, methods based on next-generation sequencing or droplet-digital PCR were employed to detect and quantify ESR1 mutations. We applied the method to detect ESR1 mutations in circulating free DNA from the plasma of 56 patients with metastatic ER-positive BC. Fifteen of these patients were found to have ESR1 mutations at codons 536-538. This study demonstrates the utility of the enhanced-ice-COLD-PCR approach for simplifying and improving the detection of ESR1 tumor mutations in liquid biopsies. Because of its high sensitivity, the approach may potentially be applicable to patients with non-metastatic disease.

Prognostic meaning of neutrophil to lymphocyte ratio (NLR) and lymphocyte to monocyte ration (LMR) in newly diagnosed Hodgkin lymphoma patients treated upfront with a PET-2 based strategy.

PubMed

Romano, Alessandra; Parrinello, Nunziatina Laura; Vetro, Calogero; Chiarenza, Annalisa; Cerchione, Claudio; Ippolito, Massimo; Palumbo, Giuseppe Alberto; Di Raimondo, Francesco

2018-06-01

Recent reports identify NLR (the ratio between absolute neutrophils counts, ANC, and absolute lymphocyte count, ALC), as predictor of progression-free survival (PFS) and overall survival (OS) in cancer patients. We retrospectively tested NLR and LMR (the ratio between absolute lymphocyte and monocyte counts) in newly diagnosed Hodgkin lymphoma (HL) patients treated upfront with a PET-2 risk-adapted strategy. NLR and LMR were calculated using records obtained from the complete blood count (CBC) from 180 newly diagnosed HL patients. PFS was evaluated accordingly to Kaplan-Meier method. Higher NLR was associated to advanced stage, increased absolute counts of neutrophils and reduced count of lymphocytes, and markers of systemic inflammation. After a median follow-up of 68 months, PFS at 60 months was 86.6% versus 70.1%, respectively, in patients with NLR ≥ 6 or NLR < 6. Predictors of PFS at 60 months were PET-2 scan (p < 0.0001), NLR ≥ 6.0 (p = 0.02), LMR < 2 (p = 0.048), and ANC (p = 0.0059) in univariate analysis, but only PET-2 was an independent predictor of PFS in multivariate analysis. Advanced-stage patients (N = 119) were treated according to a PET-2 risk-adapted protocol, with an early switch to BEACOPP regimen in case of PET-2 positivity. Despite this strategy, patients with positive PET-2 still had an inferior outcome, with PFS at 60 months of 84.7% versus 40.1% (negative and positive PET-2 patients, respectively, p < 0.0001). Independent predictors of PFS by multivariate analysis were PET-2 status and to a lesser extend NLR in advanced stage, while LMR maintained its significance in early stage. By focusing on PET-2 negative patients, we found that patients with NLR ≥ 6.0 or LMR < 2 had an inferior outcome compared to patients with both ratios above the cutoff (78.7 versus 91.9 months, p = 0.01). We confirm NLR as predictor of PFS in HL patients independently from stage at diagnosis. Integration of PET-2 scan, NLR and LMR can result in a meaningful prognostic system that needs to be further validated in prospective series including patients treated upfront with PET-2 adapted-risk therapy.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Phan, Jack; Sio, Terence T.; Department of Radiation Oncology, Mayo Clinic, Scottsdale, Arizona

Purpose: Reirradiation of head and neck (H&N) cancer is a clinical challenge. Proton radiation therapy (PRT) offers dosimetric advantages for normal tissue sparing and may benefit previously irradiated patients. Here, we report our initial experience with the use of PRT for H&N reirradiation, with focus on clinical outcomes and toxicity. Methods and Materials: We retrospectively reviewed the records of patients who received H&N reirradiation with PRT from April 2011 through June 2015. Patients reirradiated with palliative intent or without prior documentation of H&N radiation therapy were excluded. Radiation-related toxicities were recorded according to the Common Terminology Criteria for Adverse Eventsmore » Version 4.0. Results: The conditions of 60 patients were evaluated, with a median follow-up time of 13.6 months. Fifteen patients (25%) received passive scatter proton therapy (PSPT), and 45 (75%) received intensity modulated proton therapy (IMPT). Thirty-five patients (58%) received upfront surgery, and 44 (73%) received concurrent chemotherapy. The 1-year rates of locoregional failure–free survival, overall survival, progression-free survival, and distant metastasis–free survival were 68.4%, 83.8%, 60.1%, and 74.9%, respectively. Eighteen patients (30%) experienced acute grade 3 (G3) toxicity, and 13 (22%) required a feeding tube at the end of PRT. The 1-year rates of late G3 toxicity and feeding tube independence were 16.7% and 2.0%, respectively. Three patients may have died of reirradiation-related effects (1 acute and 2 late). Conclusions: Proton beam therapy can be a safe and effective curative reirradiation strategy, with acceptable rates of toxicity and durable disease control.« less

Clinical outcomes following salvage Gamma Knife radiosurgery for recurrent glioblastoma

PubMed Central

Larson, Erik W; Peterson, Halloran E; Lamoreaux, Wayne T; MacKay, Alexander R; Fairbanks, Robert K; Call, Jason A; Carlson, Jonathan D; Ling, Benjamin C; Demakas, John J; Cooke, Barton S; Lee, Christopher M

2014-01-01

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor with a survival prognosis of 14-16 mo for the highest functioning patients. Despite aggressive, multimodal upfront therapies, the majority of GBMs will recur in approximately six months. Salvage therapy options for recurrent GBM (rGBM) are an area of intense research. This study compares recent survival and quality of life outcomes following Gamma Knife radiosurgery (GKRS) salvage therapy. Following a PubMed search for studies using GKRS as salvage therapy for malignant gliomas, nine articles from 2005 to July 2013 were identified which evaluated rGBM treatment. In this review, we compare Overall survival following diagnosis, Overall survival following salvage treatment, Progression-free survival, Time to recurrence, Local tumor control, and adverse radiation effects. This report discusses results for rGBM patient populations alone, not for mixed populations with other tumor histology grades. All nine studies reported median overall survival rates (from diagnosis, range: 16.7-33.2 mo; from salvage, range: 9-17.9 mo). Three studies identified median progression-free survival (range: 4.6-14.9 mo). Two showed median time to recurrence of GBM. Two discussed local tumor control. Six studies reported adverse radiation effects (range: 0%-46% of patients). The greatest survival advantages were seen in patients who received GKRS salvage along with other treatments, like resection or bevacizumab, suggesting that appropriately tailored multimodal therapy should be considered with each rGBM patient. However, there needs to be a randomized clinical trial to test GKRS for rGBM before the possibility of selection bias can be dismissed. PMID:24829861

Tamoxifen therapy benefit for patients with 70-gene signature high and low risk.

PubMed

van 't Veer, Laura J; Yau, Christina; Yu, Nancy Y; Benz, Christopher C; Nordenskjöld, Bo; Fornander, Tommy; Stål, Olle; Esserman, Laura J; Lindström, Linda Sofie

2017-11-01

Breast cancer molecular prognostic tools that predict recurrence risk have mainly been established on endocrine-treated patients and thus are not optimal for the evaluation of benefit from endocrine therapy. The Stockholm tamoxifen (STO-3) trial which randomized postmenopausal node-negative patients to 2-year tamoxifen (followed by an optional randomization for an additional 3-year tamoxifen vs nil), versus no adjuvant treatment, provides a unique opportunity to evaluate long-term 20-year benefit of endocrine therapy within prognostic risk classes of the 70-gene prognosis signature that was developed on adjuvantly untreated patients. We assessed by Kaplan-Meier analysis 20-year breast cancer-specific survival (BCSS) and 10-year distant metastasis-free survival (DMFS) for 538 estrogen receptor (ER)-positive, STO-3 trial patients with retrospectively ascertained 70-gene prognosis classification. Multivariable analysis of long-term (20 years) BCSS by STO-3 trial arm in the 70-gene high-risk and low-risk subgroups was performed using Cox proportional hazard modeling adjusting for classical patient and tumor characteristics. Tamoxifen-treated, 70-gene low- and high-risk patients had 20-year BCSS of 90 and 83%, as compared to 80 and 65% for untreated patients, respectively (log-rank p < 0.0001). Notably, there is equivalent tamoxifen benefit in both high (HR 0.42 (0.21-0.86), p = 0.018) and low (HR 0.46 (0.25-0.85), p = 0.013) 70-gene risk categories even after adjusting for clinico-pathological factors for BCSS. Limited tamoxifen exposure as given in the STO-3 trial provides persistent benefit for 10-15 years after diagnosis in a time-varying analysis. 10-year DMFS was 93 and 85% for low- and high-risk tamoxifen-treated, versus 83 and 70% for low- and high-risk untreated patients, respectively (log-rank p < 0.0001). Patients with ER-positive breast cancer, regardless of high or low 70-gene risk classification, receive significant survival benefit lasting over 10 years from adjuvant tamoxifen therapy, even when given for a relatively short duration.

Attention and memory deficits in breast cancer survivors: implications for nursing practice and research.

PubMed

Frank, Jennifer Sandson; Vance, David E; Jukkala, Angela; Meneses, Karen M

2014-10-01

Breast cancer survivors (BCSs) commonly report deficits in attention and memory, cognitive functions crucial for daily optimal functioning. Perceived deficits are reported before, during, and after adjuvant therapy and affect quality of life throughout survivorship. Deficits of attention and memory are particularly disruptive for BCSs working or attending school who report that subtle impairment diminishes their confidence and their performance at all levels of occupation. Chemotherapy and endocrine therapy contribute to attention and memory deficits, but research findings have not fully established the extent or timing of that influence. Fortunately, potential interventions for attention and memory deficits in BCSs are promising. These include cognitive remediation therapies aimed at training for specific areas of deficit, cognitive behavioral therapies aimed at developing compensatory strategies for areas of deficit, complementary therapies, and pharmacologic therapies.

Generalised peripheral oedema associated with amlodipine therapy in two dogs.

PubMed

Creevy, K E; Scuderi, M A; Ellis, A E

2013-11-01

This report details two cases of adverse drug reactions to amlodipine. The first case presented with diffuse peripheral oedema and a history of amlodipine therapy. Haematology, clinical chemistry, endocrine testing, thoracic, abdominal and cardiac imaging revealed no cause for oedema. Amlodipine therapy was discontinued and oedema diminished markedly within 72 hours. The second case presented for bilateral retinal detachments secondary to systemic hypertension. Haematology, clinical chemistry, thoracic and abdominal imaging were unremarkable and amlodipine therapy was begun. Within 72 hours, diffuse peripheral oedema developed that was unresponsive to therapy and the dog was euthanised. Veterinarians should be aware of the potential serious adverse events associated with commonly used drugs; severe, diffuse oedema is a possible adverse drug event in dogs treated with amlodipine. © 2013 British Small Animal Veterinary Association.

Medical treatment of Cushing's Disease.

PubMed

Cuevas-Ramos, Daniel; Fleseriu, Maria

2016-09-01

Cushing's Syndrome (CS) is a serious endocrine disease that results from the adverse clinical consequences of chronic exposure to high levels of glucocorticoids. Most patients with endogenous CS have an adrenocorticotropin (ACTH)-secreting pituitary corticotroph adenoma, i.e. Cushing's Disease (CD). The first-line therapy for CD is transsphenoidal pituitary surgery. If tumor removal is incomplete or unsuccessful, persistent hypercortisolism will require further treatment. Repeat surgery, medical therapy, radiation and bilateral adrenalectomy are all second line therapy options; however, medical therapy can be also used as first line therapy in patients who cannot undergo surgery, or to decrease cortisol values and/or improve co-morbidities. Medications used in the treatment of CD, classified into three groups: pituitary directed drugs, adrenal steroidogenesis inhibitors and glucocorticoid receptor blockers, are reviewed. Future 'on the horizon' treatment options are also discussed.

Clinical outcomes of gastrointestinal stromal tumor in southern Thailand

PubMed Central

Pornsuksiri, Kittima; Chewatanakornkul, Siripong; Kanngurn, Samornmas; Maneechay, Wanwisa; Chaiyapan, Walawee; Sangkhathat, Surasak

2012-01-01

AIM: To review a single institutional experience in clinical management of gastrointestinal stromal tumors (GIST) and analyze for factors determining treatment outcome. METHODS: Clinicopathological data of patients with a diagnosis of GIST who were treated at our institute during November 2004 to September 2009 were retrospectively reviewed. RESULTS: Ninety-nine cases were included in the analysis. Primary tumor sites were at the stomach in and small bowel in 44% and 33%, respectively. Thirty-one cases already had metastasis at presentation and the most common metastatic site was the liver. Sixty-four cases (65%) were in the high-risk category. Surgical treatment was performed in 77 cases (78%), 3 of whom received upfront targeted therapy. Complete resection was achieved in 56 cases (73% of operative cases) and of whom 27 developed local recurrence or distant metastasis at a median duration of 2 years. Imatinib was given as a primary therapy in unresectable cases (25 cases) and as an adjuvant in cases with residual tumor (21 cases). Targeted therapy gave partial response in 7 cases (15%), stable disease in 27 cases (57%) and progressive disease in 13 cases (28%). Four-year overall survival was 74% (95% CI: 61%-83%). Univariate survival analysis found that low-risk tumor, gastric site, complete resection and response to imatinib were associated with better survival. CONCLUSION: The overall outcomes of GIST can be predicted by risk-categorization. Surgery alone may not be a curative treatment for GIST. Response to targeted therapy is a crucial survival determinant in these patients. PMID:23444235

Systematic Review of Clinical Outcomes Following Various Treatment Options for Patients with Extraabdominal Desmoid Tumors.

PubMed

Smith, Kortnye; Desai, Jayesh; Lazarakis, Smaro; Gyorki, David

2018-06-01

Desmoid tumors (DT) are rare clonal proliferations that arise from mesenchymal cells. These tumors do not metastasize but are locally aggressive, and their growth may lead to significant morbidity. Their clinical course is both variable and unpredictable; tumors may rapidly progress but in other instances remain stable or regress without intervention. To examine current treatment of DT and assist with decision-making at time of presentation. A literature search was conducted of MEDLINE and Cochrane databases for published studies (1995-July 2015) using the search terms fibromatosis aggressive, desmoid with drug therapy, radiation therapy, prevention and control, radiotherapy, surgery, and therapy. Articles were categorized as surgery, radiation, surgery + radiation, systemic therapy, and front-line observation. Articles were included if they reported a retrospective or prospective comparative or observational study with an analyzed sample size of 10 patients or more with confirmed diagnosis of desmoid tumor and described one of the following clinical outcomes: relapse- or progression-free survival, local control rate, response rate. 258 articles were reviewed; following screening for eligibility, 54 were identified; following full-text screen, 31 were included in final evaluation. The control rate for patients treated with a "wait and see" observational approach compared favorably with management with surgery and resulted in disease control rates of between 60 and 92%. Decision-making in this rare tumor is complicated by the range of treatment options available. Our evidence supports use of an upfront observational approach.

Tracking Progesterone Receptor-Mediated Actions in Breast Cancer

PubMed Central

Knutson, Todd P.; Lange, Carol A.

2014-01-01

Ovarian steroid hormones contribute to breast cancer initiation and progression primarily through the actions of their nuclear transcription factors, the estrogen receptor alpha (ERα) and progesterone receptors (PRs). These receptors are important drivers of the luminal A and B subtypes of breast cancer, where estrogen-blocking drugs have been effective endocrine therapies for patients with these tumors. However, many patients do not respond, or become resistant to treatment. When endocrine therapies fail, the luminal subtypes of breast cancer are more difficult to treat because these subtypes are among the most heterogeneous in terms of mutation diversity and gene expression profiles. Recent evidence suggests that progestin and PR actions may be important drivers of luminal breast cancers. Clinical trial data has demonstrated that hormone replacement therapy with progestins drives invasive breast cancer and results in greater mortality. PR transcriptional activity is dependent upon cross-talk with growth factor signaling pathways that alter PR phosphorylation, acetylation, or SUMOylation as mechanisms for regulating PR target gene selection required for increased cell proliferation and survival. Site-specific PR phosphorylation is the primary driver of gene-selective PR transcriptional activity. However, PR phosphorylation and heightened transcriptional activity is coupled to rapid PR protein degradation; the range of active PR detected in tumors is likely to be dynamic. Thus, PR target gene signatures may provide a more accurate means of tracking PR’s contribution to tumor progression rather than standard clinical protein-based (IHC) assays. Further development of antiprogestin therapies should be considered along side antiestrogens and aromatase inhibitors. PMID:24291072

Recurrent papillary craniopharyngioma with BRAFV600E mutation treated with neoadjuvant-targeted therapy.

PubMed

Rostami, Elham; Witt Nyström, Petra; Libard, Sylwia; Wikström, Johan; Casar-Borota, Olivera; Gudjonsson, Olafur

2017-11-01

Craniopharyngiomas are histologically benign but locally aggressive tumors in the sellar region that may cause devastating neurological and endocrine deficits. They tend to recur following surgery with high morbidity; hence, postoperative radiotherapy is recommended following sub-total resection. BRAFV600E mutation is the principal oncogenic driver in the papillary variant of craniopharyngiomas. Recently, a dramatic tumor reduction has been reported in a patient with BRAFV600E mutated, multiply recurrent papillary craniopharyngioma using a combination therapy of BRAF inhibitor dabrafenib and MEK inhibitor trametinib. Here, we report on near-radical reduction of a growing residual BRAFV600E craniopharyngioma using the same neoadjuvant therapy.

Using tablet-based technology in patient education about systemic therapy options for early-stage breast cancer: a pilot study.

PubMed

Morgan, E R; Laing, K; McCarthy, J; McCrate, F; Seal, M D

2015-10-01

Patient education in early-stage breast cancer has been shown to improve patient well-being and quality of life, but it poses a challenge given the increasingly complex regimens and time constraints in clinical practice. Technology-aided teaching in the clinic could help to improve the understanding of adjuvant systemic therapy for patients. In this prospective pilot study, we used a clinician-administered, tablet-based teaching aid to teach patients with early-stage breast cancer about adjuvant systemic therapy. Participation was offered to newly diagnosed patients with early-stage breast cancer presenting for their first medical oncology visit at a provincial cancer centre. Participants were shown a tablet-based presentation describing procedures, rationales, risks, and benefits of adjuvant systemic therapy as an adjunct to a discussion with the medical oncologist. After the clinic visit, participants completed a questionnaire measuring satisfaction with the visit and knowledge of the treatment plan discussed. The 25 patients recruited for the study had a mean age of 57 years. An offer of upfront chemotherapy alone was made to 12 participants (48%), chemotherapy with trastuzumab to 4 (16%), and hormonal therapy to 9 (36%). Correct answers to all questions related to treatment knowledge were given by 22 patients (88%). Satisfaction with the clinic visit was high (mean satisfaction score: 4.53 ± 0.1 of a possible 5). We found that a tablet-based presentation about adjuvant systemic therapy was satisfactory to patients with early-stage breast cancer and that knowledge retention after the clinic visit was high. Tablet-based teaching could be a feasible and effective way of educating patients in the breast oncology clinic and warrants further investigation in randomized studies.

Treating ER+ Breast Cancer with CDK4/6 Inhibitors.

PubMed

2017-08-01

Data from the MONARCH2, PALOMA-1, and TREnd trials strongly support using CDK4/6 inhibitors alongside standard endocrine therapy for advanced ER-positive breast cancer. Including these targeted agents not only improves progression-free survival but may reverse acquired resistance to hormone treatment. ©2017 American Association for Cancer Research.

Endocrinopathies in thalassemia major patient

NASA Astrophysics Data System (ADS)

Lubis, D. A.; Yunir, E. M.

2018-03-01

Advanced in chelation therapy and regular blood transfusion have marked improvements in the life expectancy of patients with thalassemia major, however these patients still have to deal with several complications. We report a 19-year-old male, presented with multiple endocrine complication-related thalassemia; hypogonadism, short stature, osteoporosis with history of fracture, and subclinical hypothyroid.

[China expert consensus on the management of dyslipidemia in postmenopausal patients with early-stage breast cancer].

PubMed

2017-01-23

Estrogen has an impact on the type of lipoproteins and the blood lipid levels, thus protecting the cardiovascular system. Postmenopausal breast cancer patients suffer a significant decrease in estrogen levels due to both physiological changes and the use of drugs, and thus have a higher risk of atherosclerotic cardiovascular diseases. Therefore, strict lipid management is required for postmenopausal breast cancer patients receiving endocrine therapy. However, no guidelines have been developed in terms of lipid management and intervention for postmenopausal breast cancer patients. The Chinese expert group of multidisciplinary management of dyslipidemia in breast cancer patients with endocrine therapy, after deep investigation into the management of dyslipidemia in postmenopausal patients with early-stage breast cancer, has developed the China Expert Consensus on Dyslipidemia Management in Postmenopausal Patients with Early-stage Breast Cancer. The Consensus clearly defines the goals and measures of interventions for dyslipidemia, hoping to effectively reduce the risk of atherosclerotic cardiovascular disease in postmenopausal breast cancer patients and further improve the long-term survival of the patients.

Should sputum-negative presumptive TB patients be actively followed to identify missing cases in India?

PubMed

Waikar, S; Pathak, A; Ghule, V; Kapoor, A; Sagili, K; Babu, E R; Chadha, S

2017-12-21

Setting: Sputum smear microscopy, the primary diagnostic tool used for diagnosis of tuberculosis (TB) in India's Revised National TB Control Programme (RNTCP), has low sensitivity, resulting in a significant number of TB cases reported as sputum-negative. As the revised guidelines pose challenges in implementation, sputum-negative presumptive TB (SNPT) patients are subjected to 2 weeks of antibiotics, followed by chest X-ray (CXR), resulting in significant loss to care among these cases. Objective: To determine whether reducing delays in CXR would yield additional TB cases and reduce initial loss to follow-up for diagnosis among SNPT cases. Methods: In an ongoing intervention in five districts of Maharashtra, SNPT patients were offered upfront CXR. Results: Of 119 male and 116 female SNPT patients with a mean age of 45 years who were tested by CXR, 32 (14%) were reported with CXR suggestive of TB. Administering upfront CXR in SNPT patients yielded twice as many additional cases, doubling the proportion of cases detected among all those tested as against administering CXR 2 weeks after smear examination. Conclusion: Our interventional study showed that the yield of TB cases was significantly greater when upfront CXR examination was undertaken without waiting for a 2-week antibiotic trial.

Mammostrat as a tool to stratify breast cancer patients at risk of recurrence during endocrine therapy.

PubMed

Bartlett, John M S; Thomas, Jeremy; Ross, Douglas T; Seitz, Robert S; Ring, Brian Z; Beck, Rodney A; Pedersen, Hans Christian; Munro, Alison; Kunkler, Ian H; Campbell, Fiona M; Jack, Wilma; Kerr, Gillian R; Johnstone, Laura; Cameron, David A; Chetty, Udi

2010-01-01

Patients with early-stage breast cancer, treated with endocrine therapy, have approximately 90% 5-year disease-free survival. However, for patients at higher risk of relapse despite endocrine therapy, additional adjuvant therapy, such as chemotherapy, may be indicated. The challenge is to prospectively identify such patients. The Mammostrat® test uses five immunohistochemical markers to stratify patients on tamoxifen therapy into risk groups to inform treatment decisions. We tested the efficacy of this panel in a mixed population of cases treated in a single center with breast-conserving surgery and long-term follow-up. Tissue microarrays from a consecutive series (1981 to 1998) of 1,812 women managed by wide local excision and postoperative radiotherapy were collected following appropriate ethical review. Of 1,390 cases stained, 197 received no adjuvant hormonal or chemotherapy, 1,044 received tamoxifen only, and 149 received a combination of hormonal therapy and chemotherapy. Median age at diagnosis was 57, 71% were postmenopausal, 23.9% were node-positive and median tumor size was 1.5 cm. Samples were stained using triplicate 0.6 mm2 tissue microarray cores, and positivity for p53, HTF9C, CEACAM5, NDRG1 and SLC7A5 was assessed. Each case was assigned a Mammostrat risk score, and distant recurrence-free survival (DRFS), relapse-free survival (RFS) and overall survival (OS) were analyzed by marker positivity and risk score. Increased Mammostrat scores were significantly associated with reduced DRFS, RFS and OS in estrogen receptor (ER)-positive breast cancer (P < 0.00001). In multivariate analyses the risk score was independent of conventional risk factors for DRFS, RFS and OS (P < 0.05). In node-negative, tamoxifen-treated patients, 10-year recurrence rates were 7.6 ± 1.5% in the low-risk group versus 20.0 ± 4.4% in the high-risk group. Further, exploratory analyses revealed associations with outcome in both ER-negative and untreated patients. This is the fifth independent study providing evidence that Mammostrat can act as an independent prognostic tool for ER-positive, tamoxifen-treated breast cancer. In addition, this study revealed for the first time a possible association with outcome regardless of node status and ER-negative tumors. When viewed in the context of previous results, these data provide further support for this antibody panel as an aid to patient management in early-stage breast cancer.

Mammostrat® as a tool to stratify breast cancer patients at risk of recurrence during endocrine therapy

PubMed Central

2010-01-01

Introduction Patients with early-stage breast cancer, treated with endocrine therapy, have approximately 90% 5-year disease-free survival. However, for patients at higher risk of relapse despite endocrine therapy, additional adjuvant therapy, such as chemotherapy, may be indicated. The challenge is to prospectively identify such patients. The Mammostrat® test uses five immunohistochemical markers to stratify patients on tamoxifen therapy into risk groups to inform treatment decisions. We tested the efficacy of this panel in a mixed population of cases treated in a single center with breast-conserving surgery and long-term follow-up. Methods Tissue microarrays from a consecutive series (1981 to 1998) of 1,812 women managed by wide local excision and postoperative radiotherapy were collected following appropriate ethical review. Of 1,390 cases stained, 197 received no adjuvant hormonal or chemotherapy, 1,044 received tamoxifen only, and 149 received a combination of hormonal therapy and chemotherapy. Median age at diagnosis was 57, 71% were postmenopausal, 23.9% were node-positive and median tumor size was 1.5 cm. Samples were stained using triplicate 0.6 mm2 tissue microarray cores, and positivity for p53, HTF9C, CEACAM5, NDRG1 and SLC7A5 was assessed. Each case was assigned a Mammostrat® risk score, and distant recurrence-free survival (DRFS), relapse-free survival (RFS) and overall survival (OS) were analyzed by marker positivity and risk score. Results Increased Mammostrat® scores were significantly associated with reduced DRFS, RFS and OS in estrogen receptor (ER)-positive breast cancer (P < 0.00001). In multivariate analyses the risk score was independent of conventional risk factors for DRFS, RFS and OS (P < 0.05). In node-negative, tamoxifen-treated patients, 10-year recurrence rates were 7.6 ± 1.5% in the low-risk group versus 20.0 ± 4.4% in the high-risk group. Further, exploratory analyses revealed associations with outcome in both ER-negative and untreated patients. Conclusions This is the fifth independent study providing evidence that Mammostrat® can act as an independent prognostic tool for ER-positive, tamoxifen-treated breast cancer. In addition, this study revealed for the first time a possible association with outcome regardless of node status and ER-negative tumors. When viewed in the context of previous results, these data provide further support for this antibody panel as an aid to patient management in early-stage breast cancer. PMID:20615243

Drug resistance to targeted therapies: déjà vu all over again.

PubMed

Groenendijk, Floris H; Bernards, René

2014-09-12

A major limitation of targeted anticancer therapies is intrinsic or acquired resistance. This review emphasizes similarities in the mechanisms of resistance to endocrine therapies in breast cancer and those seen with the new generation of targeted cancer therapeutics. Resistance to single-agent cancer therapeutics is frequently the result of reactivation of the signaling pathway, indicating that a major limitation of targeted agents lies in their inability to fully block the cancer-relevant signaling pathway. The development of mechanism-based combinations of targeted therapies together with non-invasive molecular disease monitoring is a logical way forward to delay and ultimately overcome drug resistance development. Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Colchicine triggered severe rhabdomyolysis after long-term low-dose simvastatin therapy: a case report.

PubMed

Frydrychowicz, Clara; Pasieka, Bastian; Pierer, Matthias; Mueller, Wolf; Petros, Sirak; Weidhase, Lorenz

2017-01-04

Rhabdomyolysis is a widely recognized yet rare complication in statin use. Rhabdomyolysis might be triggered by the prescription of high doses of statins or by statin accumulation due to interactions with concomitant medication. Muscle cell destruction as evidenced by myoglobin elevation can induce potentially life-threatening acute renal failure. We report a case of a 70-year-old obese white man with sudden onset of severe rhabdomyolysis with consecutive renal failure. His medication included low-dose simvastatin, which he had taken for 6 years up until the event. The statin was withdrawn immediately. After 3 days of veno-venous hemofiltration his renal function was completely restored. Clinicians in both primary and special care might be unaware that side effects of statins do occur even after a long uneventful statin medication; they should be advised not to exclude that possibility upfront, even if a patient has tolerated the medication for years.

Pharmacogenomics and histone deacetylase inhibitors

PubMed Central

Goey, Andrew KL; Sissung, Tristan M; Peer, Cody J; Figg, William D

2016-01-01

The histone deacetylase inhibitor valproic acid (VPA) has been used for many decades in neurology and psychiatry. The more recent introduction of the histone deacetylase inhibitors (HDIs) belinostat, romidepsin and vorinostat for treatment of hematological malignancies indicates the increasing popularity of these agents. Belinostat, romidepsin and vorinostat are metabolized or transported by polymorphic enzymes or drug transporters. Thus, genotype-directed dosing could improve pharmacotherapy by reducing the risk of toxicities or preventing suboptimal treatment. This review provides an overview of clinical studies on the effects of polymorphisms on the pharmacokinetics, efficacy or toxicities of HDIs including belinostat, romidepsin, vorinostat, panobinostat, VPA and a number of novel compounds currently being tested in Phase I and II trials. Although pharmacogenomic studies for HDIs are scarce, available data indicate that therapy with belinostat (UGT1A1), romidepsin (ABCB1), vorinostat (UGT2B17) or VPA (UGT1A6) could be optimized by upfront genotyping. PMID:27767376

Endocrine Dysfunction in Diamond-Blackfan Anemia (DBA): A Report from the DBA Registry (DBAR).

PubMed

Lahoti, Amit; Harris, Yael T; Speiser, Phyllis W; Atsidaftos, Evangelia; Lipton, Jeffrey M; Vlachos, Adrianna

2016-02-01

Diamond-Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome. The mainstays of treatment involve chronic red cell transfusions, long-term glucocorticoid therapy, and stem cell transplantation. Systematic data concerning endocrine function in DBA are limited. We studied patients in the DBA Registry (DBAR) of North America to assess the prevalence of various endocrinopathies. In a pilot study, retrospective data were collected for 12 patients with DBA. Subsequently, patients with DBA aged 1-39 years were recruited prospectively. Combined, 57 patients were studied; 38 chronically transfused, 12 glucocorticoid-dependent, and seven in remission. Data were collected on anthropometric measurements, systematic screening of pituitary, thyroid, parathyroid, adrenal, pancreatic, and gonadal function, and ferritin levels. Descriptive statistics were tabulated and group differences were assessed. Fifty-three percent of patients had ≥ 1 endocrine disorder, including adrenal insufficiency (32%), hypogonadism (29%), hypothyroidism (14%), growth hormone dysfunction (7%), diabetes mellitus (2%), and/or diabetes insipidus (2%). Ten of the 33 patients with available heights had height standard deviation less than -2. Low 25-hydroxy vitamin D (25(OH)D) levels were present in 50%. A small proportion also had osteopenia, osteoporosis, or hypercalciuria. Most with adrenal insufficiency were glucocorticoid dependent; other endocrinopathies were more common in chronically transfused patients. Endocrine dysfunction is common in DBA, as early as the teenage years. Although prevalence is highest in transfused patients, patients taking glucocorticoids or in remission also have endocrine dysfunction. Longitudinal studies are needed to better understand the etiology and true prevalence of these disorders. © 2015 Wiley Periodicals, Inc.

Development of the Clinic of Endocrinology, diabetes and metabolic disorders.

PubMed

Shubeska Stratrova, S

2013-01-01

The Clinic of Endocrinology, diabetes and metabolic disorders was founded in 1975 by Prof d-r Alexandar Plashevski. Healthcare, educational and scientific activities in the Clinic of Endocrinology are performed in its departments. The Department for hospitalized diabetic and endocrine patients consists of the metabolic and endocrine intensive care unit, the department for diagnosis and treatment of diabetics and endocrine patients, day hospital, the department for education of diabetic patients, and the national center for insulin pump therapy. The Center for Diabetes was established in 1972 by Prof d-r Dimitar Arsov. In 1975, Prof d-r Alexandar Plasheski broadened the activities of the Center for Diabetes. It was dislocated in 1980, with new accommodation outside the clinic. Since then the Center has consisted of several organized units: two specialist outpatient clinics for diabetic patients, biochemical and endocrine laboratory, sub-departments for: diabetic foot, cardiovascular diagnosis, ophthalmology, and urgent interventions. The Department of Endocrinology and Metabolic Disorders for outclinic endocrine patients was established in 1980, and it integrates the following sub-departments: thyrology, andrology, reproductive endocrinology, obesity and lipid disorders and sub-department for osteoporosis. The educational staff of the Clinic of Endocrinology organizes theoretical and practical education about Clinical Investigation and Internal Medicine with credit transfer system course of study of the Medical Faculty, Faculty of Stomatology, postgraduate studies, specializations and sub-specializations. Symposiums, 3 congresses, schools for diabetes and osteoporosis and continuous medical education were also organized. The Clinic of Endocrinology was initiator, organizer, founder and the seat of several medical associations.

Growth and endocrine disorders in thalassemia: The international network on endocrine complications in thalassemia (I-CET) position statement and guidelines

PubMed Central

De Sanctis, Vincenzo; Soliman, Ashraf T.; Elsedfy, Heba; Skordis, Nicos; Kattamis, Christos; Angastiniotis, Michael; Karimi, Mehran; Yassin, Mohd Abdel Daem Mohd; El Awwa, Ahmed; Stoeva, Iva; Raiola, Giuseppe; Galati, Maria Concetta; Bedair, Elsaid M.; Fiscina, Bernadette; El Kholy, Mohamed

2013-01-01

The current management of thalassemia includes regular transfusion programs and chelation therapy. It is important that physicians be aware that endocrine abnormalities frequently develop mainly in those patients with significant iron overload due to poor compliance to treatment, particularly after the age of 10 years. Since the quality of life of thalassemia patients is a fundamental aim, it is vital to monitor carefully their growth and pubertal development in order to detect abnormalities and to initiate appropriate and early treatment. Abnormalities should be identified and treatment initiated in consultation with a pediatric or an adult endocrinologist and managed accordingly. Appropriate management shall put in consideration many factors such as age, severity of iron overload, presence of chronic liver disease, thrombophilia status, and the presence of psychological problems. All these issues must be discussed by the physician in charge of the patient's care, the endocrinologist and the patient himself. Because any progress in research in the field of early diagnosis and management of growth disorders and endocrine complications in thalassemia should be passed on to and applied adequately to all those suffering from the disease, on the 8 May 2009 in Ferrara, the International Network on Endocrine Complications in Thalassemia (I-CET) was founded in order to transmit the latest information on these disorders to the treating physicians. The I-CET position statement outlined in this document applies to patients with transfusion-dependent thalassemia major to help physicians to anticipate, diagnose, and manage these complications properly. PMID:23776848

Dual origin, development, and fate of bovine pancreatic islets

PubMed Central

Merkwitz, Claudia; Lochhead, Paul; Böttger, Jan; Matz-Soja, Madlen; Sakurai, Michiharu; Gebhardt, Rolf; Ricken, Albert M

2013-01-01

Endocrine cells are evident at an early stage in bovine pancreatic development when the pancreas still consists of primitive epithelial cords. At this stage, the endocrine cells are interspersed between the precursor cells destined to form the ductulo-acinar trees of later exocrine lobules. We here demonstrate that, in bovine fetuses of crown rump length ≥ 11 cm, the endocrine cells become increasingly segregated from the developing exocrine pancreas by assembly into two units that differ in histogenesis, architecture, and fate. Small numbers of ‘perilobular giant islets’ are distinguishable from larger numbers of ‘intralobular small islets’. The two types of islets arise in parallel from the ends of the ductal tree. Aside from differences in number, location, and size, the giant and small islets differ in cellular composition (predominantly insulin-synthesising cells vs. mixtures of endocrine cells), morphology (epithelial trabeculae with gyriform and rosette-like appearance vs. compact circular arrangements of endocrine cells), and in their relationships to intrapancreatic ganglia and nerves. A further difference becomes apparent during the antenatal period; while the ‘interlobular small islets’ persist in the pancreata of calves and adult cattle, the perilobular giant islets are subject to regression, characterised by involution of the parenchyma, extensive haemorrhage, leukocyte infiltration (myeloid and T-cells) and progressive fibrotic replacement. In conclusion, epithelial precursor cells of the ductolo-acinar tree may give rise to populations of pancreatic islets with different histomorphology, cellular composition and fates. This should be taken into account when using these cells for the generation of pancreatic islets for transplantation therapy. PMID:23171225

Endocrine tumours in the guinea pig.

PubMed

Künzel, Frank; Mayer, Jörg

2015-12-01

Functional endocrine tumours have long been thought to be rare in guinea pigs, although conditions such as hyperthyroidism and hyperadrenocorticism have been documented with increasing frequency so the prevalence of hormonal disorders may have been underestimated. Both the clinical signs and diagnosis of hyperthyroidism in guinea pigs appear to be very similar to those described in feline hyperthyroidism, and methimazole has been proven to be a practical therapy option. Hyperadrenocorticism has been confirmed in several guinea pigs with an adrenocorticotropic hormone stimulation test using saliva as a non-invasive sample matrix; trilostane has been successfully used to treat a guinea pig with hyperadrenocorticism. Insulinomas have only rarely been documented in guinea pigs and one animal was effectively treated with diazoxide. Copyright © 2015 Elsevier Ltd. All rights reserved.

What do women with breast cancer expect from their treatment? Correlates of negative treatment expectations about endocrine therapy.

PubMed

Heisig, Sarah R; Shedden-Mora, Meike C; von Blanckenburg, Pia; Rief, Winfried; Witzel, Isabell; Albert, Ute-Susann; Nestoriuc, Yvonne

2016-12-01

Patients' negative treatment expectations can lead to nocebo-related side effects and non-initiation of treatment. This study aims to identify correlates of treatment expectations in patients with breast cancer before the start of endocrine therapy. Expectations were assessed in a cross-sectional sample of 166 patients with breast cancer after receiving treatment information. Side effect expectations (one item) and treatment necessity-concern balance (Beliefs about Medicines Questionnaire) were assessed. Correlates were analyzed using regression analyses. The structure of treatment expectations was investigated using a network analysis. About 25% of patients expressed negative expectations. Higher side effect expectations were associated with lower treatment efficacy expectations (ß = -0.20, p = 0.01), higher medication overuse beliefs (ß = 0.17, p = 0.01), and a negative treatment appraisal before study treatment information (ß = -0.17, p = 0.02). A negative necessity-concern balance was associated with lower treatment efficacy expectations (ß = 0.36, p < 0.001), lower adherence intention (ß = 0.21, p < 0.001), and no knowledge of tumor's receptor status (ß = 0.21, p < 0.001); furthermore, it was associated with higher medication harmfulness beliefs (ß = -0.16, p = 0.02), negative treatment pre-appraisal (ß = 0.15, p = 0.01), higher somatosensory amplification (ß = -0.14, p = 0.02), and higher education (ß = -0.12, p = 0.02). The most important network node was the concern that endocrine therapy disrupts life. Negative treatment expectations before treatment start are mainly associated with psychological variables. These results are relevant for patient education in clinical settings. To improve expectations, clinicians might emphasize treatment efficacy and discuss general and specific medication concerns. Improving treatment knowledge could also be beneficial. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Targeting the cyclin D–cyclin-dependent kinase (CDK)4/6–retinoblastoma pathway with selective CDK 4/6 inhibitors in hormone receptor-positive breast cancer: rationale, current status, and future directions

PubMed Central

Spring, Laura; Bardia, Aditya; Modi, Shanu

2017-01-01

Dysregulation of the cyclin D–cyclin-dependent kinase (CDK)4/6–INK4–retinoblastoma (Rb) pathway is an important contributor to endocrine therapy resistance. Recent clinical development of selective inhibitors of CDK4 and CDK6 kinases has led to renewed interest in cell cycle regulators, following experience with relatively nonselective pan-CDK inhibitors that often resulted in limited activity and poor safety profiles in the clinic. The highly selective oral CDK 4/6 inhibitors palbociclib (PD0332991), ribociclib (LEE011), and abemaciclib (LY2835219) are able to inhibit the proliferation of Rb-positive tumor cells and have demonstrated dose-dependent growth inhibition in ER+ breast cancer models. In metastatic breast cancer, all three agents are being explored in combination with endocrine therapy in Phase III studies. Results so far indicate promising efficacy and manageable safety profiles, and led to the FDA approval of palbociclib. Phase II–III studies of these agents, in combination with endocrine therapy, are also underway in early breast cancer in the neoadjuvant and adjuvant settings. Selective CDK 4/6 inhibitors are also being investigated with other targeted agents or chemotherapy in the advanced setting. This article reviews the rationale for targeting cyclin D–CDK 4/6 in hormone receptor-positive (HR+) breast cancer, provides an overview of the available preclinical and clinical data with CDK 4/6 inhibitors in breast cancer to date, and summarizes the main features of ongoing clinical trials of these new agents in breast cancer. Future trials evaluating further combinations strategies with CDK 4/6 backbone and translational studies refining predictive biomarkers are needed to help personalize the optimal treatment regimen for individual patients with ER+ breast cancer. PMID:26896604

Heterogeneity of Estrogen Receptor Expression in Circulating Tumor Cells from Metastatic Breast Cancer Patients

PubMed Central

Babayan, Anna; Hannemann, Juliane; Spötter, Julia; Müller, Volkmar

2013-01-01

Background Endocrine treatment is the most preferable systemic treatment in metastatic breast cancer patients that have had an estrogen receptor (ER) positive primary tumor or metastatic lesions, however, approximately 20% of these patients do not benefit from the therapy and demonstrate further metastatic progress. One reason for failure of endocrine therapy might be the heterogeneity of ER expression in tumor cells spreading from the primary tumor to distant sites which is reflected in detectable circulating tumor cells (CTCs). Methods A sensitive and specific staining protocol for ER, keratin 8/18/19, CD45 was established. Peripheral blood from 35 metastatic breast cancer patients with ER-positive primary tumors was tested for the presence of CTCs. Keratin 8/18/19 and DAPI positive but CD45 negative cells were classified as CTCs and evaluated for ER staining. Subsequently, eight individual CTCs from four index patients (2 CTCs per patient) were isolated and underwent whole genome amplification and ESR1 gene mutation analysis. Results CTCs were detected in blood of 16 from 35 analyzed patients (46%), with a median of 3 CTCs/7.5 ml. In total, ER-negative CTCs were detected in 11/16 (69%) of the CTC positive cases, including blood samples with only ER-negative CTCs (19%) and samples with both ER-positive and ER-negative CTCs (50%). No correlation was found between the intensity and/or percentage of ER staining in the primary tumor with the number and ER status of CTCs of the same patient. ESR1 gene mutations were not found. Conclusion CTCs frequently lack ER expression in metastatic breast cancer patients with ER-positive primary tumors and show a considerable intra-patient heterogeneity, which may reflect a mechanism to escape endocrine therapy. Provided single cell analysis did not support a role of ESR1 mutations in this process. PMID:24058649

Anticancer drugs in surface waters: what can we say about the occurrence and environmental significance of cytotoxic, cytostatic and endocrine therapy drugs?

PubMed

Besse, Jean-Philippe; Latour, Jean-François; Garric, Jeanne

2012-02-01

This study considers the implications and research needs arising from anticancer (also referred to as antineoplastic) drugs being released into the aquatic environment, for the entire therapeutic classes used: cytotoxic, cytostatic and endocrine therapy drugs. A categorization approach, based on French consumption amounts, allowed to highlight parent molecules and several metabolites on which further occurrence and ecotoxicological studies should be conducted. Investigations of consumption trends at a national and a local scale show an increase in the use of anticancer drugs between 2004 and 2008, thus leading to increased levels released in the environment. It therefore appears necessary to continue surveying their presence in surface waters and in wastewater treatment plant (WWTP) effluents. Furthermore, due to the rise of anticancer home treatments, most of the prescribed molecules are now available in town pharmacies. Consequently, hospital effluents are no longer the main expected entry route of anticancer drugs into the aquatic environment. Concerning ecotoxicological risks, current knowledge remains insufficient to support a definitive conclusion. Risk posed by cytotoxic molecules is still not well documented and it is not possible to conclude on their long-term effects on non-target organisms. To date, ecotoxicological effects have been assessed using standardized or in vitro assays. Such tests however may not be suitable for anticancer drugs, and further work should focus on full-life cycle or even multigenerational tests. Environmental significance (i.e. occurrence and effects) of cytostatics (protein kinases inhibitors and monoclonal antibodies), if any, is not documented. Protein kinases inhibitors, in particular, deserve further investigation due to their universal mode of action. Finally, concerning endocrine therapy drugs, molecules such as antiestrogen Tamoxifen and its active metabolites, could be of concern. Overall, to accurately assess the ecotoxicological risk of anticancer drugs, we discuss the need to break away from tests on isolated molecules and to test effects of mixtures at the low ng.l(-1) range. Copyright © 2011 Elsevier Ltd. All rights reserved.

Specific adverse events predict survival benefit in patients treated with tamoxifen or aromatase inhibitors: an international tamoxifen exemestane adjuvant multinational trial analysis.

PubMed

Fontein, Duveken B Y; Seynaeve, Caroline; Hadji, Peyman; Hille, Elysée T M; van de Water, Willemien; Putter, Hein; Kranenbarg, Elma Meershoek-Klein; Hasenburg, Annette; Paridaens, Robert J; Vannetzel, Jean-Michel; Markopoulos, Christos; Hozumi, Yasuo; Bartlett, John M S; Jones, Stephen E; Rea, Daniel William; Nortier, Johan W R; van de Velde, Cornelis J H

2013-06-20

Specific adverse events (AEs) associated with endocrine therapy and related to depletion or blocking of circulating estrogens may be related to treatment efficacy. We investigated the relationship between survival outcomes and specific AEs including vasomotor symptoms (VMSs), musculoskeletal adverse events (MSAEs), and vulvovaginal symptoms (VVSs) in postmenopausal patients with breast cancer participating in the international Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. Primary efficacy end points were disease-free survival (DFS), overall survival (OS), and distant metastases (DM). VMSs, MSAEs, and VVSs arising in the first year of endocrine treatment were considered. Patients who did not start or who discontinued their allocated therapy and/or had an event (recurrence/death) within 1 year after randomization were excluded. Landmark analyses and time-dependent multivariate Cox proportional hazards models assessed survival differences up to 5 years from the start of treatment. A total of 9,325 patients were included. Patients with specific AEs (v nonspecific or no AEs) had better DFS and OS (multivariate hazard ratio [HR] for DFS: VMSs, 0.731 [95% CI, 0.618 to 0.866]; MSAEs, 0.826 [95% CI, 0.694 to 0.982]; VVSs, 0.769 [95% CI, 0.585 to 1.01]; multivariate HR for OS: VMSs, 0.583 [95% CI, 0.424 to 0.803]; MSAEs, 0.811 [95% CI, 0.654 to 1.005]; VVSs, 0.570 [95% CI, 0.391 to 0.831]) and fewer DM (VMSs, 0.813 [95% CI, 0.664 to 0.996]; MSAEs, 0.749 [95% CI, 0.601 to 0.934]; VVSs, 0.687 [95% CI, 0.436 to 1.085]) than patients not reporting these symptoms. Increasing numbers of specific AEs were also associated with better survival outcomes. Outcomes were unrelated to treatment allocation. Certain specific AEs are associated with superior survival outcomes and may therefore be useful in predicting treatment responses in patients with breast cancer treated with endocrine therapy.

Timing of Radiotherapy and Outcome in Patients Receiving Adjuvant Endocrine Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Karlsson, Per, E-mail: per.karlsson@oncology.gu.s; Cole, Bernard F.; International Breast Cancer Study Group Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA

2011-06-01

Purpose: To evaluate the association between the interval from breast-conserving surgery (BCS) to radiotherapy (RT) and the clinical outcome among patients treated with adjuvant endocrine therapy. Patients and Methods: Patient information was obtained from three International Breast Cancer Study Group trials. The analysis was restricted to 964 patients treated with BCS and adjuvant endocrine therapy. The patients were divided into two groups according to the median number of days between BCS and RT and into four groups according to the quartile of time between BCS and RT. The endpoints were the interval to local recurrence, disease-free survival, and overall survival.more » Proportional hazards regression analysis was used to perform comparisons after adjustment for baseline factors. Results: The median interval between BCS and RT was 77 days. RT timing was significantly associated with age, menopausal status, and estrogen receptor status. After adjustment for these factors, no significant effect of a RT delay {<=}20 weeks was found. The adjusted hazard ratio for RT within 77 days vs. after 77 days was 0.94 (95% confidence interval [CI], 0.47-1.87) for the interval to local recurrence, 1.05 (95% CI, 0.82-1.34) for disease-free survival, and 1.07 (95% CI, 0.77-1.49) for overall survival. For the interval to local recurrence the adjusted hazard ratio for {<=}48, 49-77, and 78-112 days was 0.90 (95% CI, 0.34-2.37), 0.86 (95% CI, 0.33-2.25), and 0.89 (95% CI, 0.33-2.41), respectively, relative to {>=}113 days. Conclusion: A RT delay of {<=}20 weeks was significantly associated with baseline factors such as age, menopausal status, and estrogen-receptor status. After adjustment for these factors, the timing of RT was not significantly associated with the interval to local recurrence, disease-free survival, or overall survival.« less

How I treat CLL up front.

PubMed

Gribben, John G

2010-01-14

Although chronic lymphocytic leukemia (CLL) remains incurable, over the past decade there have been major advances in understanding the pathophysiology of CLL and in the treatment of this disease. This has led to greatly increased response rates and durations of response but not yet improved survival. Advances in the use of prognostic factors that identify patients at high risk for progression have led us to the question whether there is still a role for a "watch and wait" approach in asymptomatic high-risk patients or whether they should be treated earlier in their disease course. Questions remain, including, what is the optimal first-line treatment and its timing and is there any role of maintenance therapy or stem cell transplantation in this disease? CLL is a disease of the elderly and not all patients are eligible for aggressive up-front chemoimmunotherapy regimens, so what is the optimal treatment approach for more frail elderly patients? It is highly likely that our treatment approaches will continue to evolve as the results of ongoing clinical trials are released and that further improvements in the outcome of this disease will result from identification of therapies that target the underlying pathophysiology of CLL.

An old drug with a new future: bendamustine in multiple myeloma.

PubMed

Gentile, Massimo; Recchia, Anna Grazia; Mazzone, Carla; Vigna, Ernesto; Martino, Massimo; Morabito, Lucio; Lucia, Eugenio; Bossio, Sabrina; De Stefano, Laura; Granata, Teresa; Palummo, Angela; Morabito, Fortunato

2013-11-01

Bendamustine is a unique bifunctional alkylating agent with promising activity in multiple myeloma (MM). It is currently licensed in Europe for use as frontline treatment with prednisolone for patients with MM who are unsuitable for transplantation and who are contraindicated for thalidomide and bortezomib therapy. Studies evaluating the safety and efficacy of bendamustine administered alone or in combination in both the upfront and relapse settings of MM patients, including those with renal insufficiency, were reviewed. The use of bendamustine as conditioning for autologous stem-cell transplantation and the possibility of stem-cell mobilization after bendamustine therapy are discussed. Bendamustine seems to be efficacious either in monotherapy or in combination with other drugs in previously treated or untreated patients. This is due to its unique mechanism of action including its ability to activate apoptosis and inhibit mitotic checkpoints, making it potentially more effective than other alkylating agents. Moreover, it has an acceptable toxicity profile and is suitable for patients with renal impairment. Finally, this drug does not seem to compromise the possibility of achieving a stem-cell mobilization. Nonetheless, data from Phase III studies demonstrating its effectiveness in terms of overall survival are not yet available.

Post-transplant lymphoproliferative disorders.

PubMed

Singavi, Arun K; Harrington, Alexandra M; Fenske, Timothy S

2015-01-01

Post-transplant lymphoproliferative disorders (PTLD) are a serious complication after solid organ or allogeneic hematopoietic stem cell transplantation and include a range of diseases from benign proliferations to malignant lymphomas. Risk factors for developing PTLD include Epstein-Barr virus (EBV) infection, recipient age, transplanted organ, type of immunosuppression, and genetics. Uncontrolled proliferation of EBV-infected B cells is implicated in EBV-positive PTLD, whereas the pathogenesis of EBV-negative PTLD may be similar to non-Hodgkin's lymphoma in the general population. The World Health Organization (WHO) classifies PTLD into four categories: early lesions, polymorphic PTLD, monomorphic PTLD, and classical Hodgkin's lymphoma (cHL). Treatment is aimed at cure of PTLD, while maintaining transplanted organ function. However, there are no established guidelines for the treatment of PTLD. Immune suppression reduction (ISR) is the first line of treatment in most cases, with more recent data suggesting early use of rituximab. In more aggressive forms of PTLD, upfront chemotherapy may offer a better and more durable response. Sequential therapy using rituximab followed by chemotherapy has demonstrated promising results and may establish a standard of care. Novel therapies including anti-viral agents, adoptive immunotherapy, and monoclonal antibodies targeting cytokines require further study in the prevention and treatment of PTLD.

State of the art and perspectives in the treatment of glioblastoma.

PubMed

Grimm, Sean A; Chamberlain, Marc C

2012-09-01

Glioblastoma is the most common malignant primary brain tumor. Cures are rare and median survival varies from several to 22 months. Standard treatment for good performance patients consists of maximal safe surgical resection followed by radiotherapy with concurrent temozolomide (TMZ) chemotherapy and six cycles of postradiotherapy TMZ. At recurrence, treatment options include repeat surgery (with or without Gliadel wafer placement), reirradiation or systemic therapy. Most patients with good performance status are treated with cytotoxic chemotherapy or targeted biologic therapy following or in lieu of repeat surgery. Cytotoxic chemotherapy options include nitrosoureas, rechallenge with TMZ, platins, phophoramides and topoisomerase inhibitors, although efficacy is limited. Despite the intense effort of developing biologic agents that target angiogenesis and growth and proliferative pathways, bevacizumab is the only agent that has shown efficacy in clinical trials. It was awarded accelerated approval in the USA after demonstrating an impressive radiographic response in two open-label, prospective Phase II studies. Two randomized, Phase III trials of upfront bevacizumab have completed and may demonstrate survival benefit; however, results are pending at this time. Given the limited treatment options at tumor recurrence, consideration for enrollment on a clinical trial is encouraged.

Outcomes and predictors of survival in blast phase myeloproliferative neoplasms.

PubMed

Lancman, Guido; Brunner, Andrew; Hoffman, Ronald; Mascarenhas, John; Hobbs, Gabriela

2018-05-21

We retrospectively reviewed treatment outcomes for 57 patients with myeloproliferative neoplasms in blast phase (MPN-BP). The median overall survival (OS) of the entire cohort was 5.8 months. For patients receiving induction therapy, 67% achieved a complete response (CR) and 75% received stem cell transplantation (SCT). Median OS for all transplanted patients (n = 19) was not reached after a median follow-up of 19.2 months compared with 3.8 months in non-transplanted patients (p < 0.0001); patients who did not receive SCT after induction chemotherapy survived a median of 4.9 months. OS was not improved in patients transplanted after CR (OS not reached after median follow-up of 26.7 months) compared with those transplanted upfront or after suboptimal response to initial therapy (9.0 months; p = .097). Those who were transfusion-dependent during their MPN course and received SCT had a median OS of 4.4 months, with all patients dying from SCT complications. Patients receiving hypomethylating agents (HMA) survived 6.7 months, while those receiving supportive care survived 1.1 months. Although outcomes for MPN-BP remain poor, long-term survival can be achieved in appropriately selected patients utilizing SCT, optimally after attaining a complete response with induction therapy. For patients ineligible for SCT, HMAs can offer similar survival to induction chemotherapy with less toxicity. Copyright © 2018 Elsevier Ltd. All rights reserved.

The STAMPEDE trial: paradigm-changing data through innovative trial design.

PubMed

Carthon, Bradley C; Antonarakis, Emmanuel S

2016-09-01

Despite the numerous regulatory approvals for prostate cancer, metastatic prostate cancer remains a huge burden for men worldwide. In an exciting development, James et al . recently published data from the Systemic Therapy in Advanced or Metastatic Prostate Cancer: Evaluation of Drug Efficacy: a multi-stage multi-arm randomised control trial (STAMPEDE). This is an innovative multi-arm multi-stage (MAMS) trial that has utilized one control arm and several comparator arms in order to provide evidence for the inclusion of therapies beyond standard androgen deprivation alone. The patient population included: (I) men with high-risk, non-metastatic, node-negative disease; (II) men with distant-metastatic or node-positive disease; and (III) men with previously-treated prostate cancer by prostatectomy or definitive radiotherapy presenting with relapse. Men were to continue androgen deprivation for at least 2 years. The current data published by this group supports earlier results and provides additional evidence that docetaxel utilized in an up-front fashion provides a survival benefit in men with hormone-sensitive metastatic prostate cancer. Moreover, the initial results from STAMPEDE show how therapies without a demonstrated survival benefit can be efficiently excluded from further study once the likelihood of a benefit is ruled out by a predetermined analysis. In this piece, we will review the STAMPEDE data, contrast it with existing results, and provide our perspectives on how this will affect future trial conduct in the field of prostate cancer.

Effects of icotinib with and without radiation therapy on patients with EGFR mutant non-small cell lung cancer and brain metastases

PubMed Central

Fan, Yun; Xu, Yanjun; Gong, Lei; Fang, luo; Lu, Hongyang; Qin, Jing; Han, Na; Xie, Fajun; Qiu, Guoqin; Huang, Zhiyu

2017-01-01

EGFR-TKIs and radiation therapy (RT) are the principal treatment for patients with brain metastases (BM) and EGFR mutant NSCLC. However, the optimal use of brain RT for patients with asymptomatic BM remains undefined. A total of 152 patients were identified. 58 patients were excluded. Of the remaining 97 patients, 56 patients received upfront RT followed by icotinib, including WBRT or SRS. 41 patients received icotinib therapy alone. The mOS from diagnosis of BM was 27.0 months for the whole cohort (95% CI, 23.9–30.1 months). There was no difference in OS between the RT followed by icotinib group and the icotinib alone group (31.9 vs. 27.9 months, P = 0.237), and similar results were found in the SRS subgroup (35.5 vs. 27.9 months, P = 0.12). Patients with the EGFR Del19 mutation had a longer OS than patients with the exon 21 L858R mutation (32.7 vs. 27.4, P = 0.037). Intracranial progression-free survival (PFS) was improved in the patients who received RT followed by icotinib compared to those receiving icotinib alone (22.4 vs. 13.9 months, P = 0.043). Patients with EGFR-mutant adenocarcinoma and BM treated with icotinib exhibited prolonged survival. A longer duration of intracranial control was observed with brain RT. PMID:28332624

Effects of icotinib with and without radiation therapy on patients with EGFR mutant non-small cell lung cancer and brain metastases.

PubMed

Fan, Yun; Xu, Yanjun; Gong, Lei; Fang, Luo; Lu, Hongyang; Qin, Jing; Han, Na; Xie, Fajun; Qiu, Guoqin; Huang, Zhiyu

2017-03-23

EGFR-TKIs and radiation therapy (RT) are the principal treatment for patients with brain metastases (BM) and EGFR mutant NSCLC. However, the optimal use of brain RT for patients with asymptomatic BM remains undefined. A total of 152 patients were identified. 58 patients were excluded. Of the remaining 97 patients, 56 patients received upfront RT followed by icotinib, including WBRT or SRS. 41 patients received icotinib therapy alone. The mOS from diagnosis of BM was 27.0 months for the whole cohort (95% CI, 23.9-30.1 months). There was no difference in OS between the RT followed by icotinib group and the icotinib alone group (31.9 vs. 27.9 months, P = 0.237), and similar results were found in the SRS subgroup (35.5 vs. 27.9 months, P = 0.12). Patients with the EGFR Del19 mutation had a longer OS than patients with the exon 21 L858R mutation (32.7 vs. 27.4, P = 0.037). Intracranial progression-free survival (PFS) was improved in the patients who received RT followed by icotinib compared to those receiving icotinib alone (22.4 vs. 13.9 months, P = 0.043). Patients with EGFR-mutant adenocarcinoma and BM treated with icotinib exhibited prolonged survival. A longer duration of intracranial control was observed with brain RT.

Prognostic factors of afatinib as a first-line therapy for advanced EGFR mutation-positive lung adenocarcinoma: a real-world, large cohort study.

PubMed

Liang, Sheng-Kai; Lee, Meng-Rui; Liao, Wei-Yu; Ho, Chao-Chi; Ko, Jen-Chung; Shih, Jin-Yuan

2018-05-04

Lung cancer remains the primary cause of cancer-related mortality worldwide. Several treatment modalities are available for lung cancer, including surgery, radiation, and chemotherapy. Among the chemotherapeutics available, afatinib has been shown to be effective for those with epidermal growth factor receptor ( EGFR ) mutation-positive lung adenocarcinoma. Herein, we analyzed the factors affecting the prognosis of patients who received afatinib as a first-line therapy for advanced EGFR mutation-positive lung adenocarcinoma in the real-world setting. Patients who received afatinib as a first-line therapy and were reimbursed by the National Health Insurance were recruited in this study. Data on patient characteristics and treatment courses were collected. In total, 259 patients were enrolled (median follow-up, 22.0 months). Of them, 82 (31.7%) were identified to have brain metastases at baseline, which were associated with poor Eastern Cooperative Oncology Group performance status, high incidence of central nervous system progression, and short overall survival. However, the results of our analysis showed that overall survival was not affected by reductions in the afatinib dosage or any upfront local treatments for brain tumors. Multivariate analyses showed that brain metastases at diagnosis and treatment response to afatinib are two important prognostic factors for the overall survival of patients with EGFR mutation-positive lung adenocarcinoma.

PI3K inhibition to overcome endocrine resistance in breast cancer.

PubMed

Keegan, Niamh M; Gleeson, Jack P; Hennessy, Bryan T; Morris, Patrick G

2018-01-01

Activation of the phosphatidylinositol-3 kinase (PI3K) pathway is a critical step in oncogenesis and plays a role in the development of treatment resistance for both estrogen receptor (ER) positive and human epidermal growth factor receptor 2 (HER2) positive breast cancers. Hence, there have been efforts to therapeutically inhibit this pathway. Areas covered: Several inhibitors of PI3K are now progressing through clinical trials with varying degrees of efficacy and toxicity to date. Numerous unresolved questions remain concerning the optimal isoform selectivity of PI3K inhibitors and use of predictive biomarkers. This review examines the most important PI3K inhibitors in ER positive breast cancer to date, with a particular focus on their role in overcoming endocrine therapy resistance and the possible use of PIK3CA mutations as a predictive biomarker. Expert opinion: We discuss some of the emerging challenges and questions encountered during the development of PI3K inhibitors from preclinical to phase III studies, including other novel biomarkers and future combinations to overcome endocrine resistance.

The adipose organ and multiple myeloma: Impact of adipokines on tumor growth and potential sites for therapeutic intervention.

PubMed

Allegra, Alessandro; Innao, Vanessa; Gerace, Demetrio; Allegra, Andrea Gaetano; Vaddinelli, Doriana; Bianco, Oriana; Musolino, Caterina

2018-07-01

In addition to its capacity to store lipids the adipose tissue is now identified as a real organ with both endocrine and metabolic roles. Preclinical results indicate that modifying adipose tissue and bone marrow adipose tissue (BMAT) could be a successful multiple myeloma (MM) therapy. BMAT interrelates with bone marrow cells and other immune cells, and may influence MM disease progression. The BM adipocytes may have a role in MM progression, bone homing, chemoresistance, and relapse, due to local endocrine, paracrine, or metabolic factors. BM adipocytes isolated from MM subjects have been shown to increase myeloma growth in vitro and may preserve cells from chemotherapy-induced apoptosis. By producing free fatty acids and emitting signaling molecules such as growth factors and adipokines, BM adipocytes are both an energy font and an endocrine signaling factory. This review should suggest future research approaches toward developing novel treatments to target MM by targeting BMAT and its products. Copyright © 2018 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Transcription factors in pancreatic development. Animal models.

PubMed

Martin, Merce; Hauer, Viviane; Messmer, Mélanie; Orvain, Christophe; Gradwohl, Gérard

2007-01-01

Through the analysis of genetically modified mice a hierarchy of transcription factors regulating pancreas specification, endocrine destiny as well as endocrine subtype specification and differentiation has been established. In addition to conventional approaches such as transgenic technologies and gene targeting, recombinase fate mapping in mice has been key in establishing the lineage relationship between progenitor cells and their progeny in understanding pancreas formation. Moreover, the design of specific mouse models to conditionally express transcription factors in different populations of progenitor cells has revealed to what extent transcription factors required for islet cell development are also sufficient to induce endocrine differentiation and the importance of the competence of progenitor cells to respond to the genetic program implemented by these factors. Taking advantage of this basic science knowledge acquired in rodents, immature insulin-producing cells have recently been differentiated in vitro from human embryonic stem cells. Taken together these major advances emphasize the need to gain further in-depth knowledge of the molecular and cellular mechanisms controlling beta-cell differentiation in mice to generate functional beta-cells in the future that could be used for cell therapy in diabetes.

Prediction of late disease recurrence and extended adjuvant letrozole benefit by the HOXB13/IL17BR biomarker.

PubMed

Sgroi, Dennis C; Carney, Erin; Zarrella, Elizabeth; Steffel, Lauren; Binns, Shemeica N; Finkelstein, Dianne M; Szymonifka, Jackie; Bhan, Atul K; Shepherd, Lois E; Zhang, Yi; Schnabel, Catherine A; Erlander, Mark G; Ingle, James N; Porter, Peggy; Muss, Hyman B; Pritchard, Katherine I; Tu, Dongsheng; Rimm, David L; Goss, Paul E

2013-07-17

Biomarkers to optimize extended adjuvant endocrine therapy for women with estrogen receptor (ER)-positive breast cancer are limited. The HOXB13/IL17BR (H/I) biomarker predicts recurrence risk in ER-positive, lymph node-negative breast cancer patients. H/I was evaluated in MA.17 trial for prognostic performance for late recurrence and treatment benefit from extended adjuvant letrozole. A prospective-retrospective, nested case-control design of 83 recurrences matched to 166 nonrecurrences from letrozole- and placebo-treated patients within MA.17 was conducted. Expression of H/I within primary tumors was determined by reverse-transcription polymerase chain reaction with a prespecified cutpoint. The predictive ability of H/I for ascertaining benefit from letrozole was determined using multivariable conditional logistic regression including standard clinicopathological factors as covariates. All statistical tests were two-sided. High H/I was statistically significantly associated with a decrease in late recurrence in patients receiving extended letrozole therapy (odds ratio [OR] = 0.35; 95% confidence interval [CI] = 0.16 to 0.75; P = .007). In an adjusted model with standard clinicopathological factors, high H/I remained statistically significantly associated with patient benefit from letrozole (OR = 0.33; 95% CI = 0.15 to 0.73; P = .006). Reduction in the absolute risk of recurrence at 5 years was 16.5% for patients with high H/I (P = .007). The interaction between H/I and letrozole treatment was statistically significant (P = .03). In the absence of extended letrozole therapy, high H/I identifies a subgroup of ER-positive patients disease-free after 5 years of tamoxifen who are at risk for late recurrence. When extended endocrine therapy with letrozole is prescribed, high H/I predicts benefit from therapy and a decreased probability of late disease recurrence.

Age-specific nonpersistence of endocrine therapy in postmenopausal patients diagnosed with hormone receptor-positive breast cancer: a TEAM study analysis.

PubMed

van de Water, Willemien; Bastiaannet, Esther; Hille, Elysée T M; Meershoek-Klein Kranenbarg, Elma M; Putter, Hein; Seynaeve, Caroline M; Paridaens, Robert; de Craen, Anton J M; Westendorp, Rudi G J; Liefers, Gerrit-Jan; van de Velde, Cornelis J H

2012-01-01

Early discontinuation of adjuvant endocrine therapy may affect the outcome of treatment in breast cancer patients. The aim of this study was to assess age-specific persistence and age-specific survival outcome based on persistence status. Patients enrolled in the Tamoxifen Exemestane Adjuvant Multinational trial were included. Nonpersistence was defined as discontinuing the assigned endocrine treatment within 1 year of follow-up because of adverse events, intercurrent illness, patient refusal, or other reasons. Endpoints were the breast cancer-specific and overall survival times. Analyses were stratified by age at diagnosis (<65 years, 65-74 years, ≥75 years). Overall, 3,142 postmenopausal breast cancer patients were included: 1,682 were aged <65 years, 951 were aged 65-74 years, and 509 were aged ≥75 years. Older age was associated with a higher proportion of nonpersistence within 1 year of follow-up. In patients aged <65 years, nonpersistent patients had lower breast cancer-specific and overall survival probabilities. In patients aged 65-74 years and patients aged ≥75 years, the survival times of persistent and nonpersistent patients were similar. Nonpersistence within 1 year of follow-up was associated with lower breast cancer-specific and overall survival probabilities in patients aged <65 years, but it was not associated with survival outcomes in patients aged 65-74 years or in patients aged ≥75 years. These results suggest that extrapolation of outcomes from a young to an elderly breast cancer population may be insufficient and urge age-specific breast cancer studies.

Evolving Concepts and Translational Relevance of Enteroendocrine Cell Biology.

PubMed

Drucker, Daniel J

2016-03-01

Classical enteroenteroendocrine cell (EEC) biology evolved historically from identification of scattered hormone-producing endocrine cells within the epithelial mucosa of the stomach, small and large intestine. Purification of functional EEC hormones from intestinal extracts, coupled with molecular cloning of cDNAs and genes expressed within EECs has greatly expanded the complexity of EEC endocrinology, with implications for understanding the contribution of EECs to disease pathophysiology. Pubmed searches identified manuscripts highlighting new concepts illuminating the molecular biology, classification and functional role(s) of EECs and their hormonal products. Molecular interrogation of EECs has been transformed over the past decade, raising multiple new questions that challenge historical concepts of EEC biology. Evidence for evolution of the EEC from a unihormonal cell type with classical endocrine actions, to a complex plurihormonal dynamic cell with pleiotropic interactive functional networks within the gastrointestinal mucosa is critically assessed. We discuss gaps in understanding how EECs sense and respond to nutrients, cytokines, toxins, pathogens, the microbiota, and the microbial metabolome, and highlight the expanding translational relevance of EECs in the pathophysiology and therapy of metabolic and inflammatory disorders. The EEC system represents the largest specialized endocrine network in human physiology, integrating environmental and nutrient cues, enabling neural and hormonal control of metabolic homeostasis. Updating EEC classification systems will enable more accurate comparative analyses of EEC subpopulations and endocrine networks in multiple regions of the gastrointestinal tract.

Endocrine manifestations and management of Prader-Willi syndrome.

PubMed

Emerick, Jill E; Vogt, Karen S

2013-08-21

Prader-Willi syndrome (PWS) is a complex genetic disorder, caused by lack of expression of genes on the paternally inherited chromosome 15q11.2-q13. In infancy it is characterized by hypotonia with poor suck resulting in failure to thrive. As the child ages, other manifestations such as developmental delay, cognitive disability, and behavior problems become evident. Hypothalamic dysfunction has been implicated in many manifestations of this syndrome including hyperphagia, temperature instability, high pain threshold, sleep disordered breathing, and multiple endocrine abnormalities. These include growth hormone deficiency, central adrenal insufficiency, hypogonadism, hypothyroidism, and complications of obesity such as type 2 diabetes mellitus. This review summarizes the recent literature investigating optimal screening and treatment of endocrine abnormalities associated with PWS, and provides an update on nutrition and food-related behavioral intervention. The standard of care regarding growth hormone therapy and surveillance for potential side effects, the potential for central adrenal insufficiency, evaluation for and treatment of hypogonadism in males and females, and the prevalence and screening recommendations for hypothyroidism and diabetes are covered in detail. PWS is a genetic syndrome in which early diagnosis and careful attention to detail regarding all the potential endocrine and behavioral manifestations can lead to a significant improvement in health and developmental outcomes. Thus, the important role of the provider caring for the child with PWS cannot be overstated.

Decision analytic cost-effectiveness model to compare prostate cryotherapy to androgen deprivation therapy for treatment of radiation recurrent prostate cancer

PubMed Central

Boyd, Kathleen A; Jones, Rob J; Paul, Jim; Birrell, Fiona; Briggs, Andrew H; Leung, Hing Y

2015-01-01

Objective To determine the cost-effectiveness of salvage cryotherapy (SC) in men with radiation recurrent prostate cancer (RRPC). Design Cost-utility analysis using decision analytic modelling by a Markov model. Setting and methods Compared SC and androgen deprivation therapy (ADT) in a cohort of patients with RRPC (biopsy proven local recurrence, no evidence of metastatic disease). A literature review captured published data to inform the decision model, and resource use data were from the Scottish Prostate Cryotherapy Service. The model was run in monthly cycles for RRPC men, mean age of 70 years. The model was run over the patient lifetime, to assess changes in patient health states and the associated quality of life, survival and cost impacts. Results are reported in terms of the discounted incremental costs and discounted incremental quality-adjusted life years (QALYs) gained between the 2 alternative interventions. Probabilistic sensitivity analysis used a 10 000 iteration Monte Carlo simulation. Results SC has a high upfront treatment cost, but delays the ongoing monthly cost of ADT. SC is the dominant strategy over the patient lifetime; it is more effective with an incremental 0.56 QALY gain (95% CI 0.28 to 0.87), and less costly with a reduced lifetime cost of £29 719 (€37 619) (95% CI −51 985 to −9243). For a ceiling ratio of £30 000, SC has a 100% probability to be cost-effective. The cost neutral point was at 3.5 years, when the upfront cost of SC (plus any subsequent cumulative cost of side effects and ADT) equates the cumulative cost in the ADT arm. Limitations of our model may arise from its insensitivity to parameter or structural uncertainty. Conclusions The platform for SC versus ADT cost-effective analysis can be employed to evaluate other treatment modalities or strategies in RRPC. SC is the dominant strategy, costing less over a patient's lifetime with improvements in QALYs. Trial registration number This economic analysis was undertaken as part of the CROP RCT study ISRCTN:72677390; it was a pre-trial economic model developed and analysed during the pre-results stage of the RCT. PMID:26482768

Specialized Veterinary Manpower Needs through 1990,

DTIC Science & Technology

1982-01-01

vaccines and diagnostic tests; and the increased technical sophistication in artificial insemination , embryo culture and transplantation, and hormonal...are included. Artificial insemination , synchronization of estrus, endocrine therapy, spermatozoan and ovum genetic engineering, and ovum and embryo...hospital facility surrounded by satellite clinics that offer restricted medical and surgical services. 26 Qualified animal-health technicians are used to a

Endocrine Therapy of Breast Cancer

DTIC Science & Technology

2007-06-01

our existing algorithms and have recently submitted for publication a short communication on the implementation and uses of our VISDA algorithms...binding domain and related intramolecular communication restores tamoxifen sensitivity in resistant breast cancer.” Cancer Cell, 10: 487-499, 2006...reviewed publications comparable to short communications in biomedical journals. Comment on Subcontracts: Please also note that the majority of our

Endocrine Therapy of Breast Cancer

DTIC Science & Technology

2006-06-01

Becker muscular dystrophy (BMD, hypomorphic for dys- trophin, n = 5), Dysferlin deficiency (putative vesicle traf- fic defect, n = 9), and Calpain III...this study. (1) Limb-girdle muscular dystrophy (LGMD, provided by Children National Medical Center, Center for Genetic Medicine): 4 diagnostic...groups, Fukutin related protein de- ficiency (FKRP) (homozygous missense for glycosylation enzyme, limb-girdle muscular dystrophy sub-type, n = 7

Mouse pancreas tissue slice culture facilitates long-term studies of exocrine and endocrine cell physiology in situ.

PubMed

Marciniak, Anja; Selck, Claudia; Friedrich, Betty; Speier, Stephan

2013-01-01

Studies on pancreatic cell physiology rely on the investigation of exocrine and endocrine cells in vitro. Particularly, in the case of the exocrine tissue these studies have suffered from a reduced functional viability of acinar cells in culture. As a result not only investigations on dispersed acinar cells and isolated acini were limited in their potential, but also prolonged studies on pancreatic exocrine and endocrine cells in an intact pancreatic tissue environment were unfeasible. To overcome these limitations, we aimed to establish a pancreas tissue slice culture platform to allow long-term studies on exocrine and endocrine cells in the intact pancreatic environment. Mouse pancreas tissue slice morphology was assessed to determine optimal long-term culture settings for intact pancreatic tissue. Utilizing optimized culture conditions, cell specificity and function of exocrine acinar cells and endocrine beta cells were characterized over a culture period of 7 days. We found pancreas tissue slices cultured under optimized conditions to have intact tissue specific morphology for the entire culture period. Amylase positive intact acini were present at all time points of culture and acinar cells displayed a typical strong cell polarity. Amylase release from pancreas tissue slices decreased during culture, but maintained the characteristic bell-shaped dose-response curve to increasing caerulein concentrations and a ca. 4-fold maximal over basal release. Additionally, endocrine beta cell viability and function was well preserved until the end of the observation period. Our results show that the tissue slice culture platform provides unprecedented maintenance of pancreatic tissue specific morphology and function over a culture period for at least 4 days and in part even up to 1 week. This analytical advancement now allows mid -to long-term studies on the cell biology of pancreatic disorder pathogenesis and therapy in an intact surrounding in situ.

Mouse Pancreas Tissue Slice Culture Facilitates Long-Term Studies of Exocrine and Endocrine Cell Physiology in situ

PubMed Central

Marciniak, Anja; Selck, Claudia; Friedrich, Betty; Speier, Stephan

2013-01-01

Studies on pancreatic cell physiology rely on the investigation of exocrine and endocrine cells in vitro. Particularly, in the case of the exocrine tissue these studies have suffered from a reduced functional viability of acinar cells in culture. As a result not only investigations on dispersed acinar cells and isolated acini were limited in their potential, but also prolonged studies on pancreatic exocrine and endocrine cells in an intact pancreatic tissue environment were unfeasible. To overcome these limitations, we aimed to establish a pancreas tissue slice culture platform to allow long-term studies on exocrine and endocrine cells in the intact pancreatic environment. Mouse pancreas tissue slice morphology was assessed to determine optimal long-term culture settings for intact pancreatic tissue. Utilizing optimized culture conditions, cell specificity and function of exocrine acinar cells and endocrine beta cells were characterized over a culture period of 7 days. We found pancreas tissue slices cultured under optimized conditions to have intact tissue specific morphology for the entire culture period. Amylase positive intact acini were present at all time points of culture and acinar cells displayed a typical strong cell polarity. Amylase release from pancreas tissue slices decreased during culture, but maintained the characteristic bell-shaped dose-response curve to increasing caerulein concentrations and a ca. 4-fold maximal over basal release. Additionally, endocrine beta cell viability and function was well preserved until the end of the observation period. Our results show that the tissue slice culture platform provides unprecedented maintenance of pancreatic tissue specific morphology and function over a culture period for at least 4 days and in part even up to 1 week. This analytical advancement now allows mid -to long-term studies on the cell biology of pancreatic disorder pathogenesis and therapy in an intact surrounding in situ. PMID:24223842

Clinical outcomes of transfusion-associated iron overload in patients with refractory chronic anemia.

PubMed

Gao, Chong; Li, Li; Chen, Baoan; Song, Huihui; Cheng, Jian; Zhang, Xiaoping; Sun, Yunyu

2014-01-01

The purpose of this study was to evaluate the clinical outcomes of transfusion-associated iron overload in patients with chronic refractory anemia. Clinical manifestations, main organ function, results of computed tomography (CT), endocrine evaluation, and serum ferritin levels were analyzed retrospectively in 13 patients who were transfusion-dependent for more than 1 year (receiving >50 units of red blood cells) to determine the degree of iron overload and efficacy of iron-chelating therapy. Serum ferritin levels increased to 1,830-5,740 ng/mL in all patients. Ten patients had abnormal liver function. The CT Hounsfield units in the liver increased significantly in eleven patients, and were proportional to their serum ferritin levels. Skin pigmentation, liver dysfunction, and endocrine dysfunction were observed in nine patients with serum ferritin >3,500 ng/mL, eight of whom have since died. Interestingly, serum ferritin levels did not decrease significantly in nine transfusion-dependent patients who had received 15-60 days of iron-chelating therapy. Transfusion-dependent patients may progress to secondary iron overload with organ impairment, which may be fatal in those who are heavily iron-overloaded. The CT Hounsfield unit is a sensitive indicator of iron overload in the liver. Iron chelation therapy should be initiated when serum ferritin is >1,000 ng/mL and continued until it is <1,000 ng/mL in transfusional iron-overloaded patients.

Prescription refill, patient self-report and physician report in assessing adherence to oral endocrine therapy in early breast cancer patients: a retrospective cohort study in Catalonia, Spain

PubMed Central

Font, R; Espinas, J A; Gil-Gil, M; Barnadas, A; Ojeda, B; Tusquets, I; Segui, M A; Margelí, M; Arcusa, A; Prat, A; Garcia, M; Borras, J M

2012-01-01

Aims: To compare different methods in order to assess adherence and persistence with oral endocrine therapy in women diagnosed with breast cancer (BC) in Catalonia. Materials and methods: This study covered all women newly diagnosed with stage I, II or IIIa BC and positive hormone receptors at six hospitals in Catalonia (Spain) in 2004. Adherence was assessed on the basis of physician report and patient self-report using a telephone questionnaire. Persistence was measured by refill prescriptions. We used the Kappa index to compare adherence measures and logistic regression to evaluate adherence-related risk factors. Results: The study covered a total of 692 women. Adherence ranged from 92% (self-report) to 94.7% (physician report), depending on the measure used; persistence was 74.7% at 5 years of follow-up. Low concordance between measures was observed (Kappa range: 0.018–0.267). Patients aged 50–74 years showed higher adherence than those aged <50 years. Adherence was also associated with: adjuvant chemotherapy and sequential hormonal therapy. Conclusions: Concordance between the different measures was remarkably low, indicating the need for further research. Adherence is an issue in the management of BC patients taking oral drugs, and should be assessed in clinical practice. PMID:22955858

Direct endoscopic necrosectomy versus step-up approach for walled-off pancreatic necrosis: comparison of clinical outcome and health care utilization.

PubMed

Kumar, Nitin; Conwell, Darwin L; Thompson, Christopher C

2014-11-01

Infected walled-off pancreatic necrosis (WOPN) is a complication of acute pancreatitis requiring intervention. Surgery is associated with considerable morbidity. Percutaneous catheter drainage (PCD), initial therapy in the step-up approach, minimizes complications. Direct endoscopic necrosectomy (DEN) has demonstrated safety and efficacy. We compared outcome and health care utilization of DEN versus step-up approach. This was a matched cohort study using a prospective registry. Twelve consecutive DEN patients were matched with 12 step-up approach patients. Outcomes were clinical resolution after primary therapeutic modality, new organ failure, mortality, endocrine or exocrine insufficiency, length of stay, and health care utilization. Clinical resolution in 11 of 12 patients after DEN versus 3 of 12 step-up approach patients after PCD (P < 0.01). Nine step-up approach patients required surgery; 7 of these experienced complications. Direct endoscopic necrosectomy resulted in less new antibiotic use, pulmonary failure, endocrine insufficiency, and shorter length of stay (P < 0.05). Health care utilization was lower after DEN by 5.2:1 (P < 0.01). Direct endoscopic necrosectomy may be superior to step-up approach for WOPN with suspected or established infection. Primary PCD generally delayed definitive therapy. Given the higher efficacy, shorter length of stay, and lower health care utilization, DEN could be the first-line therapy for WOPN, with primary PCD for inaccessible or immature collections.

Predicting nonadherence to adjuvant endocrine therapy in women with early stage breast cancer.

PubMed

Corter, Arden L; Broom, Reuben; Porter, David; Harvey, Vernon; Findlay, Michael

2018-05-18

Failing to take endocrine therapy (ET) as prescribed (nonadherence) increases risk of morbidity and mortality from breast cancer recurrence. We explored predictors of nonadherence, including demographic, clinical, treatment, and personal factors, among women newly prescribed ET for early stage breast cancer. We also examined predictors of their thoughts about stopping treatment (TST). A baseline survey prior to ET assessed demographics, illness beliefs, beliefs about medicines, fear of recurrence, symptoms, and negative affect. A follow-up survey at 3 months repeated these measures with additional questions about nonadherence and TST. Nonadherence and TST were analyzed using logistic and multiple regression, respectively. Patient record review provided clinical data. The baseline survey was completed by 125 women, with a 96% retention rate at follow-up. Thirty-six percent reported nonadherence, and 30% reported TST. Results of regression analyses showed that TST was most strongly associated with symptom severity at follow-up, whereas, lower coherence beliefs, and the absence of comorbid conditions were the strongest predictors of actual nonadherence. This is the first longitudinal study to examine concurrently the association of demographic, personal and treatment factors with nonadherence, and TST. Findings have potentially important clinical implications; interventions to improve adherence and reduce TST may need to target women's understanding of their diagnosis and treatment, illness beliefs, and symptoms prior to starting therapy. Copyright © 2018 John Wiley & Sons, Ltd.

Late effects of childhood leukemia therapy.

PubMed

Fulbright, Joy M; Raman, Sripriya; McClellan, Wendy S; August, Keith J

2011-09-01

As survival rates for children treated for childhood cancers become significantly better, the focus is increasingly on determining the late effects of treatments and the best ways to monitor for them and prevent their occurrence. This review focuses on recent literature discussing the late effects of treatment in patients treated for acute myeloid leukemia and acute lymphoblastic leukemia during childhood. The late effects of therapy for childhood leukemia include secondary malignancy, cardiotoxicity, obesity, endocrine abnormalities, reproductive changes, neurocognitive deficits, and psychosocial effects. As clinicians have become more aware of the late effects of therapy, treatment regimens have been changed to decrease late effects, but patients still require long-term follow-up for their prevention and treatment.

[Music therapy as a part of complex healing].

PubMed

Sliwka, Agnieszka; Jarosz, Anna; Nowobilski, Roman

2006-10-01

Music therapy is a method which takes the adventage of therapeutic influence of musie on psychological and somatic sphere of the human body. Its therapeutic properties are more and more used. Current scientific research have proved its modifying influence on vegetative, circulatory, respiratory and endocrine systems. Works devoted to the effects of musie on the patients' psychological sphere have also confirmed that it reduces psychopathologic symptoms (anxiety and depression), improves self-rating, influences quality and disorders of sleep, reduces pain, improves moral immunity and patients' openness, readiness, co-operation in treatment process. Music therapy is treated as a method which complements conventional treatment and makes up part of an integral whole together with physiotherapy, kinesitherapy and recuperation.

Understanding discontinuation of oral adjuvant endocrine therapy by women with hormone receptor-positive invasive breast cancer nearly 4 years from diagnosis.

PubMed

Bell, Robin J; Fradkin, Pamela; Schwarz, Max; Davis, Susan R

2013-01-01

The aim of this study was to investigate the extent of discontinuation of oral adjuvant endocrine therapy (OAET) in women nearly 4 years from the diagnosis of their first episode of invasive breast cancer and the reasons for such discontinuation. We used a large, prospective cohort study of women who had been diagnosed with their first episode of invasive breast cancer between 2004 and 2006, recruited through a state-based cancer registry. All participants completed an enrollment questionnaire (EQ) within 12 months of diagnosis and annual follow-up questionnaires (FQs) thereafter. The data in this report were obtained from the EQ and the first three FQs. A total of 1,370 women with hormone receptor-positive disease completed the EQ. At the completion of the third FQ nearly 4 years from diagnosis, 1,193 women remained in the study. Use of OAET peaked by 2 years postdiagnosis. At nearly 4 years from diagnosis, 18% of the 1,193 women remaining in the study were not taking OAET. Of these women, just more than half had ceased therapy mainly owing to a range of adverse effects, predominantly estrogen deficiency symptoms, but the remainder (8% of women remaining in the study) had never used OAET. Our study confirms that early discontinuation of OAET due to estrogen deficiency symptoms remains an important issue despite calls for strategies to address this problem. The number of women potentially suitable for OAET but not receiving it was almost as great as the number of those who have discontinued therapy.

Endocrine effects of the tyrosine kinase inhibitor vandetanib in patients treated for thyroid cancer.

PubMed

Brassard, Maryse; Neraud, Barbara; Trabado, Séverine; Salenave, Sylvie; Brailly-Tabard, Sylvie; Borget, Isabelle; Baudin, Eric; Leboulleux, Sophie; Chanson, Philippe; Schlumberger, Martin; Young, Jacques

2011-09-01

The purpose of the study was to assess the endocrine effects of vandetanib, a multikinase inhibitor targeting RET, vascular endothelial growth factor receptor, and epidermal growth factor receptor, in 39 patients with progressive thyroid cancer included in two randomized placebo-controlled trials using vandetanib 300 mg/d. Endocrine samplings were performed at baseline and then every 6 months. We compared differences in endocrine parameters between baseline and on vandetanib therapy or placebo. During vandetanib treatment, several changes were observed. 1) Calcium (P = 0.0004) and vitamin D (P = 0.001) mean replacement doses were increased; calcium level remained unchanged, but serum 25(OH) vitamin D level decreased (P = 0.001); and serum PTH (P = 0.01) and 1,25(OH)(2) vitamin D (P = 0.01) levels increased, suggesting a decreased intestinal absorption of vitamin D or lack of sun exposure as a result of photosensitization. 2) l-T(4) doses were increased (P < 0.0001) to maintain serum TSH within the normal range. 3) In male patients, total testosterone (P = 0.048), bioavailable testosterone (P = 0.03), and SHBG (P = 0.02) levels increased. Serum inhibin B decreased (P = 0.02) and stimulated FSH increased (P = 0.006), suggesting a Sertoli cells insufficiency. 4) Cortisol level increased (P = 0.007) as well as ACTH level (P = 0.03) and cortisol-binding globulin (P = 0.02), but free urinary cortisol levels remained in the normal range. None of these changes were observed in patients randomized to the placebo arm. In patients with locally advanced or metastatic thyroid cancer, the tyrosine kinase inhibitor vandetanib has several endocrine effects. Thyroid hormone, calcium, and vitamin D analog requirements increased, but consequences of the biological alterations on phosphocalcic metabolism and gonadotrope and adrenal functions are unknown.

Ewing’s Sarcoma: Overcoming the Therapeutic Plateau

PubMed Central

Subbiah, Vivek; Kurzrock, Razelle

2013-01-01

The hallmark of Ewing’s sarcoma (EWS) is a translocation -- t(11;22)(q24;q12) -- that most frequently results in the EWS/FLI1 aberrant chimeric gene. Because EWS afflicts young patients, it stands out among the diverse sarcoma subtypes. The frontline, standard-of-care cytotoxic chemotherapy regimens produce minimal benefit in patients with metastases at presentation or those with relapsed disease. While the outcomes of chemorefractory EWS patients are poor, recent developments have led to the promising use of targeted therapy. Specifically, inhibition of insulin-like growth factor 1 receptor (IGF1R) signaling and the mammalian target of rapamycin (mTOR) pathways has emerged as a targeted therapy in EWS, with select patients experiencing dramatic therapeutic responses. However, targeted therapies in general, and these responders in particular, are faced with the ultimate conundrum of eventual resistance. To optimize response, combining IGF1R and mTOR inhibitor-based regimens with chemotherapy in the upfront setting in newly diagnosed high-risk EWS may clarify the true benefit of IGF1R inhibitors in these patients. Another option is to explore novel targeted multikinase inhibitors and poly(ADP-ribose) polymerase (PARP) inhibitors, which have experienced a surge in supporting preclinical data. Drugs inhibiting the downstream targets of EWS/FLI1 are also in preclinical development. However, ultimately, the underlying biomarker correlates of resistance and response must be delineated along with ways to overcome them. Novel agents, together with integration of advances in multimodal approaches (including surgery and radiation), as well as offering targeted therapies early in the disease course represent new strategies for confronting the challenges of EWS. PMID:22742646

Palbociclib: A Novel Cyclin-Dependent Kinase Inhibitor for Hormone Receptor-Positive Advanced Breast Cancer.

PubMed

Mangini, Neha S; Wesolowski, Robert; Ramaswamy, Bhuvaneswari; Lustberg, Maryam B; Berger, Michael J

2015-11-01

To review palbociclib, a novel small-molecule inhibitor of cyclin-dependent kinases 4 and 6, and its current place in therapy for the treatment of hormone receptor (HMR)-positive, human epidermal growth factor receptor 2 (Her2)-negative advanced breast cancer. Four phase I trials, 2 phase II trials, and 1 phase III trial were identified from May 2004 to May 2015 using PubMed, American Society of Clinical Oncology (ASCO) abstracts, and European Society of Medical Oncology (ESMO) abstracts. In the first-line setting, the phase II PALbociclib: Ongoing trials in the Management of breast cAncer (PALOMA)-1 trial randomized patients to receive letrozole alone or letrozole plus palbociclib 125 mg daily for 3 weeks, followed by 1 week off, as initial therapy for advanced breast cancer. The investigator-assessed median progression-free survival (PFS) was 20. 2 months for the combination versus 10.2 months for letrozole alone (hazard ratio [HR] = 0.488; 95% CI = 0.319-0.748; 1-sided P = 0.0004). The ensuing Food and Drug Administration approval of palbociclib was given a "breakthrough therapy" designation, where preliminary evidence suggests substantial improvement over existing therapies for a serious or life-threatening disease. A confirmatory phase III trial, PALOMA-2, is under way. In patients who were previously treated with endocrine therapy for advanced breast cancer, the phase III PALOMA-3 trial randomized patients to fulvestrant plus palbociclib versus fulvestrant plus placebo. The investigator-assessed median PFS at the time of a preplanned analysis was 9.2 months with palbociclib-fulvestrant compared with 3.8 months with placebo-fulvestrant (HR = 0.42; 95% CI = 0.32-0.56; P < 0.001). Palbociclib, the first-in-class CDK4/6 inhibitor, significantly extended PFS in combination with endocrine therapy in the first and subsequent lines of treatment for HMR-positive, Her2-negative advanced breast cancer. © The Author(s) 2015.

Endocrine Society of Australia position statement on male hypogonadism (part 1): assessment and indications for testosterone therapy.

PubMed

Yeap, Bu B; Grossmann, Mathis; McLachlan, Robert I; Handelsman, David J; Wittert, Gary A; Conway, Ann J; Stuckey, Bronwyn Ga; Lording, Douglas W; Allan, Carolyn A; Zajac, Jeffrey D; Burger, Henry G

2016-08-15

This article, Part 1 of the Endocrine Society of Australia's position statement on male hypogonadism, focuses on assessment of male hypogonadism, including the indications for testosterone therapy. (Part 2 will deal with treatment and therapeutic considerations.) Key points and recommendations are:Pathological hypogonadism arises due to diseases of the hypothalamus or pituitary gland (hypogonadotropic hypogonadism) or testes (hypergonadotropic hypogonadism). It is a clinical diagnosis with a pathological basis, confirmed by hormone assays.Hormonal assessment is based on measurement of circulating testosterone, luteinising hormone (LH) and follicle-stimulating hormone (FSH) concentrations. Measurement of sex hormone-binding globulin levels can be informative, but use of calculated free testosterone is not recommended for clinical decision making.Testosterone replacement therapy is warranted in men with pathological hypogonadism, regardless of age.Currently, there are limited data from high-quality randomised controlled trials with clinically meaningful outcomes to justify testosterone treatment in older men, usually with chronic disease, who have low circulating testosterone levels but without hypothalamic, pituitary or testicular disease.Obesity, metabolic syndrome and type 2 diabetes are associated with lowering of circulating testosterone level, but without elevation of LH and FSH levels. Whether these are non-specific consequences of non-reproductive disorders or a correctable deficiency state is unknown, but clear evidence for efficacy and safety of testosterone therapy in this setting is lacking.Glucocorticoid and opioid use is associated with possibly reversible reductions in circulating testosterone level, without elevation of LH and FSH levels. Where continuation of glucocorticoid or opioid therapy is necessary, review by an endocrinologist may be warranted.Changes in management as result of the position statement: Men with pathological hypogonadism should be identified and considered for testosterone therapy, while further research is needed to clarify whether there is a role for testosterone in these other settings.

Small-animal PET of steroid hormone receptors predicts tumor response to endocrine therapy using a preclinical model of breast cancer.

PubMed

Fowler, Amy M; Chan, Szeman Ruby; Sharp, Terry L; Fettig, Nicole M; Zhou, Dong; Dence, Carmen S; Carlson, Kathryn E; Jeyakumar, M; Katzenellenbogen, John A; Schreiber, Robert D; Welch, Michael J

2012-07-01

Estrogen receptor-α (ERα) and progesterone receptor (PR) are expressed in most human breast cancers and are important predictive factors for directing therapy. Because of de novo and acquired resistance to endocrine therapy, there remains a need to identify which ERα-positive (ERα(+))/PR-positive (PR(+)) tumors are most likely to respond. The purpose of this study was to use estrogen- and progestin-based radiopharmaceuticals to image ERα and PR in mouse mammary tumors at baseline and after hormonal therapy and to determine whether changes in these imaging biomarkers can serve as an early predictive indicator of therapeutic response. Mammary adenocarcinomas that spontaneously develop in aged female mice deficient in signal transducer and activator of transcription-1 (STAT1) were used. Imaging of ERα and PR in primary tumor-bearing mice and mice implanted with mammary cell lines (SSM1, SSM2, and SSM3) derived from primary STAT1-deficient (STAT1(-/-)) tumors was performed. Hormonal treatments consisted of estradiol, an ER agonist; letrozole, an aromatase inhibitor; and fulvestrant, a pure ER antagonist. Small-animal PET/CT was performed using (18)F-fluoroestradiol ((18)F-FES) for ER, (18)F-fluoro furanyl norprogesterone ((18)F-FFNP) for PR, and (18)F-FDG for glucose uptake. Tracer uptake in the tumor was quantified and compared with receptor concentration determined by in vitro assays of resected tumors. Primary STAT1(-/-) mammary tumors and implanted SSM2 and SSM3 tumors showed high (18)F-FES and (18)F-FFNP uptake and were confirmed to be ERα(+)/PR(+). Classic estrogen-induced regulation of the progesterone receptor gene was demonstrated by increased (18)F-FFNP uptake of estradiol-treated SSM3 tumors. Treatment with fulvestrant decreased (18)F-FFNP, (18)F-FES, and (18)F-FDG uptake and inhibited growth of SSM3 tumors but decreased only (18)F-FES uptake in SSM2 tumors, with no effect on growth, despite both tumors being ERα(+)/PR(+). Decreased (18)F-FFNP uptake by SSM3 tumors occurred early after initiation of treatment, before measurable tumor growth inhibition. Using small-animal PET, a profile was identified that distinguished fulvestrant-sensitive from fulvestrant-resistant ERα(+)/PR(+) tumors before changes in tumor size. This work demonstrates that imaging baseline tumoral (18)F-FES uptake and initial changes in (18)F-FFNP uptake in a noninvasive manner is a potentially useful strategy to identify responders and nonresponders to endocrine therapy at an early stage.

Immune-mediated Adverse Effects of Anti-CTLA-4 Antibody Therapy in Metastatic Melanoma

PubMed Central

Quirk, Shannon K.; Shure, Anna K.; Agrawal, Devendra K.

2015-01-01

Ipilimumab, an antibody that blocks cytotoxic T lymphocyte-associated antigen-4 (CTLA-4; CD152), was approved by the Food and Drug Administration (FDA) in 2011 for the treatment of unresectable stage III or IV malignant melanoma. Although the addition of this particular immunotherapy has broadened treatment options, immune-related adverse events (irAEs) are associated with ipilimumab therapy, including dermatologic effects, colitis and diarrhea, endocrine effects, hepatotoxicity, ocular effects, renal effects, neurologic effects, and others. In this article, a critical evaluation of the underlying mechanisms of irAEs associated with anti-CTLA-4 therapy is presented. Additionally, potentially beneficial effects of combinational therapies to alleviate ipilimumab-induced irAEs in malignant melanoma are discussed. Future research is warranted to elucidate the efficacy of such combination therapies as well as specific biomarkers that would help to predict a clinical response to ipilimumab in patients with malignant melanoma. PMID:26118951

Implications of ESR1 Mutations in Hormone Receptor-Positive Breast Cancer.

PubMed

Reinert, Tomás; Gonçalves, Rodrigo; Bines, José

2018-04-17

Endocrine treatment resistance eventually develops during adjuvant and even more often during hormonal treatment for advanced breast cancer (ABC). An ESR1 gene mutation, which encodes for the estrogen receptor (ER) protein, is one of the potential mechanisms of therapy resistance. The ESR1 mutations result in conformational changes in the ER leading to subsequent estrogen-independent transcriptional activity. These mutations are found at a lower level in early stage when compared to metastatic BC, more often through selective pressure after aromatase inhibitor (AI) treatment. Recent studies have explored the role of ESR1 mutations as potential prognostic and predictive biomarkers and showed that ESR1 mutations are likely associated with a more aggressive disease. However, definitive associations with outcome in order to make a specific treatment recommendation are yet to be found. The development of targeted therapy directed to ESR1-mutated clones is an appealing concept, and preclinical and clinical works are in progress. ESR1 mutations represent an exciting field with a rapidly increasing number of recent publications that will likely advance the knowledge of treatment resistance mechanisms and pave the way into more individualized patient endocrine treatment.

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Oestrogen receptors, nodes and stage as predictors of post-recurrence survival in 457 breast cancer patients.

PubMed

Shek, L L; Godolphin, W; Spinelli, J J

1987-12-01

The relationship to survival after first recurrence of oestrogen receptor (ER), nodal status and TNM stage at diagnosis, and treatment for advanced disease was studied in 457 females whose primary breast cancer was diagnosed in 1975 to 1981. Receptor concentration was the most important predictor of post-recurrence survival, with some additional information conveyed by nodal status. ER predicted survival after recurrence independently of nodal status, clinical stage or mode of therapy. Response to endocrine therapy is only a facet of the generally favourable prognosis of ER positive patients, rather than the sole explanation.

[Secondary osteoporosis and glucocorticoid-induced osteoporosis].

PubMed

Orcel, P; Krane, S M

2000-10-01

In order to assess properly the diagnosis of osteoporosis, a short clinical investigation is required to address potential causes for bone loss. Osteoporosis used to be suspected in a patient with vertebral demineralization, but nowadays it is often diagnosed in a patient with a low bone mass on a screening dual-energy X-ray absorptiometry (DEXA). In this setting, it is important for the clinician to look for secondary osteoporosis, especially in men in whom secondary osteoporosis is more frequent than in women, before discussing any specific therapy. The major causes are longterm glucocorticoid therapy, endocrine (hypogonadism, primary hyperparathyroidism, hyperthyroidism), or digestive diseases.

Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial.

PubMed

Tripathy, Debu; Im, Seock-Ah; Colleoni, Marco; Franke, Fabio; Bardia, Aditya; Harbeck, Nadia; Hurvitz, Sara A; Chow, Louis; Sohn, Joohyuk; Lee, Keun Seok; Campos-Gomez, Saul; Villanueva Vazquez, Rafael; Jung, Kyung Hae; Babu, K Govind; Wheatley-Price, Paul; De Laurentiis, Michelino; Im, Young-Hyuck; Kuemmel, Sherko; El-Saghir, Nagi; Liu, Mei-Ching; Carlson, Gary; Hughes, Gareth; Diaz-Padilla, Ivan; Germa, Caroline; Hirawat, Samit; Lu, Yen-Shen

2018-05-24

In MONALEESA-2, ribociclib plus letrozole showed improved progression-free survival compared with letrozole alone as first-line treatment for postmenopausal patients with hormone receptor (HR)-positive, HER2-negative, advanced breast cancer. MONALEESA-7 aimed to assess the efficacy and safety of ribociclib plus endocrine therapy in premenopausal women with advanced, HR-positive breast cancer. This phase 3, randomised, double-blind, placebo-controlled trial was done at 188 centres in 30 countries. Eligible patients were premenopausal women aged 18-59 years who had histologically or cytologically confirmed HR-positive, HER2-negative, advanced breast cancer; an Eastern Cooperative Oncology Group performance status of 0 or 1; measurable disease as per Response Evaluation Criteria in Solid Tumors version 1.1 criteria, or at least one predominantly lytic bone lesion; and had not received previous treatment with cyclin-dependent kinases 4 and 6 inhibitors. Endocrine therapy and chemotherapy in the adjuvant or neoadjuvant setting was permitted, as was up to one line of chemotherapy for advanced disease. Patients were randomly assigned (1:1) via interactive response technology to receive oral ribociclib (600 mg/day on a 3-weeks-on, 1-week-off schedule) or matching placebo with either oral tamoxifen (20 mg daily) or a non-steroidal aromatase inhibitor (letrozole 2·5 mg or anastrozole 1 mg, both oral, daily), all with goserelin (3·6 mg administered subcutaneously on day 1 of every 28-day cycle). Patients and investigators were masked to treatment assignment. Efficacy analyses were by intention to treat, and safety was assessed in all patients who received at least one dose of any study treatment. The primary endpoint was investigator-assessed progression-free survival. MONALEESA-7 is registered with ClinicalTrials.gov, NCT02278120 and is ongoing, but no longer enrolling patients. Between Dec 17, 2014, and Aug 1, 2016, 672 patients were randomly assigned: 335 to the ribociclib group and 337 to the placebo group. Per investigator's assessment, median progression-free survival was 23·8 months (95% CI 19·2-not reached) in the ribociclib group compared with 13·0 months (11·0-16·4) in the placebo group (hazard ratio 0·55, 95% CI 0·44-0·69; p<0·0001). Grade 3 or 4 adverse events reported in more than 10% of patients in either group were neutropenia (203 [61%] of 335 patients in the ribociclib group and 12 [4%] of 337 in the placebo group) and leucopenia (48 [14%] and four [1%]). Serious adverse events occurred in 60 (18%) of 335 patients in the ribociclib group and 39 (12%) of 337 in the placebo group, of which 15 (4%) and six (2%), respectively, were attributed to the study regimen. 12 (4%) of 335 patients in the ribociclib group and ten (3%) of 337 in the placebo group discontinued treatment because of adverse events. No treatment-related deaths occurred. 11 deaths occurred (five [1%] in the ribociclib group and six [2%] in the placebo group) during or within 30 days after treatment, most of which were due to progression of the underlying breast cancer (three [1%] and six [2%]). The remaining two deaths in the ribociclib group were due to an intracranial haemorrhage in an anticoagulated patient, and a pre-existing wound haemorrhage in another patient. Ribociclib plus endocrine therapy improved progression-free survival compared with placebo plus endocrine therapy, and had a manageable safety profile in patients with premenopausal, HR-positive, HER2-negative, advanced breast cancer. The combination could represent a new first-line treatment option for these patients. Novartis. Copyright © 2018 Elsevier Ltd. All rights reserved.

Detection of Activating Estrogen Receptor Gene (ESR1) Mutations in Single Circulating Tumor Cells.

PubMed

Paolillo, Carmela; Mu, Zhaomei; Rossi, Giovanna; Schiewer, Matthew J; Nguyen, Thomas; Austin, Laura; Capoluongo, Ettore; Knudsen, Karen; Cristofanilli, Massimo; Fortina, Paolo

2017-10-15

Purpose: Early detection is essential for treatment plans before onset of metastatic disease. Our purpose was to demonstrate feasibility to detect and monitor estrogen receptor 1 ( ESR1 ) gene mutations at the single circulating tumor cell (CTC) level in metastatic breast cancer (MBC). Experimental Design: We used a CTC molecular characterization approach to investigate heterogeneity of 14 hotspot mutations in ESR1 and their correlation with endocrine resistance. Combining the CellSearch and DEPArray technologies allowed recovery of 71 single CTCs and 12 WBC from 3 ER-positive MBC patients. Forty CTCs and 12 WBC were subjected to whole genome amplification by MALBAC and Sanger sequencing. Results: Among 3 selected patients, 2 had an ESR1 mutation (Y537). One showed two different ESR1 variants in a single CTC and another showed loss of heterozygosity. All mutations were detected in matched cell-free DNA (cfDNA). Furthermore, one had 2 serial blood samples analyzed and showed changes in both cfDNA and CTCs with emergence of mutations in ESR1 (Y537S and T570I), which has not been reported previously. Conclusions: CTCs are easily accessible biomarkers to monitor and better personalize management of patients with previously demonstrated ER-MBC who are progressing on endocrine therapy. We showed that single CTC analysis can yield important information on clonal heterogeneity and can be a source of discovery of novel and potential driver mutations. Finally, we also validate a workflow for liquid biopsy that will facilitate early detection of ESR1 mutations, the emergence of endocrine resistance and the choice of further target therapy. Clin Cancer Res; 23(20); 6086-93. ©2017 AACR . ©2017 American Association for Cancer Research.

Clinical utility of endocrine markers predicting myocardial siderosis in transfusion dependent thalassemia major.

PubMed

Ehsan, Lubaina; Rashid, Mariam; Alvi, Najveen; Awais, Khadija; Nadeem, Omair; Asghar, Aleezay; Sajjad, Fatimah; Fatima, Malika; Qidwai, Asim; Hussain, Shabneez; Hasan, Erum; Brown, Nick; Altaf, Sadaf; Hasan, Babar; Kirmani, Salman

2018-06-12

Endocrinopathy due to iron overload is the most common morbidity whereas myocardial siderosis causing toxic cardiomyopathy is the leading cause of mortality among patients with transfusion dependent thalassemia major (TDTM). If detected early, this can be treated with aggressive chelation. T2* cardiac magnetic resonance imaging (CMR) guided chelation protocols are now the gold standard but have limited availability in low and middle-income countries. We hypothesized that markers of endocrine dysfunction would correlate with T2* CMR and can be used to predict the severity of myocardial siderosis and guide chelation therapy. We undertook a multicenter retrospective study of 280 patients with TDTM to assess the prevalence of endocrinopathies and the predictive value of a number of individual and composite markers of endocrinopathy with T2* CMR. The prevalence of hypogonadism, stunting, hypoparathyroidism, and hypothyroidism was 82%, 69%, 40%, and 30%, respectively. The sensitivity of hypogonadism and stunting predicting severe myocardial siderosis was 90% and 80%, respectively. We conclude that clinical markers of endocrine dysfunction, especially hypogonadism (positive likelihood ratio [LR+] = 1.4, 95% confidence interval [CI] = 1.0-1.9; positive predictive value [PPV] = 77%, 95% CI = 70-82; negative predictive value [NPV] = 57%, 95% CI = 34-77] and stunting (LR+ = 1.3, 95% CI = 1.1-1.6; PPV = 64%, 95% CI = 60-69; NPV = 55%, 95% CI = 45-64) in TDTM can predict severe myocardial siderosis and can potentially guide chelation therapy, especially where access to T2* CMR is limited. © 2018 Wiley Periodicals, Inc.

A current and comprehensive review of cyclin-dependent kinase inhibitors for the treatment of metastatic breast cancer.

PubMed

Bilgin, Burak; Sendur, Mehmet A N; Şener Dede, Didem; Akıncı, Muhammed Bülent; Yalçın, Bülent

2017-09-01

Resistance to endocrine treatment generally occurs over time, especially in the metastatic stage. In this paper, we aimed to review the mechanisms of cyclin-dependent kinase (CDK) 4/6 inhibition and clinical usage of new agents in the light of recent literature updates. A literature search was carried out using PubMed, Medline and ASCO and ESMO annual-meeting abstracts by using the following search keywords; "palbociclib", "abemaciclib", "ribociclib", "cyclin-dependent kinase inhibitors" and "CDK 4/6" in metastatic breast cancer (MBC). The last search was on 10 June 2017. CDKs and cyclins are two molecules that have a key role in cell cycle progression. Today, there are three highly selective CDK4/6 inhibitors in clinical development - palbociclib, ribociclib and abemaciclib. Palbociclib and ribociclib were recently approved by the US FDA in combination with letrozole for the treatment of MBC in a first-line setting, as well as palbociclib in combination with fulvestrant for hormone-receptor (HR)-positive MBC that had progressed while on previous endocrine therapy according to the PALOMA-1, MONALEESA-2 and PALOMA-3 trials, respectively. In the recently published randomized phase III MONARCH 2 trial, abemaciclib plus letrozole had longer progression-free survival and higher objective response rates with less serious adverse events in advanced HR-positive breast cancer previously treated with hormonal treatment. CDK4/6 inhibition is a new and promising target for patients with hormone-receptor-positive MBC. Both palbociclib and ribociclib showed significant additive benefit for patients receiving first-line treatment for HR-positive, epidermal growth factor receptor-2-negative advanced breast cancer. Palbociclib and abemaciclib also had significant activity in combination with fulvestrant for patients with MBC that progressed on previous endocrine therapy.

Progress with palbociclib in breast cancer: latest evidence and clinical considerations

PubMed Central

Rocca, Andrea; Schirone, Alessio; Maltoni, Roberta; Bravaccini, Sara; Cecconetto, Lorenzo; Farolfi, Alberto; Bronte, Giuseppe; Andreis, Daniele

2016-01-01

Deregulation of the cell cycle is a hallmark of cancer, and research on cell cycle control has allowed identification of potential targets for anticancer treatment. Palbociclib is a selective inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6), which are involved, with their coregulatory partners cyclin D, in the G1-S transition. Inhibition of this step halts cell cycle progression in cells in which the involved pathway, including the retinoblastoma protein (Rb) and the E2F family of transcription factors, is functioning, although having been deregulated. Among breast cancers, those with functioning cyclin D-CDK4/6-Rb-E2F are mainly hormone-receptor (HR) positive, with some HER2-positive and rare triple-negative cases. Deregulation results from genetic or otherwise occurring hyperactivation of molecules subtending cell cycle progression, or inactivation of cell cycle inhibitors. Based on results of randomized clinical trials, palbociclib was granted accelerated approval by the US Food and Drug Administration (FDA) for use in combination with letrozole as initial endocrine-based therapy for metastatic disease in postmenopausal women with HR-positive, HER2-negative breast cancer, and was approved for use in combination with fulvestrant in women with HR-positive, HER2-negative advanced breast cancer with disease progression following endocrine therapy. This review provides an update of the available knowledge on the cell cycle and its regulation, on the alterations in cyclin D-CDK4/6-Rb-E2F axis in breast cancer and their roles in endocrine resistance, on the preclinical activity of CDK4/6 inhibitors in breast cancer, both as monotherapy and as partners of combinatorial synergic treatments, and on the clinical development of palbociclib in breast cancer. PMID:28203301

Review of hormone-based treatments in postmenopausal patients with advanced breast cancer focusing on aromatase inhibitors and fulvestrant

PubMed Central

Kümler, Iben; Knoop, Ann S; Jessing, Christina A R; Ejlertsen, Bent; Nielsen, Dorte L

2016-01-01

Background Endocrine therapy constitutes a central modality in the treatment of oestrogen receptor (ER)-positive advanced breast cancer. Purpose To evaluate the evidence for endocrine treatment in postmenopausal patients with advanced breast cancer focusing on the aromatase inhibitors, letrozole, anastrozole, exemestane and fulvestrant. Methods A review was carried out using PubMed. Randomised phase II and III trials reporting on ≥100 patients were included. Results 35 trials met the inclusion criteria. If not used in the adjuvant setting, a non-steroid aromatase inhibitor was the optimal first-line option. In general, the efficacy of the different aromatase inhibitors and fulvestrant was similar in tamoxifen-refractory patients. A randomised phase II trial of palbociclib plus letrozole versus letrozole alone showed significantly increased progression-free survival (PFS) when compared with endocrine therapy alone in the first-line setting (20.2 vs 10.2 months). Furthermore, the addition of everolimus to exemestane in the Breast Cancer Trials of OraL EveROlimus-2 (BOLERO-2) study resulted in an extension of median PFS by 4.5 months after recurrence/progression on a non-steroid aromatase inhibitor. However, overall survival was not significantly increased. Conclusion Conventional treatment with an aromatase inhibitor or fulvestrant may be an adequate treatment option for most patients with hormone receptor-positive advanced breast cancer. Mammalian target of rapamycin (mTOR) inhibition and cyclin-dependent kinase 4/6 (CDK4/6) inhibition might represent substantial advances for selected patients in some specific settings. However, there is an urgent need for prospective biomarker-driven trials to identify patients for whom these treatments are cost-effective. PMID:27843622

Age-Specific Nonpersistence of Endocrine Therapy in Postmenopausal Patients Diagnosed with Hormone Receptor–Positive Breast Cancer: A TEAM Study Analysis

PubMed Central

van de Water, Willemien; Bastiaannet, Esther; Hille, Elysée T.M.; Meershoek-Klein Kranenbarg, Elma M.; Putter, Hein; Seynaeve, Caroline M.; Paridaens, Robert; de Craen, Anton J.M.; Westendorp, Rudi G.J.; Liefers, Gerrit-Jan

2012-01-01

Background. Early discontinuation of adjuvant endocrine therapy may affect the outcome of treatment in breast cancer patients. The aim of this study was to assess age-specific persistence and age-specific survival outcome based on persistence status. Methods. Patients enrolled in the Tamoxifen Exemestane Adjuvant Multinational trial were included. Nonpersistence was defined as discontinuing the assigned endocrine treatment within 1 year of follow-up because of adverse events, intercurrent illness, patient refusal, or other reasons. Endpoints were the breast cancer–specific and overall survival times. Analyses were stratified by age at diagnosis (<65 years, 65–74 years, ≥75 years). Results. Overall, 3,142 postmenopausal breast cancer patients were included: 1,682 were aged <65 years, 951 were aged 65–74 years, and 509 were aged ≥75 years. Older age was associated with a higher proportion of nonpersistence within 1 year of follow-up. In patients aged <65 years, nonpersistent patients had lower breast cancer–specific and overall survival probabilities. In patients aged 65–74 years and patients aged ≥75 years, the survival times of persistent and nonpersistent patients were similar. Conclusion. Nonpersistence within 1 year of follow-up was associated with lower breast cancer–specific and overall survival probabilities in patients aged <65 years, but it was not associated with survival outcomes in patients aged 65–74 years or in patients aged ≥75 years. These results suggest that extrapolation of outcomes from a young to an elderly breast cancer population may be insufficient and urge age-specific breast cancer studies. PMID:22210087

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Science.gov Websites

integrating ZEVs with renewable energy initiatives; Establish ZEV purchase targets for governmental agency effectiveness of, monetary incentives to reduce the upfront purchase price of ZEVs as well as non-monetary

Response-adapted treatment with upfront high-dose chemotherapy followed by autologous stem-cell transplantation rescue or consolidation phase high-dose methotrexate for primary central nervous system lymphoma: a long-term mono-center study.

PubMed

Nakasu, Yoko; Mitsuya, Koichi; Hayashi, Nakamasa; Okamura, Ikue; Mori, Keita; Enami, Terukazu; Tatara, Raine; Nakasu, Satoshi; Ikeda, Takashi

2016-01-01

Treatment regimens for primary central nervous system lymphoma (PCNSL) include high-dose methotrexate (HD-MTX)-based chemotherapy, with or without radiotherapy and are based on studies of selected patient groups. This retrospective study assessed a consistent strategy of response-adapted protocol applied for patients including age >65 years in a cancer center for 10 years longitudinally. Case notes were studied of 61 consecutively treated patients with PCNSL histologically diagnosed between 2003 and 2013. Clinical follow-up during and after treatment included neurologic examination and magnetic resonance imaging. Of the patients studied, 14.8 % (9/61) were clinically unfit for chemotherapy; the remaining 85.2 % (52/61) of patients were treated with HD-MTX. Of these patients, 58 % (30/52) achieved an initial complete response, with a median survival of 100.1 months. Of these response-adapted patients, 33 % (10/30) were <65 years and were treated with upfront high-dose chemotherapy and autologous stem-cell transplantation (HDC-ASCT). The remaining response-adapted patients included 53 % (16/30) who were ≥65 years underwent consolidation with HD-MTX, and 14 % (4/30) who chose radiotherapy. The median survival of patients with HDC-ASCT had not yet been reached compared with 67.6 months for patients with HD-MTX consolidation treatment (p = 0.26). At the end of the study, 75 % (39/52) of patients had died mainly owing to progression or relapse of PCNSL. Multivariate analysis showed that age younger than 65 years (p = 0.02) and complete response for up-front HD-MTX (p = 0.001) were independent prognostic indicators of overall survival. In conclusion, this single-center retrospective clinical study has shown that treatment of PCNSL with upfront HDC-ASCT and consolidation phase HD-MTX monotherapy may be feasible, even for elderly patients in a routine clinical setting, using the three-step selection by eligibility and response to initial HD-MTX, and age threshold of 65 years for ASCT.

Growth and Endocrine Function in Tunisian Thalassemia Major Patients.

PubMed

Dhouib, Naouel Guirat; Ben Khaled, Monia; Ouederni, Monia; Besbes, Habib; Kouki, Ridha; Mellouli, Fethi; Bejaoui, Mohamed

2018-01-01

β-thalassemia major (β-TM) is among the most common hereditary disorders imposing high expenses on health-care system worldwide. The patient's survival is dependent on lifetime blood transfusion which leads to iron overload and its toxicity in various organs including endocrine glands. This article provides an overview of endocrine disorders in beta-TM patients. This single center investigation enrolled 28 β-TM patients (16 males, 12 females) regularly transfused with packed red cell since early years of life. For each patient were determined: age, sex, number of transfusions received, history of splenectomy and anthropometric parameters. All patients underwent an evaluation of hormonal status including growth, gonadal, thyroid, adrenal cortex, and parathyroid glands. Dual-energy X-ray absorptiometry was used to diagnose low bone mass. Assessment of iron overload status was performed by measuring the serum ferritin concentration and the results of magnetic resonance imaging T 2 *. Growth retardation was found in 16 of the 28 studied patients (57 %). Thirteen among them had delayed puberty. Spontaneous puberty was achieved in 16 cases. Growth hormone (GH) deficiency was found in 10 cases (35 %). Seventeen among the studied patients (60 %) developed disorders of glucose homeostasis. Subclinical hypothyroidism was found in six patients (21 %). Intensive chelation therapy had allowed the reversibility of this complication in five cases. Adrenal Insufficiency was observed in 9 cases (32%). Hypoparathyroidism has occurred in one case. Ten of the 28 studied patients had low bone mass (35%). Twenty-three of the 28 studied patients (82%) had at least one endocrine complication.

Iron chelation therapy in transfusion-dependent thalassemia patients: current strategies and future directions

PubMed Central

Saliba, Antoine N; Harb, Afif R; Taher, Ali T

2015-01-01

Transfusional iron overload is a major target in the care of patients with transfusion-dependent thalassemia (TDT) and other refractory anemias. Iron accumulates in the liver, heart, and endocrine organs leading to a wide array of complications. In this review, we summarize the characteristics of the approved iron chelators, deferoxamine, deferiprone, and deferasirox, and the evidence behind the use of each, as monotherapy or as part of combination therapy. We also review the different guidelines on iron chelation in TDT. This review also discusses future prospects and directions in the treatment of transfusional iron overload in TDT whether through innovation in chelation or other therapies, such as novel agents that improve transfusion dependence. PMID:26124688

Association of time-to-surgery with outcomes in clinical stage I-II pancreatic adenocarcinoma treated with upfront surgery.

PubMed

Swords, Douglas S; Zhang, Chong; Presson, Angela P; Firpo, Matthew A; Mulvihill, Sean J; Scaife, Courtney L

2018-04-01

Time-to-surgery from cancer diagnosis has increased in the United States. We aimed to determine the association between time-to-surgery and oncologic outcomes in patients with resectable pancreatic ductal adenocarcinoma undergoing upfront surgery. The 2004-2012 National Cancer Database was reviewed for patients undergoing curative-intent surgery without neoadjuvant therapy for clinical stage I-II pancreatic ductal adenocarcinoma. A multivariable Cox model with restricted cubic splines was used to define time-to-surgery as short (1-14 days), medium (15-42), and long (43-120). Overall survival was examined using Cox shared frailty models. Secondary outcomes were examined using mixed-effects logistic regression models. Of 16,763 patients, time-to-surgery was short in 34.4%, medium in 51.6%, and long in 14.0%. More short time-to-surgery patients were young, privately insured, healthy, and treated at low-volume hospitals. Adjusted hazards of mortality were lower for medium (hazard ratio 0.94, 95% confidence interval, .90, 0.97) and long time-to-surgery (hazard ratio 0.91, 95% confidence interval, 0.86, 0.96) than short. There were no differences in adjusted odds of node positivity, clinical to pathologic upstaging, being unresectable or stage IV at exploration, and positive margins. Medium time-to-surgery patients had higher adjusted odds (odds ratio 1.11, 95% confidence interval, 1.03, 1.20) of receiving an adequate lymphadenectomy than short. Ninety-day mortality was lower in medium (odds ratio 0.75, 95% confidence interval, 0.65, 0.85) and long time-to-surgery (odds ratio 0.72, 95% confidence interval, 0.60, 0.88) than short. In this observational analysis, short time-to-surgery was associated with slightly shorter OS and higher perioperative mortality. These results may suggest that delays for medical optimization and referral to high volume surgeons are safe. Published by Elsevier Inc.

Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy.

PubMed

Hofmann, Lars; Forschner, Andrea; Loquai, Carmen; Goldinger, Simone M; Zimmer, Lisa; Ugurel, Selma; Schmidgen, Maria I; Gutzmer, Ralf; Utikal, Jochen S; Göppner, Daniela; Hassel, Jessica C; Meier, Friedegund; Tietze, Julia K; Thomas, Ioannis; Weishaupt, Carsten; Leverkus, Martin; Wahl, Renate; Dietrich, Ursula; Garbe, Claus; Kirchberger, Michael C; Eigentler, Thomas; Berking, Carola; Gesierich, Anja; Krackhardt, Angela M; Schadendorf, Dirk; Schuler, Gerold; Dummer, Reinhard; Heinzerling, Lucie M

2016-06-01

Anti-programmed cell death receptor-1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma as well as for other cancer entities. They act via blockade of the PD-1 receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects affect skin, gastrointestinal tract, liver, endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential. In total, 496 patients with metastatic melanoma from 15 skin cancer centers were treated with pembrolizumab or nivolumab; 242 side-effects were described in 138 patients. In 116 of the 138 patients, side-effects affected the skin, gastrointestinal tract, liver, endocrine, and renal system. Rare side-effects included diabetes mellitus, lichen planus, and pancreas insufficiency due to pancreatitis. Anti-PD1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity. Copyright © 2016 Elsevier Ltd. All rights reserved.

The pros and cons of phytoestrogens

PubMed Central

Patisaul, Heather B.; Jefferson, Wendy

2011-01-01

Phytoestrogens are plant derived compounds found in a wide variety of foods, most notably soy. A litany of health benefits including a lowered risk of osteoporosis, heart disease, breast cancer, and menopausal symptoms, are frequently attributed to phytoestrogens but many are also considered endocrine disruptors, indicating that they have the potential to cause adverse health effects as well. Consequently, the question of whether or not phytoestrogens are beneficial or harmful to human health remains unresolved. The answer is likely complex and may depend on age, health status, and even the presence or absence of specific gut microflora. Clarity on this issue is needed because global consumption is rapidly increasing. Phytoestrogens are present in numerous dietary supplements and widely marketed as a natural alternative to estrogen replacement therapy. Soy infant formula now constitutes up to a third of the US market, and soy protein is now added to many processed foods. As weak estrogen agonists/antagonists with molecular and cellular properties similar to synthetic endocrine disruptors such as Bisphenol A (BPA), the phytoestrogens provide a useful model to comprehensively investigate the biological impact of endocrine disruptors in general. This review weighs the evidence for and against the purported health benefits and adverse effects of phytoestrogens. PMID:20347861

Anorexia Nervosa and its Associated Endocrinopathy in Young People

PubMed Central

Misra, Madhusmita; Klibanski, Anne

2016-01-01

Anorexia nervosa (AN) is a condition of severe undernutrition associated with adaptive changes in many endocrine axes. These changes include hypogonadotropic hypogonadism, acquired growth hormone resistance with low insulin like growth factor-1 (IGF-1) levels, hypercortisolemia, altered secretion of adipokines and appetite regulating hormones, and low bone mineral density (BMD). Bone health is impaired subsequent to low BMI, decreased lean mass, and the endocrine changes described above. In addition to low areal BMD, AN is characterized by a decrease in volumetric BMD, changes in bone geometry, and reductions in strength estimates, leading to an increased risk for fracture. Weight restoration is essential for restoration of normal endocrine function; however, hypercortisolemia, high PYY levels, and ghrelin dynamics may not completely normalize. In some patients, hypogonadotropic hypogonadism persists despite weight restoration. Weight gain and menstrual recovery are critical for improving bone health in AN, however, residual deficits may persist. Physiologic estrogen replacement using transdermal, but not oral, estrogen increases bone accrual in adolescents with AN, while bisphosphonates improve BMD in adults. Recombinant human IGF-1 and teriparatide have been used in a few studies as bone anabolic therapies. More data are necessary to determine the optimal therapeutic strategies for low BMD in AN. PMID:26863308

Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management

PubMed Central

Birnkrant, David J; Bushby, Katharine; Bann, Carla M; Apkon, Susan D; Blackwell, Angela; Brumbaugh, David; Case, Laura E; Clemens, Paula R; Hadjiyannakis, Stasia; Pandya, Shree; Street, Natalie; Tomezsko, Jean; Wagner, Kathryn R; Ward, Leanne M; Weber, David R

2018-01-01

Since the publication of the Duchenne muscular dystrophy (DMD) care considerations in 2010, multidisciplinary care of this severe, progressive neuromuscular disease has evolved. In conjunction with improved patient survival, a shift to more anticipatory diagnostic and therapeutic strategies has occurred, with a renewed focus on patient quality of life. In 2014, a steering committee of experts from a wide range of disciplines was established to update the 2010 DMD care considerations, with the goal of improving patient care. The new care considerations aim to address the needs of patients with prolonged survival, to provide guidance on advances in assessments and interventions, and to consider the implications of emerging genetic and molecular therapies for DMD. The committee identified 11 topics to be included in the update, eight of which were addressed in the original care considerations. The three new topics are primary care and emergency management, endocrine management, and transitions of care across the lifespan. In part 1 of this three-part update, we present care considerations for diagnosis of DMD and neuromuscular, rehabilitation, endocrine (growth, puberty, and adrenal insufficiency), and gastrointestinal (including nutrition and dysphagia) management. PMID:29395989

Doxorubicin With Upfront Dexrazoxane Plus Olaratumab for the Treatment of Advanced or Metastatic Soft Tissue Sarcoma

ClinicalTrials.gov

2018-02-08

Sarcoma, Soft Tissue; Soft Tissue Sarcoma; Undifferentiated Pleomorphic Sarcoma; Leiomyosarcoma; Liposarcoma; Synovial Sarcoma; Myxofibrosarcoma; Angiosarcoma; Fibrosarcoma; Malignant Peripheral Nerve Sheath Tumor; Epithelioid Sarcoma

Ketogenic diet in endocrine disorders: Current perspectives

PubMed Central

Gupta, L; Khandelwal, D; Kalra, S; Gupta, P; Dutta, D; Aggarwal, S

2017-01-01

Ketogenic diet (KD) is a high-fat, adequate-protein, and low-carbohydrate diet that leads to nutritional ketosis, long known for antiepileptic effects and has been used therapeutically to treat refractory epilepsy. This review attempts to summarize the evidence and clinical application of KD in diabetes, obesity, and other endocrine disorders. KD is usually animal protein based. An empiric vegetarian Indian variant of KD has been provided keeping in mind the Indian food habits. KD has beneficial effects on cardiac ischemic preconditioning, improves oxygenation in patients with respiratory failure, improves glycemic control in diabetics, is associated with significant weight loss, and has a beneficial impact on polycystic ovarian syndrome. Multivitamin supplementations are recommended with KD. Recently, ketones are being proposed as super-metabolic fuel; and KD is currently regarded as apt dietary therapy for “diabesity.” PMID:29022562

Interpreting Breast International Group (BIG) 1-98: a randomized, double-blind, phase III trial comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive, early breast cancer.

PubMed

Regan, Meredith M; Price, Karen N; Giobbie-Hurder, Anita; Thürlimann, Beat; Gelber, Richard D

2011-05-26

The Breast International Group (BIG) 1-98 study is a four-arm trial comparing 5 years of monotherapy with tamoxifen or with letrozole or with sequences of 2 years of one followed by 3 years of the other for postmenopausal women with endocrine-responsive early invasive breast cancer. From 1998 to 2003, BIG -98 enrolled 8,010 women. The enhanced design f the trial enabled two complementary analyses of efficacy and safety. Collection of tumor specimens further enabled treatment comparisons based on tumor biology. Reports of BIG 1-98 should be interpreted in relation to each individual patient as she weighs the costs and benefits of available treatments. Clinicaltrials.gov ID: NCT00004205.

Influence of high intensity focused ultrasound (HIFU) treatment to the pancreatic function in pancreatic cancer patients.

PubMed

Shi, Yulan; Ying, Xiao; Hu, Xiaoye; Zhao, Jing; Fang, Xuefeng; Wu, Minghui; Chen, Tian Zhou; Shen, Hong

2015-05-01

Present study was designed to investigate the pancreatic endocrine and exocrine function damage after High Intensity Focused Ultrasound (HIFU) therapy in patients with advanced pancreatic cancer. It was a retrospective analysis of blood glucose and amylase changes in 59 advanced pancreatic cancer patients treated with HIFU from 2010 February to 2014 January. The mean glucose and amylase before HIFU treatment were 6.02mmol/L and 59.17 U/L respectively. After HIFU treatment, it was shown that the mean glucose and amylase levels were 5.66mmol/L and 57.86/L respectively. There was no statistical significance between them. No acute pancreatitis was observed. The endocrine and exocrine function of pancreatic cancer patients was not damaged by HIFU treatment. HIFU treatment for the pancreatic cancer patients seems to be safe.

Interpreting breast international group (BIG) 1-98: a randomized, double-blind, phase III trial comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive, early breast cancer

PubMed Central

2011-01-01

The Breast International Group (BIG) 1-98 study is a four-arm trial comparing 5 years of monotherapy with tamoxifen or with letrozole or with sequences of 2 years of one followed by 3 years of the other for postmenopausal women with endocrine-responsive early invasive breast cancer. From 1998 to 2003, BIG -98 enrolled 8,010 women. The enhanced design f the trial enabled two complementary analyses of efficacy and safety. Collection of tumor specimens further enabled treatment comparisons based on tumor biology. Reports of BIG 1-98 should be interpreted in relation to each individual patient as she weighs the costs and benefits of available treatments. Clinicaltrials.gov ID: NCT00004205. PMID:21635709

Implication of epigenetics in pancreas development and disease.

PubMed

Quilichini, Evans; Haumaitre, Cécile

2015-12-01

Pancreas development is controlled by a complex interaction of signaling pathways and transcription factor networks that determine pancreatic specification and differentiation of exocrine and endocrine cells. Epigenetics adds a new layer of gene regulation. DNA methylation, histone modifications and non-coding RNAs recently appeared as important epigenetic factors regulating pancreas development. In this review, we report recent findings obtained by analyses in model organisms as well as genome-wide approaches that demonstrate the role of these epigenetic regulators in the control of exocrine and endocrine cell differentiation, identity, function, proliferation and regeneration. We also highlight how altered epigenetic processes contribute to pancreatic disorders: diabetes and pancreatic cancer. Uncovering these epigenetic events can help to better understand these diseases, provide novel therapeutical targets for their treatment, and improve cell-based therapies for diabetes. Copyright © 2015 Elsevier Ltd. All rights reserved.

Surgical management of medullary thyroid cancer.

PubMed

Mazeh, H; Sippel, R S

2012-12-01

Although thyroid cancer accounts for only 1.5% of all malignancies in the US it is the most rapidly increasing cancer in incidence and it is the most common endocrine malignancy that accounts for over 95% of the endocrine malignancies. Medullary thyroid cancer (MTC) originates from the parafollicular C cells and it represents 6-8% of all thyroid cancer cases. As many as 25% of the MTCs are familial and carry a specific germline mutation as compared to only than 10% familial inheritance in non-medullary thyroid cancers. While well-differentiated thyroid malignancies carry a very good prognosis, recurrence and survival rates of patients with MTC are significantly worse. The difference in cell origin and differentiation also results in different available adjunct therapy. The aim of this study is to review in detail the surgical management of patients with MTC.

Allele-Specific Chromatin Recruitment and Therapeutic Vulnerabilities of ESR1 Activating Mutations.

PubMed

Jeselsohn, Rinath; Bergholz, Johann S; Pun, Matthew; Cornwell, MacIntosh; Liu, Weihan; Nardone, Agostina; Xiao, Tengfei; Li, Wei; Qiu, Xintao; Buchwalter, Gilles; Feiglin, Ariel; Abell-Hart, Kayley; Fei, Teng; Rao, Prakash; Long, Henry; Kwiatkowski, Nicholas; Zhang, Tinghu; Gray, Nathanael; Melchers, Diane; Houtman, Rene; Liu, X Shirley; Cohen, Ofir; Wagle, Nikhil; Winer, Eric P; Zhao, Jean; Brown, Myles

2018-02-12

Estrogen receptor α (ER) ligand-binding domain (LBD) mutations are found in a substantial number of endocrine treatment-resistant metastatic ER-positive (ER + ) breast cancers. We investigated the chromatin recruitment, transcriptional network, and genetic vulnerabilities in breast cancer models harboring the clinically relevant ER mutations. These mutants exhibit both ligand-independent functions that mimic estradiol-bound wild-type ER as well as allele-specific neomorphic properties that promote a pro-metastatic phenotype. Analysis of the genome-wide ER binding sites identified mutant ER unique recruitment mediating the allele-specific transcriptional program. Genetic screens identified genes that are essential for the ligand-independent growth driven by the mutants. These studies provide insights into the mechanism of endocrine therapy resistance engendered by ER mutations and potential therapeutic targets. Copyright © 2018 Elsevier Inc. All rights reserved.

Gastrointestinal Neuroendocrine Tumors: Pancreatic Endocrine Tumors

PubMed Central

Metz, David C.

2008-01-01

Pancreatic endocrine tumors (PETs) have long fascinated clinicians and investigators despite their relative rarity. Their clinical presentation varies depending upon whether the tumor is functional or not and also according to the specific hormonal syndrome produced. Tumors may be sporadic or inherited but little is known about their molecular pathology, especially the sporadic forms. Chromogranin A appears to be the most useful serum marker for diagnosis, staging and monitoring. Initially, therapy should be directed at the hormonal syndrome as this has the major initial impact on the patient's health. Most PETs are relatively indolent but ultimately malignant, except for insulinomas which are predominantly benign. Surgery is the only modality that offers the possibility of cure although it is generally noncurative in patients with Zollinger-Ellison syndrome or nonfunctional PETs with MEN1. Preoperative staging of disease extent is necessary to determine the likelihood of complete resection though debulking surgery is often felt to be useful in unresectable patients. Once metastatic, biotherapy is usually the first modality employed because it is generally well tolerated. Systemic or regional therapies are generally reserved until symptoms occur or tumor growth is rapid. Recently a number of newer agents, as well as receptor-directed radiotherapy, are being evalulated for patients with advanced disease. This review addresses a number of recent advances regarding the molecular pathology, diagnosis, localization and management of PETs including discussion of peptide receptor radionuclide therapy and other novel antitumor approaches. We conclude with a discussion of future directions and unsettled problems in the field. PMID:18703061

KIBRA; a novel biomarker predicting recurrence free survival of breast cancer patients receiving adjuvant therapy.

PubMed

Mudduwa, Lakmini; Peiris, Harshini; Gunasekara, Shania; Abeysiriwardhana, Deepthika; Liyanage, Nimsha; Rayala, Suresh K; Liyanage, Thusharie

2018-05-24

This study was carried out to evaluate the prognostic value of KIBRA in breast cancer. This retrospective study included breast cancer patients who sought the services of the immunohistochemistry laboratory of our unit from 2006 to 2015. Tissue microarrays were constructed and immunohistochemical staining was done to assess the KIBRA expression. The Kaplan-Meier model for univariate and Cox-regression model with backward stepwise factor retention method for multivariate analyses were used. Chi square test was used to find out the associations with the established prognostic features. A total of 1124 patients were included in the study and KIBRA staining of 909 breast cancers were available for analysis. Cytoplasmic KIBRA expression was seen in 39.5% and nuclear expression in 44.8%. Overall KIBRA-low breast cancers accounted for 41.5%. KIBRA nuclear expression was significantly associated with positive ER and PR expression. Luminal breast cancer patients who had endocrine therapy and KIBRA-low expression had a RFS disadvantage over those who were positive for KIBRA (p = 0.02). Similarly, patients who received chemotherapy and had overall KIBRA-low expression also demonstrated a RFS disadvantage compared to those who had overall positive KIBRA expression (p = 0.018). This effect of KIBRA was independent of the other factors considered for the model. Overall low-KIBRA expression has an independent effect on the RFS and predicts the RFS outcome of luminal breast cancer patients who received endocrine therapy and breast cancer patients who received chemotherapy.

24 CFR 4001.122 - Fees and closing costs.

Code of Federal Regulations, 2010 CFR

2010-04-01

... originating the Program mortgage; (3) Premium pricing by the mortgagee providing the Program mortgage; (4... loan-to-value ratio does not exceed 90 percent (including the up-front premium required under § 4001...

Stereotactic radiosurgery (SRS) in the modern management of patients with brain metastases

PubMed Central

Soliman, Hany; Das, Sunit; Larson, David A.; Sahgal, Arjun

2016-01-01

Stereotactic radiosurgery (SRS) is an established non-invasive ablative therapy for brain metastases. Early clinical trials with SRS proved that tumor control rates are superior to whole brain radiotherapy (WBRT) alone. As a result, WBRT plus SRS was widely adopted for patients with a limited number of brain metastases (“limited number” customarily means 1-4). Subsequent trials focused on answering whether WBRT upfront was necessary at all. Based on current randomized controlled trials (RCTs) and meta-analyses comparing SRS alone to SRS plus WBRT, adjuvant WBRT results in better intracranial control; however, at the expense of neurocognitive functioning and quality of life. These adverse effects of WBRT may also negatively impact on survival in younger patients. Based on the results of these studies, treatment has shifted to SRS alone in patients with a limited number of metastases. Additionally, RCTs are evaluating the role of SRS alone in patients with >4 brain metastases. New developments in SRS include fractionated SRS for large tumors and the integration of SRS with targeted systemic therapies that cross the blood brain barrier and/or stimulate an immune response. We present in this review the current high level evidence and rationale supporting SRS as the standard of care for patients with limited brain metastases, and emerging applications of SRS. PMID:26848525

Rhabdomyosarcoma treatment and outcome at a multidisciplinary pediatric cancer center in Lebanon.

PubMed

Salman, Maysaa; Tamim, Hani; Medlej, Fouad; El-Ariss, Tarek; Saad, Fatima; Boulos, Fouad; Eid, Toufic; Muwakkit, Samar; Khoury, Nabil; Abboud, Miguel; Saab, Raya

2012-05-01

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Outcome of patients treated on standard protocols, in a multidisciplinary cancer center setting outside of clinical trials, is not well reported. We reviewed characteristics and outcome of 23 pediatric patients treated at a single, multidisciplinary cancer center in Lebanon, between April 2002 and December 2010. Median follow-up was 41 months. The most commonly affected primary site was the head and neck (48%, n = 11). Nineteen tumors (82.6%) were of embryonal histology. Tumor size was ≥5 cm in eight (34.8%) patients. Sixteen patients (69.6%) had localized disease, and one (4.4%) had metastatic disease. Fifteen (65.2%) had Group III tumors. All patients received chemotherapy, for a duration ranging 21-51 weeks. Upfront surgical resection was performed in 10 patients (43.5%). Eighteen patients (78.3%) received radiation therapy. The 5-year overall and disease-free survival rates were 83% and 64%, respectively. Relapse correlated with absence of surgery. Treatment of childhood RMS in a multidisciplinary cancer center in Lebanon results in similar survival to that in developed countries when similar protocols are applied. There was a higher incidence of local relapse, but those were salvageable with further therapy and surgical local control.

Evaluation of the influence of ayurvedic formulation (Ayushman-15) on psychopathology, heart rate variability and stress hormonal level in major depression (Vishada).

PubMed

Kishore, Ramakrishna K; Abhishekh, Hulegar A; Udupa, Kaviraja; Thirthalli, Jagadisha; Lavekar, Gandhidas S; Gangadhar, Bangalore N; Raju, Trichur R; Sathyaprabha, Talakad N

2014-12-01

Ayurveda (Indian-complimentary and alternative medicine) is still most sought after in India and has promising potential in management of Vishada [major depressive disorder (MDD)]. But, systematic research is lacking. In this study we evaluated of influence of ayurvedic treatment (Panchakarma and Ayushman-15) on psychopathology, heart rate variability (HRV) and endocrinal parameters in patients with major depression. 81 drug naive patients diagnosed as Vishada by ayurvedic physician and MDD according to DSM IV-TR were given ayurvedic Virechana module (therapeutic purgation) and were randomized into two groups. Patients in group A (n=41) received Ayushman-15A while group B (n=40) received Ayushman-15B for two months and Shirodhara (forehead-oil pouring therapy). Patients were assessed with Hamilton Depression Rating Scale (HDRS), Montgomery Asberg Depression Rating Scale (MADRS), Heart Rate Variability (HRV). Cortisol and adrenocorticotropic hormone (ACTH) were estimated at baseline and after ayurvedic therapy. HRV and endocrinal parameters were compared with age and gender matched healthy volunteers. HRV parameters showed significant sympathetic dominance in patients compared to healthy volunteers. Two months of ayurvedic treatment significantly decreased psychopathology, showed increase in vagal tone, decrease in sympathetic tone and reduced cortisol levels. However, there was no significant difference between groups receiving Ayushman A and B. This study provides evidence for antidepressant, cardiac (HRV) and beneficial neuroendocrine modulatory influence of Ayurveda therapy in patients of Vishada (MDD). Further studies are needed to confirm these findings. Greater insight into the neurobiology behind this therapy might provide valuable information about newer drug target. Copyright © 2014 Elsevier B.V. All rights reserved.

Pulsatile GnRH Therapy May Restore Hypothalamus-Pituitary-Testis Axis Function in Patients With Congenital Combined Pituitary Hormone Deficiency: A Prospective, Self-Controlled Trial.

PubMed

Zheng, Junjie; Mao, Jiangfeng; Xu, Hongli; Wang, Xi; Huang, Bingkun; Liu, Zhaoxiang; Cui, Mingxuan; Xiong, Shuyu; Ma, Wanlu; Min, Le; Kaiser, Ursula B; Nie, Min; Wu, Xueyan

2017-07-01

The effectiveness of pulsatile gonadotropin-releasing hormone (GnRH) therapy in patients with congenital combined pituitary hormone deficiency (CCPHD) has not been investigated because of the limited number of patients, as well as these patients' presumed pituitary hypoplasia, poor gonadotrophic cell reserve, and impaired gonadotrophic response to GnRH. To assess the pituitary response to pulsatile GnRH therapy in men with CCPHD. Prospective, self-controlled, 3-month clinical trial. University endocrine clinic. Men with hypogonadotropic hypogonadism caused by CCPHD. Pulsatile GnRH was administered subcutaneously for 3 months. Primary endpoints were total serum testosterone, testicular volume, and luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels. Secondary endpoints included occurrence of spermatogenesis. A total of 40 men with CCPHD completed the study. Of these, 60% (24 of 40) showed a good response to pulsatile GnRH treatment (response group). At 3 months, their LH and FSH levels increased to within the normal range and their testosterone levels increased to 8.67 ± 4.83 nmol/L. Of the patients in the response group, 33.3% (8 of 24) of them achieved spermatogenesis. The remaining 40% (16 of 40) of patients had a poor response to pulsatile GnRH treatment. Magnetic resonance imaging (MRI) did not reveal any correlation between pituitary response and pituitary height and/or integrity of the pituitary stalk. This study suggests that gonadotrophs in patients with CCPHD can exist and be functional-even with MRI evidence of pituitary hypoplasia or dysplasia. Pulsatile GnRH therapy restored pituitary-testis axis function in 60% of patients with CCPHD. These results may directly guide the clinical therapeutic choice. Copyright © 2017 Endocrine Society

Cognitive function after the initiation of adjuvant endocrine therapy in early-stage breast cancer: an observational cohort study.

PubMed

Ganz, Patricia A; Petersen, Laura; Castellon, Steven A; Bower, Julienne E; Silverman, Daniel H S; Cole, Steven W; Irwin, Michael R; Belin, Thomas R

2014-11-01

This report examines cognitive complaints and neuropsychological (NP) testing outcomes in patients with early-stage breast cancer after the initiation of endocrine therapy (ET) to determine whether this therapy plays any role in post-treatment cognitive complaints. One hundred seventy-three participants from the Mind Body Study (MBS) observational cohort provided data from self-report questionnaires and NP testing obtained at enrollment (T1, before initiation of ET), and 6 months later (T2). Bivariate analyses compared demographic and treatment variables, cognitive complaints, depressive symptoms, quality of life, and NP functioning between those who received ET versus not. Multivariable linear regression models examined predictors of cognitive complaints at T2, including selected demographic variables, depressive symptoms, ET use, and other medical variables, along with NP domains that were identified in bivariate analyses. Seventy percent of the 173 MBS participants initiated ET, evenly distributed between tamoxifen or aromatase inhibitors. ET-treated participants reported significantly increased language and communication (LC) cognitive complaints at T2 (P = .003), but no significant differences in NP test performance. Multivariable regression on LC at T2 found higher LC complaints significantly associated with T1 LC score (P < .001), ET at T2 (P = .004), interaction between ET and past hormone therapy (HT) (P < .001), and diminished improvement in NP psychomotor function (P = .05). Depressive symptoms were not significant (P = .10). Higher LC complaints are significantly associated with ET 6 months after starting treatment and reflect diminished improvements in some NP tests. Past HT is a significant predictor of higher LC complaints after initiation of ET. © 2014 by American Society of Clinical Oncology.

Cognitive Function After the Initiation of Adjuvant Endocrine Therapy in Early-Stage Breast Cancer: An Observational Cohort Study

PubMed Central

Ganz, Patricia A.; Petersen, Laura; Castellon, Steven A.; Bower, Julienne E.; Silverman, Daniel H.S.; Cole, Steven W.; Irwin, Michael R.; Belin, Thomas R.

2014-01-01

Purpose This report examines cognitive complaints and neuropsychological (NP) testing outcomes in patients with early-stage breast cancer after the initiation of endocrine therapy (ET) to determine whether this therapy plays any role in post-treatment cognitive complaints. Patients and Methods One hundred seventy-three participants from the Mind Body Study (MBS) observational cohort provided data from self-report questionnaires and NP testing obtained at enrollment (T1, before initiation of ET), and 6 months later (T2). Bivariate analyses compared demographic and treatment variables, cognitive complaints, depressive symptoms, quality of life, and NP functioning between those who received ET versus not. Multivariable linear regression models examined predictors of cognitive complaints at T2, including selected demographic variables, depressive symptoms, ET use, and other medical variables, along with NP domains that were identified in bivariate analyses. Results Seventy percent of the 173 MBS participants initiated ET, evenly distributed between tamoxifen or aromatase inhibitors. ET-treated participants reported significantly increased language and communication (LC) cognitive complaints at T2 (P = .003), but no significant differences in NP test performance. Multivariable regression on LC at T2 found higher LC complaints significantly associated with T1 LC score (P < .001), ET at T2 (P = .004), interaction between ET and past hormone therapy (HT) (P < .001), and diminished improvement in NP psychomotor function (P = .05). Depressive symptoms were not significant (P = .10). Conclusion Higher LC complaints are significantly associated with ET 6 months after starting treatment and reflect diminished improvements in some NP tests. Past HT is a significant predictor of higher LC complaints after initiation of ET. PMID:25267747

The Role of Testosterone Supplemental Therapy in Opioid-Induced Hypogonadism: A Retrospective Pilot Analysis.

PubMed

Raheem, Omer A; Patel, Sunil H; Sisul, David; Furnish, Tim J; Hsieh, Tung-Chin

2017-07-01

Chronic opioid therapy for pain management is known to induce several endocrine changes. The authors examined the effect of testosterone supplemental therapy (TST) in patients with chronic, noncancer pain undergoing opioid therapy. It was hypothesized that treatment of opioid-induced hypogonadism (OIH) can reduce opioid requirements in patients suffering from chronic pain and approve their quality of life. Over 18 months period, patients with OIH were identified in a tertiary referral pain center, Numerical Rating Scale (NRS) pain scores and daily morphine equivalent dose (MED) were the primary outcomes measured. Data were collected and comparative analysis performed between men undergoing TST versus nontreatment group. Twenty-seven OIH patients (total testosterone <300 ng/dL) were identified during the study period. TST group consists of 11 patients, while non-TST group consists of 16 patients as control cohort. Mean patient age (55 and 54.4, p = .4) and basic metabolic index (28.5 and 31.9, p = .07) in TST and non-TST groups, respectively. Mean follow-up total testosterone (ng/dL) was significantly higher after TST compared with the non-TST group (497.5 vs. 242.4 ng/dL, p = .03). Median follow-up NRS was 0 and 2 in the TST and non-TST groups ( p = .02). Mean MED (mg) decreased by 21 mg in TST group and increased by 2.5 mg in non-TST group ( p < .05). This study reports that treatment of OIH with TST can reduce opioid requirements in men with chronic pain as quantified by MED. It also confirms previous reports on the potential effects of OIH and that TST is effective in correcting opioid-induced endocrine abnormalities.

The Role of Testosterone Supplemental Therapy in Opioid-Induced Hypogonadism: A Retrospective Pilot Analysis

PubMed Central

Raheem, Omer A.; Patel, Sunil H.; Sisul, David; Furnish, Tim J.; Hsieh, Tung-Chin

2016-01-01

Chronic opioid therapy for pain management is known to induce several endocrine changes. The authors examined the effect of testosterone supplemental therapy (TST) in patients with chronic, noncancer pain undergoing opioid therapy. It was hypothesized that treatment of opioid-induced hypogonadism (OIH) can reduce opioid requirements in patients suffering from chronic pain and approve their quality of life. Over 18 months period, patients with OIH were identified in a tertiary referral pain center, Numerical Rating Scale (NRS) pain scores and daily morphine equivalent dose (MED) were the primary outcomes measured. Data were collected and comparative analysis performed between men undergoing TST versus nontreatment group. Twenty-seven OIH patients (total testosterone <300 ng/dL) were identified during the study period. TST group consists of 11 patients, while non-TST group consists of 16 patients as control cohort. Mean patient age (55 and 54.4, p = .4) and basic metabolic index (28.5 and 31.9, p = .07) in TST and non-TST groups, respectively. Mean follow-up total testosterone (ng/dL) was significantly higher after TST compared with the non-TST group (497.5 vs. 242.4 ng/dL, p = .03). Median follow-up NRS was 0 and 2 in the TST and non-TST groups (p = .02). Mean MED (mg) decreased by 21 mg in TST group and increased by 2.5 mg in non-TST group (p < .05). This study reports that treatment of OIH with TST can reduce opioid requirements in men with chronic pain as quantified by MED. It also confirms previous reports on the potential effects of OIH and that TST is effective in correcting opioid-induced endocrine abnormalities. PMID:28625114

Endocrine Drugs in Aircrew

DTIC Science & Technology

2001-06-01

cells (ICA) present the case, the primary goal of diet therapy is simply in their serum at the time of diagnosis, and some caloric reduction to achieve...transplantation caloric intake and weight gain, and suppresses rejection, pemphigus, and immune hematologic inflammation and the immune system.10 Cortisol...hypoglycemic normal.24𔃼 5 agents is still accompanied by the risk of hypo - glycemia and of the micro- and macrovascular Secondary adrenal

Design, conduct, and analyses of Breast International Group (BIG) 1-98: a randomized, double-blind, phase-III study comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with receptor-positive, early breast cancer.

PubMed

Giobbie-Hurder, Anita; Price, Karen N; Gelber, Richard D

2009-06-01

Aromatase inhibitors provide superior disease control when compared with tamoxifen as adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer. To present the design, history, and analytic challenges of the Breast International Group (BIG) 1-98 trial: an international, multicenter, randomized, double-blind, phase-III study comparing the aromatase inhibitor letrozole with tamoxifen in this clinical setting. From 1998-2003, BIG 1-98 enrolled 8028 women to receive monotherapy with either tamoxifen or letrozole for 5 years, or sequential therapy of 2 years of one agent followed by 3 years of the other. Randomization to one of four treatment groups permitted two complementary analyses to be conducted several years apart. The first, reported in 2005, provided a head-to-head comparison of letrozole versus tamoxifen. Statistical power was increased by an enriched design, which included patients who were assigned sequential treatments until the time of the treatment switch. The second, reported in late 2008, used a conditional landmark approach to test the hypothesis that switching endocrine agents at approximately 2 years from randomization for patients who are disease-free is superior to continuing with the original agent. The 2005 analysis showed the superiority of letrozole compared with tamoxifen. The patients who were assigned tamoxifen alone were unblinded and offered the opportunity to switch to letrozole. Results from other trials increased the clinical relevance about whether or not to start treatment with letrozole or tamoxifen, and analysis plans were expanded to evaluate sequential versus single-agent strategies from randomization. Due to the unblinding of patients assigned tamoxifen alone, analysis of updated data will require ascertainment of the influence of selective crossover from tamoxifen to letrozole. BIG 1-98 is an example of an enriched design, involving complementary analyses addressing different questions several years apart, and subject to evolving analytic plans influenced by new data that emerge over time.

Minimising Immunohistochemical False Negative ER Classification Using a Complementary 23 Gene Expression Signature of ER Status

PubMed Central

Li, Qiyuan; Eklund, Aron C.; Juul, Nicolai; Haibe-Kains, Benjamin; Workman, Christopher T.; Richardson, Andrea L.; Szallasi, Zoltan; Swanton, Charles

2010-01-01

Background Expression of the oestrogen receptor (ER) in breast cancer predicts benefit from endocrine therapy. Minimising the frequency of false negative ER status classification is essential to identify all patients with ER positive breast cancers who should be offered endocrine therapies in order to improve clinical outcome. In routine oncological practice ER status is determined by semi-quantitative methods such as immunohistochemistry (IHC) or other immunoassays in which the ER expression level is compared to an empirical threshold[1], [2]. The clinical relevance of gene expression-based ER subtypes as compared to IHC-based determination has not been systematically evaluated. Here we attempt to reduce the frequency of false negative ER status classification using two gene expression approaches and compare these methods to IHC based ER status in terms of predictive and prognostic concordance with clinical outcome. Methodology/Principal Findings Firstly, ER status was discriminated by fitting the bimodal expression of ESR1 to a mixed Gaussian model. The discriminative power of ESR1 suggested bimodal expression as an efficient way to stratify breast cancer; therefore we identified a set of genes whose expression was both strongly bimodal, mimicking ESR expression status, and highly expressed in breast epithelial cell lines, to derive a 23-gene ER expression signature-based classifier. We assessed our classifiers in seven published breast cancer cohorts by comparing the gene expression-based ER status to IHC-based ER status as a predictor of clinical outcome in both untreated and tamoxifen treated cohorts. In untreated breast cancer cohorts, the 23 gene signature-based ER status provided significantly improved prognostic power compared to IHC-based ER status (P = 0.006). In tamoxifen-treated cohorts, the 23 gene ER expression signature predicted clinical outcome (HR = 2.20, P = 0.00035). These complementary ER signature-based strategies estimated that between 15.1% and 21.8% patients of IHC-based negative ER status would be classified with ER positive breast cancer. Conclusion/Significance Expression-based ER status classification may complement IHC to minimise false negative ER status classification and optimise patient stratification for endocrine therapies. PMID:21152022

Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE for Metastatic Neuroendocrine Tumor Occurring in Association with Multiple Endocrine Neoplasia Type 1 and Cushing's Syndrome.

PubMed

Naik, Chinna; Basu, Sandip

2017-01-01

Neuroendocrine tumor (NET) occurring in association with other endocrine syndromes forms a distinct entity. The aim was to assess the therapy response profile of the routine peptide receptor radionuclide therapy (PRRT) in this relatively uncommon but clinically challenging subgroup of patients. A retrospective analysis was undertaken from the case records from those who were treated with 177 Lu-DOTATATE for metastatic NET. In addition to assessing the therapeutic efficacy, emphasis was also given to study lesional sites and scan pattern. A total of 5 cases were found: In this series of five cases, four belonged to multiple endocrine neoplasia type 1 (MEN1) syndrome; in these four MEN1 syndrome patients, the primary site of NET was thymic region ( n = 1), duodenum ( n = 1), and pancreas ( n = 2). The fifth case was of Cushing's syndrome with the primary site of NET in the thymus. A good symptomatic response was observed in all MEN1 syndrome cases (100%) and progression of symptoms in the patient with Cushing's syndrome. The biochemical response (assessed by measurement of tumor marker serum chromogranin A) demonstrated very good partial response (defined by more than 75% reduction of tumor marker) in 2 MEN1 cases and Cushing's syndrome, good partial response (25-75% reduction of tumor marker) in the remaining 2 MEN1 cases. Scan wise (assessed by technetium [ 99m Tc]-hydrazinonicotinamide [HYNIC]-tektrotyd [TOC]/ 68 Ga-DOTA-NOC/TATE positron emission tomography-computed tomography [PET-CT] and fluorodeoxyglucose [FDG] PET-CT) partial response was observed in 3 MEN1 cases, stable disease was noted in one MEN1 case and disease progression was noted in the patient with Cushing's syndrome. The change in FDG uptake was found to be an important sensitive scan parameter in the treatment evaluation of NETs compared to somatostatin receptor-based imaging in the cases with low MiB1 index. In our series, good palliative response to 177 Lu-DOTA-octreotate (DOTATATE) PRRT was observed in most NET patients associated with MEN1 syndrome without any major hematological or renal toxicity.

Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy

PubMed Central

Kong, Xiangju; Hong, Aayoung; Koya, Richard C.; Moriceau, Gatien; Chodon, Thinle; Guo, Rongqing; Johnson, Douglas B.; Dahlman, Kimberly B.; Kelley, Mark C.; Kefford, Richard F.; Chmielowski, Bartosz; Glaspy, John A.; Sosman, Jeffrey A.; van Baren, Nicolas; Long, Georgina V.; Ribas, Antoni; Lo, Roger S.

2013-01-01

BRAF inhibitors elicit rapid anti-tumor responses in the majority of patients with V600BRAF mutant melanoma, but acquired drug resistance is almost universal. We sought to identify the core resistance pathways and the extent of tumor heterogeneity during disease progression. We show that MAPK reactivation mechanisms were detected among 70% of disease-progressive tissues, with RAS mutations, mutant BRAF amplification and alternative splicing being most common. We also detected PI3K-PTEN-AKT-upregulating genetic alterations among 22% of progressive melanomas. Distinct molecular lesions, in both core drug escape pathways, were commonly detected concurrently in the same tumor or among multiple tumors from the same patient. Beyond harboring extensively heterogeneous resistance mechanisms, melanoma re-growth emerging from BRAF inhibitor selection displayed branched evolution marked by altered mutational spectra/signatures and increased fitness. Thus, melanoma genomic heterogeneity contributes significantly to BRAF inhibitor treatment failure, implying upfront, co-targeting of two core pathways as an essential strategy for durable responses. PMID:24265155

Monitoring p53 by MDM2 and MDMX is required for endocrine pancreas development and function in a spatio-temporal manner.

PubMed

Zhang, Yiwei; Zeng, Shelya X; Hao, Qian; Lu, Hua

2017-03-01

Although p53 is not essential for normal embryonic development, it plays a pivotal role in many biological and pathological processes, including cell fate determination-dependent and independent events and diseases. The expression and activity of p53 largely depend on its two biological inhibitors, MDM2 and MDMX, which have been shown to form a complex in order to tightly control p53 to an undetectable level during early stages of embryonic development. However, more delicate studies using conditional gene-modification mouse models show that MDM2 and MDMX may function separately or synergistically on p53 regulation during later stages of embryonic development and adulthood in a cell and tissue-specific manner. Here, we report the role of the MDM2/MDMX-p53 pathway in pancreatic islet morphogenesis and functional maintenance, using mouse lines with specific deletion of MDM2 or MDMX in pancreatic endocrine progenitor cells. Interestingly, deletion of MDM2 results in defects of embryonic endocrine pancreas development, followed by neonatal hyperglycemia and lethality, by inducing pancreatic progenitor cell apoptosis and inhibiting cell proliferation. However, unlike MDM2-knockout animals, mice lacking MDMX in endocrine progenitor cells develop normally. But, surprisingly, the survival rate of adult MDMX-knockout mice drastically declines compared to control mice, as blockage of neonatal development of endocrine pancreas by inhibition of cell proliferation and subsequent islet dysfunction and hyperglycemia eventually lead to type 1 diabetes-like disease with advanced diabetic nephropathy. As expected, both MDM2 and MDMX deletion-caused pancreatic defects are completely rescued by loss of p53, verifying the crucial role of the MDM2 and/or MDMX in regulating p53 in a spatio-temporal manner during the development, functional maintenance, and related disease progress of endocrine pancreas. Also, our study suggests a possible mouse model of advanced diabetic nephropathy, which is complementary to other established diabetic models and perhaps useful for the development of anti-diabetes therapies. Copyright © 2017 Elsevier Inc. All rights reserved.

24 CFR 234.1 - Cross-reference.

Code of Federal Regulations, 2011 CFR

2011-04-01

... new construction. 203.14Builders' warranty. 203.18aSolar energy system. 203.18cOne-time or up-front.... 1709) apply to mortgages on individually owned units insured under section 234 of the National Housing...

24 CFR 234.1 - Cross-reference.

Code of Federal Regulations, 2010 CFR

2010-04-01

... new construction. 203.14Builders' warranty. 203.18aSolar energy system. 203.18cOne-time or up-front.... 1709) apply to mortgages on individually owned units insured under section 234 of the National Housing...

[Phyllodes tumor].

PubMed

Barbari, S G; Søreide, J A; Anda, O; Grude, T H; Bjørke, J R; Hansen, A

1989-05-10

This very rare breast tumour has been diagnosed in five cases, four females and one male, at our hospital during the last two years. The females all presented tumours with a diameter ranging from 5 to 15 cm. Age at diagnosis ranged from 21 to 54 years. We focus on diagnostic challenges, since 3 of our patients were recently treated by removal of a breast tumour diagnosed morphologically as fibroadenomatosis. Our patients underwent different surgical therapy, and we focus on local treatment modalities advocated in recent literature. Systemic chemotherapy, endocrine treatment and/or radiation therapy, in the adjuvant setting or in advanced disease, do not increase survival in patients with malignant phyllodes tumour.

Oestrogen receptors, nodes and stage as predictors of post-recurrence survival in 457 breast cancer patients.

PubMed Central

Shek, L. L.; Godolphin, W.; Spinelli, J. J.

1987-01-01

The relationship to survival after first recurrence of oestrogen receptor (ER), nodal status and TNM stage at diagnosis, and treatment for advanced disease was studied in 457 females whose primary breast cancer was diagnosed in 1975 to 1981. Receptor concentration was the most important predictor of post-recurrence survival, with some additional information conveyed by nodal status. ER predicted survival after recurrence independently of nodal status, clinical stage or mode of therapy. Response to endocrine therapy is only a facet of the generally favourable prognosis of ER positive patients, rather than the sole explanation. PMID:3435707

Effectiveness of low level laser therapy for treating male infertility

PubMed Central

Vladimirovich Moskvin, Sergey; Ivanovich Apolikhin, Oleg

2018-01-01

In half of the cases, the infertility of the couple is due to the disorder of the male fertility. The leading factors that cause male infertility are urogenital infections, disorders of the immune system, testicular and prostate pathology, as well as endocrine disorders. Low level laser therapy (LLLT) is a very effective physical therapy method, used in many areas of medicine, including obstetrics and gynaecology, andrology and urology; and it is recommended as an integral part of the complex treatment of infertility. The literature review showed that LLLT is beneficial in treating male infertility. Laser can significantly improve the survival, motility and speed of movement of spermatozoa. Laser therapy of patients with prostatitis and vesiculitis can eliminate infiltrative-exudative changes, improve reproductive and copulatory functions. Local illumination of red (635 nm) and infrared (904 nm) spectra should be combined with intravenous laser blood illumination (ILBI) of red (635 nm) and ultraviolet (UV) (365 nm) spectra. PMID:29806585

A Multidisciplinary Patient Navigation Program Improves Compliance With Adjuvant Breast Cancer Therapy in a Public Hospital.

PubMed

Castaldi, Maria; Safadjou, Saman; Elrafei, Tarek; McNelis, John

Cancer health disparities affecting low-income and minority patients have been well documented to lead to poor outcomes. This report examines the impact of patient navigation on adherence to prescribed adjuvant breast cancer treatment. A multidisciplinary patient navigation program was initiated at a public safety net hospital to improve compliance with 3 National Quality Forum measures: (1) administration of combination chemotherapy for women with Stage (defined by the American Joint Committee on Cancer [AJCC]) T1c, II, or III hormone receptor-negative breast cancer within 120 days; (2) administration of endocrine therapy for women with AJCC Stage T1c, II, or III hormone receptor-positive breast cancer within 365 days; and (3) radiation therapy for women receiving breast-conserving surgery within one year. Implementation of a multidisciplinary patient navigation program reduced time to treatment and improved compliance with adjuvant therapy for breast cancer in an underserved minority community.

[The impact of the androgen receptor splice variant AR-V7 on the prognosis and treatment of advanced prostate cancer].

PubMed

Thelen, P; Taubert, H; Duensing, S; Kristiansen, G; Merseburger, A S; Cronauer, M V

2018-01-25

A recently discovered mechanism enabling prostate cancer cells to escape the effects of endocrine therapies consists in the synthesis of C-terminally truncated, constitutively active androgen receptor (AR) splice variants (AR-V). Devoid of a functional C-terminal hormone/ligand binding domain, various AR-Vs are insensitive to therapies targeting the androgen/AR signalling axis. Preliminary studies suggest that AR-V7, the most common AR-V, is a promising predictive tumour marker and a relevant selection marker for the treatment of advanced prostate cancer. This review critically outlines recent advances in AR-V7 diagnostics and presents an overview of current AR-V7 targeted therapies. © Georg Thieme Verlag KG Stuttgart · New York.

Largazole as a Novel and Selective Anti-Breast Cancer Agent

DTIC Science & Technology

2012-10-01

shorter median time to relapse and death and significant unmet medical need due to the fact that these cancers do not respond to endocrine therapy or...Overexpression of single HDAC enzyme isoform is insufficient to convert sensitive cells to resistance or vice versa. 13 4. REPORTABLE OUTCOMES...McConkey. 2006. Aggresome disruption: a novel strategy to enhance bortezomib-induced apoptosis in pancreatic cancer cells. Cancer Res 66:3773-81

Adrenocortical Carcinoma

PubMed Central

Kim, Alex C.; Sabolch, Aaron; Raymond, Victoria M.; Kandathil, Asha; Caoili, Elaine M.; Jolly, Shruti; Miller, Barbra S.; Giordano, Thomas J.

2014-01-01

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy, often with an unfavorable prognosis. Here we summarize the knowledge about diagnosis, epidemiology, pathophysiology, and therapy of ACC. Over recent years, multidisciplinary clinics have formed and the first international treatment trials have been conducted. This review focuses on evidence gained from recent basic science and clinical research and provides perspectives from the experience of a large multidisciplinary clinic dedicated to the care of patients with ACC. PMID:24423978

Tamoxifen and Aromatase Inhibitors: Cognitive Function in Occupationally Active Breast Cancer Survivors

DTIC Science & Technology

2010-05-04

assessments of cognitive function and sedation in patients with cancer pain admitted to a palliative care unit. Palliative Medicine, 16 (6), 513-9. 71...interventions. Palliative & Supportive Care, 5(3), 273-280. 72 Noblett, K.L., & Swain, R.A. (2003). Pretraining enhances recovery from visuospatial...Self-reported cognitive problems in women receiving adjuvant endocrine therapy for breast cancer. Eurpoean Journal of Oncology Nursing , 11(1), 6

Developing a HER3 Vaccine to Prevent Resistance to Endocrine Therapy

DTIC Science & Technology

2014-10-01

Medicine , Duke University Amy Hobeika, PhD, Assistant Research Professor, Department of Surgery, Duke University H. Kim Lyerly, MD, Professor...Department of Surgery, Duke University William Gwin, MD, Fellow, Department of Medicine , Duke University Bruce Burnett, PhD, Director of Regulatory Affairs... herbal products, over- the-counter (OTC) drugs, vitamins, natural remedies, and alcohol that you are taking before you start the study and before

Associations among menopausal symptoms, sleep and fatigue in Taiwanese women with endometrial cancer.

PubMed

Li, Chia-Chun; Tsai, Yun-Fang; Chang, Ting-Chang; Chen, Lynn

2017-09-01

The purpose of this study was to explore the relationships among menopausal symptoms, sleep quality and fatigue in women with endometrial cancer. Participants were 95 women (mean age = 57.44 ± 10.15 years) diagnosed with endometrial cancer and who had completed their treatment before data collection. Each woman completed three structured questionnaires: the Functional Assessment of Cancer Therapy-Endocrine Symptoms (endocrine symptom subscale), the Pittsburgh Sleep Quality Index and the Functional Assessment of Chronic Illness Therapy-Fatigue. Participants' worst menopausal symptom was sexual pain. In addition, menopausal symptoms were worse in women with surgical menopause than with natural menopause. The majority of women had poor sleep quality (55%), and women with fatigue reported worse sleep quality and menopausal symptoms than those without fatigue. However, higher fatigue was significantly related to shorter time since diagnosis. Together, three variables (time since diagnosis, menopausal symptoms and sleep quality) explained 39% of the variance in fatigue, with menopausal symptoms being the strongest predictor. Healthcare providers can assess menopausal symptoms and sleep quality during and after treatment of women with endometrial cancer. Such assessments would allow timely interventions to alleviate fatigue and menopausal symptoms in this population, thus improving their quality of life. © 2016 John Wiley & Sons Ltd.

Endocrinology Update: Hypopituitarism.

PubMed

Heidelbaugh, Joel J

2016-12-01

Hypopituitarism is defined as a deficiency of one or more pituitary hormones due to a decline in function of the pituitary gland and/or hypothalamus, which can result in higher risks of morbidity and mortality and decreased quality of life. Although hypopituitarism is a rare condition, it commonly develops after traumatic brain injury and in the setting of functioning and nonfunctioning pituitary adenomas. The diagnosis is based on detailed investigation of symptoms of target endocrine gland function relative to the corresponding pituitary hormone deficiency. The clinical manifestations of hypopituitarism result from the degree of the specific hormone deficiency. A thorough and longitudinal history and physical examination, including visual field testing, are paramount. Management consists of prompt pharmacotherapy, surgery, and/or radiotherapy to restore normal endocrine function and quality of life. In most patients with anterior and posterior pituitary hormone deficiency, corresponding hormone replacement is the mainstay of therapy. The prognosis for patients with hypopituitarism depends on the manner of and age at presentation, degree and severity of hormonal impairment, and response to medical and surgical therapies. Patients with hypopituitarism require lifelong monitoring of serum hormone levels and symptoms of hormone deficiency or excess. Written permission from the American Academy of Family Physicians is required for reproduction of this material in whole or in part in any form or medium.

An International Consortium Update: Pathophysiology, Diagnosis, and Treatment of Polycystic Ovarian Syndrome in Adolescence.

PubMed

Ibáñez, Lourdes; Oberfield, Sharon E; Witchel, Selma; Auchus, Richard J; Chang, R Jeffrey; Codner, Ethel; Dabadghao, Preeti; Darendeliler, Feyza; Elbarbary, Nancy Samir; Gambineri, Alessandra; Garcia Rudaz, Cecilia; Hoeger, Kathleen M; López-Bermejo, Abel; Ong, Ken; Peña, Alexia S; Reinehr, Thomas; Santoro, Nicola; Tena-Sempere, Manuel; Tao, Rachel; Yildiz, Bulent O; Alkhayyat, Haya; Deeb, Asma; Joel, Dipesalema; Horikawa, Reiko; de Zegher, Francis; Lee, Peter A

2017-01-01

This paper represents an international collaboration of paediatric endocrine and other societies (listed in the Appendix) under the International Consortium of Paediatric Endocrinology (ICPE) aiming to improve worldwide care of adolescent girls with polycystic ovary syndrome (PCOS)1. The manuscript examines pathophysiology and guidelines for the diagnosis and management of PCOS during adolescence. The complex pathophysiology of PCOS involves the interaction of genetic and epigenetic changes, primary ovarian abnormalities, neuroendocrine alterations, and endocrine and metabolic modifiers such as anti-Müllerian hormone, hyperinsulinemia, insulin resistance, adiposity, and adiponectin levels. Appropriate diagnosis of adolescent PCOS should include adequate and careful evaluation of symptoms, such as hirsutism, severe acne, and menstrual irregularities 2 years beyond menarche, and elevated androgen levels. Polycystic ovarian morphology on ultrasound without hyperandrogenism or menstrual irregularities should not be used to diagnose adolescent PCOS. Hyperinsulinemia, insulin resistance, and obesity may be present in adolescents with PCOS, but are not considered to be diagnostic criteria. Treatment of adolescent PCOS should include lifestyle intervention, local therapies, and medications. Insulin sensitizers like metformin and oral contraceptive pills provide short-term benefits on PCOS symptoms. There are limited data on anti-androgens and combined therapies showing additive/synergistic actions for adolescents. Reproductive aspects and transition should be taken into account when managing adolescents. © 2017 S. Karger AG, Basel.

GPER-1/GPR30 a novel estrogen receptor sited in the cell membrane: therapeutic coupling to breast cancer.

PubMed

Molina, Luis; Figueroa, Carlos D; Bhoola, Kanti D; Ehrenfeld, Pamela

2017-08-01

Breast cancer is clinically classified as 'estrogen-positive' when at least 1% of cancer cells stain for the estrogen receptor alpha (ERα). However, recent research on both basic and clinical aspects of breast cancer suggests that GPER-1 (G protein-coupled estrogen receptor-1) may have an important role in breast cancer. Areas covered: This review provides a comprehensive and systematic literature search on GPER-1. We have focused on the role of GPER-1 in breast cancer and on resistance to endocrine therapy, an unsolved clinical issue still under discussion. Expert opinion: The discovery of GPER-1 as a novel estrogen receptor is unique and the signaling pathways activated by its stimulation, when compared to the classical nuclear ERα, indicate a potential role of GPER-1 in the genesis and mechanisms of drug resistance in breast cancer. Tumors expressing ERα represent the largest group of breast cancer patients indicating that more women eventually die from ERα-positive breast tumors than from other more malignant breast cancer subtypes such as HER2-positive and the triple negative groups. It is important to develop new strategies on endocrine therapy with regard to ERα and GPER-1 receptors to achieve innovative successful therapeutic tools.

Epigenetic activation of the prostaglandin receptor EP4 promotes resistance to endocrine therapy for breast cancer.

PubMed

Hiken, J F; McDonald, J I; Decker, K F; Sanchez, C; Hoog, J; VanderKraats, N D; Jung, K L; Akinhanmi, M; Rois, L E; Ellis, M J; Edwards, J R

2017-04-20

Approximately 75% of breast cancers express estrogen receptor α (ERα) and depend on estrogen signals for continued growth. Aromatase inhibitors (AIs) prevent estrogen production and inhibit ER signaling, resulting in decreased cancer recurrence and mortality. Advanced tumors treated with AIs almost always develop resistance to these drugs via the upregulation of alternative growth signals. The mechanisms that drive this resistance-especially epigenetic events that alter gene expression-are, however, not well understood. Genome-wide DNA methylation and expression analysis of cell line models of acquired AI resistance indicated that prostaglandin E 2 receptor 4 (PTGER4) is upregulated after demethylation in resistant cells. Knockdown and inhibitor studies demonstrate that PTGER4 is essential for estrogen-independent growth. Our exploratory analysis of downstream signaling indicates that PTGER4 likely promotes AI resistance via ligand-independent activation of the ERα-cofactor CARM1. We believe that we have discovered a novel epigenetic mechanism for altering cell signaling and acquiring endocrine therapy resistance. Our findings indicate that PTGER4 is a potential drug target in AI-resistant cancers. In addition, the epigenetic component of PTGER4 regulation suggests that further study of PTGER4 may yield valuable insights into how DNA methylation-targeted diagnoses and treatments can improve AI-resistant breast cancer treatment.

Epigenetic activation of the prostaglandin receptor EP4 promotes resistance to endocrine therapy for breast cancer

PubMed Central

Hiken, Jeffrey F.; McDonald, James I.; Decker, Keith F.; Sanchez, Cesar; Hoog, Jeremy; VanderKraats, Nathan D.; Jung, Kyle L.; Akinhanmi, Margaret; Rois, Lisa E.; Ellis, Matthew J.; Edwards, John R.

2016-01-01

Approximately 75% of breast cancers express estrogen receptor α (ERα) and depend on estrogen signals for continued growth. Aromatase inhibitors (AIs) prevent estrogen production and inhibit estrogen receptor signaling, resulting in decreased cancer recurrence and mortality. Advanced tumors treated with AIs almost always develop resistance to these drugs via the up-regulation of alternative growth signals. The mechanisms that drive this resistance—especially epigenetic events that alter gene expression—are however not well understood. Genome-wide DNA methylation and expression analysis of cell line models of acquired aromatase inhibitor resistance indicated that prostaglandin E2 receptor 4 (PTGER4) is up-regulated after demethylation in resistant cells. Knockdown and inhibitor studies demonstrate that PTGER4 is essential for estrogen independent growth. Our exploratory analysis of downstream signaling indicates that PTGER4 likely promotes AI resistance via ligand independent activation of the ERα-cofactor CARM1. We believe that we have discovered a novel epigenetic mechanism for altering cell signaling and acquiring endocrine therapy resistance. Our findings indicate that PTGER4 is a potential drug target in AI resistant cancers. Additionally, the epigenetic component of PTGER4 regulation suggests that further study of PTGER4 may yield valuable insights into how DNA methylation-targeted diagnoses and treatments can improve AI resistant breast cancer treatment. PMID:27869171

Family-building After Breast Cancer: Considering the Effect on Adherence to Adjuvant Endocrine Therapy.

PubMed

Benedict, Catherine; Thom, Bridgette; Teplinsky, Eleonora; Carleton, Jane; Kelvin, Joanne F

2017-06-01

Adherence to endocrine therapy (ET) is a longstanding problem in breast cancer (BC) survivorship care, particularly among younger women. Younger patients have reported lower ET initiation rates and greater rates of early discontinuation and are considered an "at risk" group for nonadherence. For women who hope to have children in the future, concerns about premature menopause and the implications of postponing childbearing for the 5 to 10 years of ET are widespread. Preliminary evidence suggests that prioritizing fertility, along with concerns about side effects, leads to ET noninitiation and early discontinuation. Clinical efforts to improve adherence might need to consider patients' family-building goals during the course of treatment and to appropriately counsel patients according to their priorities and family-building intentions. Educational materials about family building after cancer are still not consistently available or provided. Helping patients to access trusted informational resources and decision support tools, in conjunction with medical counseling, will promote informed decisions regarding ET adherence and pregnancy that are medically appropriate. Such shared patient-provider decision-making about ET adherence and pregnancy could help to maximize patient autonomy by incorporating their values, preferences, and priorities into decisions, using providers' medical expertise. Copyright © 2016 Elsevier Inc. All rights reserved.

Memory and Spatial Cognition in Breast Cancer Patients Undergoing Adjuvant Endocrine Therapy

PubMed Central

Berndt, Ute; Leplow, Bernd; Schoenfeld, Robby; Lantzsch, Tilmann; Grosse, Regina; Thomssen, Christoph

2016-01-01

Introduction It is generally accepted that estrogens play a protective role in cognitive function. Therefore, it can be expected that subtotal estrogen deprivation following aromatase inhibition will alter cognitive performance. Methods In a cross-sectional study we investigated 80 postmenopausal women with breast cancer. Memory and spatial cognition were compared across 4 treatment groups: tamoxifen only (TAM, n = 22), aromatase inhibitor only (AI, n = 22), TAM followed by AI (‘SWITCH group’, n = 15), and patients with local therapy (LT) only (surgery and radiation, n = 21). Duration of the 2 endocrine monotherapy arms prior to the assessment ranged from 1 to 3 years. The ‘SWITCH group’ received 2-3 years TAM followed by at least 1 year and at most 3 years of AI. Memory and spatial cognition were investigated as planned comparisons. Investigations of processing speed, attention, executive function, visuoconstruction and self-perception of memory were exploratory. Results With regard to general memory, AI patients performed significantly worse than the LT group (p = 0.013). Significant differences in verbal memory did not remain significant after p-value correction for multiple testing. We found no significant differences concerning spatial cognition between the groups. Conclusion AI treatment alone significantly impairs general memory compared to the LT group. PMID:27721710

Engineering data exchange.

PubMed

Moore, M

2001-11-01

Mount Clemens General Hospsital, Mount Clemens, Mich. performance anomalies due to multiple interfaces with separate systems. implementation of an interface engine. improved management of data exchange among disparate systems. up-front studies of vendor offerings, potential problems, and long-term needs.

47 CFR 1.8003 - Providing the FRN in Commission filings.

Code of Federal Regulations, 2011 CFR

2011-10-01

... subpart G of this part, anyone participating in a spectrum auction, making up-front payments or deposits in a spectrum auction, anyone making a payment on an auction loan, anyone making a contribution to...

47 CFR 1.8003 - Providing the FRN in Commission filings.

Code of Federal Regulations, 2010 CFR

2010-10-01

... subpart G of this part, anyone participating in a spectrum auction, making up-front payments or deposits in a spectrum auction, anyone making a payment on an auction loan, anyone making a contribution to...

47 CFR 1.8003 - Providing the FRN in Commission filings.

Code of Federal Regulations, 2013 CFR

2013-10-01

... from paying statutory charges under subpart G of this part, anyone participating in a spectrum auction, making up-front payments or deposits in a spectrum auction, anyone making a payment on an auction loan...

47 CFR 1.8003 - Providing the FRN in Commission filings.

Code of Federal Regulations, 2012 CFR

2012-10-01

... from paying statutory charges under subpart G of this part, anyone participating in a spectrum auction, making up-front payments or deposits in a spectrum auction, anyone making a payment on an auction loan...

Putting a New Filter On Cancer Screening.

PubMed

Huff, Charlotte

2016-10-01

Experts are rethinking routine cancer screening. Genetic tests could be the answer. They may add upfront expense, but might eventually lead to savings by winnowing out unnecessary screening. Concern about false positives helps push this movement along.

Treatment strategies for the infertile polycystic ovary syndrome patient.

PubMed

Tannus, Samer; Burke, Yechiel Z; Kol, Shahar

2015-11-01

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. Infertility is a prevalent presenting feature of PCOS, and approximately 75% of these women suffer infertility due to anovulation. Lifestyle modification is considered the first-line treatment and is associated with improved endocrine profile. Clomiphene citrate (CC) should be considered as the first line pharmacologic therapy for ovulation induction. In women who are CC resistant, second-line treatment should be considered, as adding metformin, laparoscopic ovarian drilling or treatment with gonadotropins. In CC treatment failure, Letrozole could be an alternative or treatment with gonadotropins. IVF is considered the third-line treatment; the 'short', antagonist-based protocol is the preferred option for PCOS patients, as it is associated with lower risk of developing ovarian hyperstimulation syndrome (specifically by using a gonadotropin--releasing hormone agonist as ovulation trigger), but with comparable outcomes as the long protocol.

Cholestasis caused by panhypopituitarism and acquired cytomegalovirus infection in a 2-month-old male infant: A case report.

PubMed

Chan, U; Chan, Wai-Tao; Ting, Wei-Hsin; Ho, Che-Sheng; Liu, Hsi-Che; Lee, Hung-Chang

2017-04-01

Septo-optic dysplasia (SOD) is a rare congenital disorder that may cause jaundice in infants. However, it is usually prone to neglect and misdiagnosis in infants with cholestasis because endocrine disorder such as panhypopituitarism is rare in the cause of infantile cholestasis. We report a case of SOD concurrent with acquired cytomegalovirus (CMV) infection, who presented with prolonged jaundice as the first clinical sign. The patient was a 2-month-old male infant who presented with cholestasis, combined with fever and panhypopituitarism. He was diagnosed with SOD and acquired CMV infection. He was treated with hormone replacement therapy and ganciclovir. After correction of the pituitary hormone deficiency and ganciclovir treatment, significant improvements of cholestasis, retinal lesions, and growth rate were seen in our patient. Although an endocrine disorder such as panhypopituitarism is rare in the cause of neonatal or infantile cholestasis, we must keep this reason in mind.

Evidence from animal models on the pathogenesis of PCOS.

PubMed

Walters, K A; Bertoldo, M J; Handelsman, D J

2018-06-01

Polycystic ovarian syndrome (PCOS) is the most common endocrine condition in women, and is characterized by reproductive, endocrine and metabolic features. However, there is no simple unequivocal diagnostic test for PCOS, its etiology remains unknown and there is no cure. Hence, the management of PCOS is suboptimal as it relies on the ad hoc empirical management of its symptoms only. Decisive studies are required to unravel the origins of PCOS, but due to ethical and logistical reasons these are not possible in humans. Experimental animal models for PCOS have been established which have enhanced our understanding of the mechanisms underlying PCOS and propose novel mechanism-based therapies to treat the condition. This review examines the findings from various animal models to reveal the current knowledge of the mechanisms underpinning the development of PCOS, and also provides insights into the implications from these studies for improved clinical management of this disorder. Copyright © 2018 Elsevier Ltd. All rights reserved.

Pancreatic endocrine tumor with neoplastic venous thrombus and bilobar liver metastasis. A case report.

PubMed

Barbier, L; Turrini, O; Sarran, A; Delpero, J-R

2010-02-01

We report the case of an asymptomatic 56-year-old woman with a metastatic pancreatic endocrine tumor, fortuitously discovered by abdominal imaging. A CT-scan showed a large mass in the pancreatic tail invading the spleen and stomach; in addition, there was neoplastic thrombus within the spleno-mesentericoportal venous confluence and bilobar liver metastases. Surgical resection was performed in two stages. The first procedure was an extended left pancreatectomy with venous thrombectomy and "clearance" of the left hepatic lobe. During the interval, embolization of the right portal vein was carried out. Right hepatectomy and radiofrequency destruction of residual metastases was then performed. On the basis of completeness of the resection and the histopathological data, the patient did not undergo any adjuvant therapy, in accordance with French guidelines. At 1 year of follow-up, there was no evidence of recurrence. (c) 2010 Elsevier Masson SAS. All rights reserved.

Successful ovarian autotransplant with no vascular reanastomosis in rats.

PubMed

Barros, Flávio S V; de Oliveira, Rodrigo M; Alves, Felipe M T; Sampaio, Marcos; Geber, Selmo

2008-12-15

Preservation of ovarian functions in woman with premature ovarian failure remains an issue in reproductive medicine. Hormone replacement therapy for maintaining endocrine functions, and cryopreservation of embryos or oocytes for those who wish pregnancy, are some of the choices. However, ovarian transplantation is a more physiological alternative, although problems related to ovarian ischemia have been reported. Herein, we investigated the viability of autologous transplantation of the ovarian tissue into the rat peritoneum, without vascular reanastomosis. Twenty animals in the study group had both ovaries excised, and each ovary was dissected into two halves. A half of an ovary was autotransplanted to the peritoneal surface, closely located to the left epigastric vessels. This simple procedure does not require surgical vascular reanastomosis while it maintains appropriate follicular growth and therefore should be further considered as an alternative for women undergoing oophorectomy, not only to maintain endocrine functions but also for fertility preservation.

Management of female infertility from hormonal causes.

PubMed

Luciano, Antony A; Lanzone, Antonio; Goverde, Angelique J

2013-12-01

Hormonal causes of female infertility involve ovulatory dysfunctions that may result from dysfunction of the hypothalamic-pituitary-ovarian axis, peripheral endocrine glands, nonendocrine organs, or metabolic disorders. It is important to think of anovulation not as a diagnosis but as a symptom of a metabolic or endocrine disorder that requires a thorough diagnostic evaluation to identify the specific cause and to implement effective therapies that assure the best possible pregnancy outcome and avoid long-term adverse health consequences. In most instances, the medical history points to the underlying dysfunction, which can usually be confirmed with laboratory or imaging tests. For more challenging cases, more extensive evaluations may be needed, including perturbation studies. Nevertheless, the management of anovulatory infertility is gratifying because its causes are often manifest and the treatment usually results in resumption of ovulatory cycles, restoration of fertility, and healthy offspring through natural conception without requiring expensive and intrusive assisted reproductive technologies. © 2013.

Effects of Anorexia Nervosa on the Endocrine System.

PubMed

Baskaran, Charumathi; Misra, Madhusmita; Klibanski, Anne

2017-03-01

Anorexia nervosa (AN) is characterized by severe undernutrition associated with alterations in multiple endocrine axes, which are primarily adaptive to the state of caloric deprivation. Hormonal changes include growth hormone (GH) resistance with low insulin like growth factor-1 (IGF-1) levels, hypothalamic hypogonadism, relative hypercortisolemia and changes in appetite regulating hormones, including leptin, ghrelin, and peptide YY. These alterations contribute to abnormalities in bone metabolism leading to low bone mass, impaired bone microarchitecture, and increased risk for fracture, and may also negatively impact cognition, emotions and mood. The best strategy to improve all biologic outcomes is weight and menstrual recovery. Physiological estrogen replacement improves bone accrual rates and measures of trait anxiety in adolescents with AN. Other therapies including testosterone and IGF-1 replacement, and use of DHEA with oral estrogen-progesterone combination pills, bisphosphonates and teriparatide have also been studied to improve bone outcomes. Copyright© of YS Medical Media ltd.

Endocrine toxicity of immune checkpoint inhibitors: essential crosstalk between endocrinologists and oncologists.

PubMed

Illouz, Frédéric; Briet, Claire; Cloix, Lucie; Le Corre, Yannick; Baize, Nathalie; Urban, Thierry; Martin, Ludovic; Rodien, Patrice

2017-08-01

Two types of immune checkpoint inhibitors, both antibodies that target cytotoxic T-lymphocyte antigen-4 and those that target programmed cell death-protein 1, have been approved for use in melanoma, non-small-cell lung cancer, and renal cell carcinoma as first-line or second-line therapy. Their adverse events are primarily regarded as immune-related adverse events. We felt it was important to pinpoint and discuss certain preconceptions or misconceptions regarding thyroid dysfunction, hypophysitis, and diabetes induced by immune checkpoint inhibitors. We have identified areas of uncertainty and unmet requirements, including essential interaction between endocrinologists and oncologists. Five issues have been identified for discussion: (1) diagnosis of endocrine toxicity, (2) assessment of toxicity severity, (3) treatment of toxicity, (4) withdrawal or continuation of immunotherapy, (5) preventive action. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Chemoselection: A Paradigm for Optimization of Organ Preservation in Locally Advanced Larynx Cancer

PubMed Central

Vainshtein, Jeffrey M.; Wu, Vivian F.; Spector, Matthew E.; Bradford, Carol R.; Wolf, Gregory T.; Worden, Francis P.

2014-01-01

Summary Definitive chemoradiation (CRT) and laryngectomy followed by postoperative radiotherapy (RT) are both considered standard of care options for the management of advanced laryngeal cancer. While organ preservation with chemoradiotherapy is often the preferred up-front approach for appropriately selected candidates, the functional benefits of organ preservation must be carefully balanced against the considerable morbidity of salvage laryngectomy in patients who fail primary chemoradiation. Up-front identification of patients who are likely to require surgical salvage, therefore, is an important aim of any organ preserving approach in order to minimize morbidity while maximizing organ preservation. To this end, a strategy of “chemoselection”, using the primary tumor's response after one cycle of induction chemotherapy as an in vivo method of selecting responders for definitive chemoradiation while reserving primary surgical management for non-responders, has been employed extensively at our institution. The rationale, treatment results, and future directions of this approach are discussed. PMID:24053204

Outreach at Washington State University: a case study in costs and attendance

NASA Astrophysics Data System (ADS)

Bernhardt, Elizabeth A.; Bollen, Viktor; Bersano, Thomas M.; Mossman, Sean M.

2016-09-01

Making effective and efficient use of outreach resources can be difficult for student groups in smaller rural communities. Washington State University's OSA/SPIE student chapter desires well attended yet cost-effective ways to educate and inform the public. We designed outreach activities focused on three different funding levels: low upfront cost, moderate continuing costs, and high upfront cost with low continuing costs. By featuring our activities at well attended events, such as a pre-football game event, or by advertising a headlining activity, such as a laser maze, we take advantage of large crowds to create a relaxed learning atmosphere. Moreover, participants enjoy casual learning while waiting for a main event. Choosing a particular funding level and associating with well-attended events makes outreach easier. While there are still many challenges to outreach, such as motivating volunteers or designing outreach programs, we hope overcoming two large obstacles will lead to future outreach success.

Conservative treatment of chronic pancreatitis.

PubMed

Löhr, J-Matthias; Haas, Stephen L; Lindgren, Fredrik; Enochsson, Lars; Hedström, Aleksandra; Swahn, Fredrik; Segersvärd, Ralf; Arnelo, Urban

2013-01-01

Chronic pancreatitis is a progressive inflammatory disease giving rise to several complications that need to be treated accordingly. Because pancreatic surgery has significant morbidity and mortality, less invasive therapy seems to be an attractive option. This paper reviews current state-of-the-art strategies to treat chronic pancreatitis without surgery and the current guidelines for the medical therapy of chronic pancreatitis. Endoscopic therapy of complications of chronic pancreatitis such as pain, main pancreatic duct strictures and stones as well as pseudocysts is technically feasible and safe. The long-term outcome, however, is inferior to definitive surgical procedures such as resection or drainage. On the other hand, the medical therapy of pancreatic endocrine and exocrine insufficiency is well established and evidence based. Endoscopic therapy may be an option to bridge for surgery and in children/young adolescents and those unfit for surgery. Pain in chronic pancreatitis as well as treatment of pancreatic exocrine insufficiency follows established guidelines. Copyright © 2013 S. Karger AG, Basel.

A pilot study of the effects of gonadotropin-releasing hormone agonist therapy on brain activation pattern in a man with pedophilia.

PubMed

Moulier, Virginie; Fonteille, Véronique; Pélégrini-Issac, Mélanie; Cordier, Bernard; Baron-Laforêt, Sophie; Boriasse, Emeline; Durand, Emmanuel; Stoléru, Serge

2012-02-01

Gonadotropin-releasing hormone (GnRH) agonists, such as leuprorelin, are recommended in the patients with pedophilia at highest risk of offending. However, the cerebral mechanisms of the effects of these testosterone-decreasing drugs are poorly known. This study aimed to identify changes caused by leuprorelin in a pedophilic patient's brain responses to pictures representing children. Clinical, endocrine, and fMRI investigations were done of a man with pedophilia before leuprorelin therapy and 5 months into leuprorelin therapy. Patient was compared with an age-matched healthy control also assessed 5 months apart. Before therapy, pictures of boys elicited activation in the left calcarine fissure, left insula, anterior cingulate cortex, and left cerebellar vermis. Five months into therapy, all the above-mentioned activations had disappeared. No such activations and, consequently, no such decreases occurred in the healthy control. The results of this pilot study suggest that leuprorelin decreased activity in regions known to mediate the perceptual, motivational, and affective responses to visual sexual stimuli.

Impact of baseline BMI and weight change in CCTG adjuvant breast cancer trials.

PubMed

Yerushalmi, R; Dong, B; Chapman, J W; Goss, P E; Pollak, M N; Burnell, M J; Levine, M N; Bramwell, V H C; Pritchard, K I; Whelan, T J; Ingle, J N; Shepherd, L E; Parulekar, W R; Han, L; Ding, K; Gelmon, K A

2017-07-01

We hypothesized that increased baseline BMI and BMI change would negatively impact clinical outcomes with adjuvant breast cancer systemic therapy. Data from chemotherapy trials MA.5 and MA.21; endocrine therapy MA.12, MA.14 and MA.27; and trastuzumab HERA/MA.24 were analyzed. The primary objective was to examine the effect of BMI change on breast cancer-free interval (BCFI) landmarked at 5 years; secondary objectives included BMI changes at 1 and 3 years; BMI changes on disease-specific survival (DSS) and overall survival (OS); and effects of baseline BMI. Stratified analyses included trial therapy and composite trial stratification factors. In pre-/peri-/early post-menopausal chemotherapy trials (N = 2793), baseline BMI did not impact any endpoint and increased BMI from baseline did not significantly affect BCFI (P = 0.85) after 5 years although it was associated with worse BCFI (P = 0.03) and DSS (P = 0.07) after 1 year. BMI increase by 3 and 5 years was associated with better DSS (P = 0.01; 0.01) and OS (P = 0.003; 0.05). In pre-menopausal endocrine therapy trial MA.12 (N = 672), patients with higher baseline BMI had worse BCFI (P = 0.02) after 1 year, worse DSS (P = 0.05; 0.004) after 1 and 5 years and worse OS (P = 0.01) after 5 years. Increased BMI did not impact BCFI (P = 0.90) after 5 years, although it was associated with worse BCFI (P = 0.01) after 1 year. In post-menopausal endocrine therapy trials MA.14 and MA.27 (N = 8236), baseline BMI did not significantly impact outcome for any endpoint. BMI change did not impact BCFI or DSS after 1 or 3 years, although a mean increased BMI of 0.3 was associated with better OS (P = 0.02) after 1 year. With the administration of trastuzumab (N = 1395) baseline BMI and BMI change did not significantly impact outcomes. Higher baseline BMI and BMI increases negatively affected outcomes only in pre-/peri-/early post-menopausal trial patients. Otherwise, BMI increases similar to those expected in healthy women either did not impact outcome or were associated with better outcomes. CAN-NCIC-MA5; National Cancer Institute (NCI)-V90-0027; MA.12-NCT00002542; MA.14-NCT00002864; MA.21-NCT00014222; HERA, NCT00045032;CAN-NCIC-MA24; MA-27-NCT00066573. © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Cost-effectiveness of fluocinolone acetonide implant versus systemic therapy for noninfectious intermediate, posterior, and panuveitis.

PubMed

Sugar, Elizabeth A; Holbrook, Janet T; Kempen, John H; Burke, Alyce E; Drye, Lea T; Thorne, Jennifer E; Louis, Thomas A; Jabs, Douglas A; Altaweel, Michael M; Frick, Kevin D

2014-10-01

To evaluate the 3-year incremental cost-effectiveness of fluocinolone acetonide implant versus systemic therapy for the treatment of noninfectious intermediate, posterior, and panuveitis. Randomized, controlled, clinical trial. Patients with active or recently active intermediate, posterior, or panuveitis enrolled in the Multicenter Uveitis Steroid Treatment Trial. Data on cost and health utility during 3 years after randomization were evaluated at 6-month intervals. Analyses were stratified by disease laterality at randomization (31 unilateral vs 224 bilateral) because of the large upfront cost of the implant. The primary outcome was the incremental cost-effectiveness ratio (ICER) over 3 years: the ratio of the difference in cost (in United States dollars) to the difference in quality-adjusted life-years (QALYs). Costs of medications, surgeries, hospitalizations, and regular procedures (e.g., laboratory monitoring for systemic therapy) were included. We computed QALYs as a weighted average of EQ-5D scores over 3 years of follow-up. The ICER at 3 years was $297,800/QALY for bilateral disease, driven by the high cost of implant therapy (difference implant - systemic [Δ]: $16,900; P < 0.001) and the modest gains in QALYs (Δ = 0.057; P = 0.22). The probability of the ICER being cost-effective at thresholds of $50,000/QALY and $100,000/QALY was 0.003 and 0.04, respectively. The ICER for unilateral disease was more favorable, namely, $41,200/QALY at 3 years, because of a smaller difference in cost between the 2 therapies (Δ = $5300; P = 0.44) and a larger benefit in QALYs with the implant (Δ = 0.130; P = 0.12). The probability of the ICER being cost-effective at thresholds of $50,000/QALY and $100,000/QALY was 0.53 and 0.74, respectively. Fluocinolone acetonide implant therapy was reasonably cost-effective compared with systemic therapy for individuals with unilateral intermediate, posterior, or panuveitis but not for those with bilateral disease. These results do not apply to the use of implant therapy when systemic therapy has failed or is contraindicated. Should the duration of implant effect prove to be substantially >3 years or should large changes in therapy pricing occur, the cost-effectiveness of implant versus systemic therapy would need to be reevaluated. Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Economic evaluation of a computed tomography directed referral strategy for chronic rhinosinusitis.

PubMed

Kilty, S J; Leung, R; Rudmik, L

2016-12-01

Chronic rhinosinusitis (CRS) is a prevalent chronic inflammatory disease. The basis of a clinical diagnosis of CRS for primary care physicians (PCPs) is based upon the recognition of a symptom constellation that manifests with the disease. However, because the symptomatology of CRS may overlap with other diagnoses, the referral of patient to the most appropriate specialist may not always occur, leading to further delays in evaluation and treatment. Given the emphasis on improving the value of health care in Canada, a decision tree model was designed to evaluate whether an upfront computed tomography (CT) scan of the paranasal sinuses ordered by the PCP for a suspected case of CRS would be more cost-effective when compared to symptom-based specialist referral practice. The CT-based strategy resulted in the patient arriving at the most appropriate specialist 95% (±5%) of the time while the symptom-based referral strategy resulted in the patient arriving at the correct specialist 77% (±18%) of the time. The incremental cost effectiveness ratio (ICER) for the CT-based strategy was $1522 per patient arriving at the correct specialist. These results suggest that PCPs can improve the effectiveness of their referrals for CRS by utilising an upfront CT referral strategy. However, it would create an additional cost of approximately $1500 per patient referred. Given these findings, the potential clinical benefits of using an upfront CT scan in the Canadian primary care setting should be further studied to determine the value of the additional money spent to improve the effectiveness of CRS referral. © 2016 John Wiley & Sons Ltd.

Upfront chemotherapy and subsequent resection for molecularly defined gliomas.

PubMed

Sasaki, Hikaru; Hirose, Yuichi; Yazaki, Takahito; Kitamura, Yohei; Katayama, Makoto; Kimura, Tokuhiro; Fujiwara, Hirokazu; Toda, Masahiro; Ohira, Takayuki; Yoshida, Kazunari

2015-08-01

Functional preservation is critical in glioma surgery, and the extent of resection influences survival outcome. Neoadjuvant chemotherapy is a promising option because of its potential to facilitate tumor shrinkage and maximum tumor resection. The object of this study was to assess the utility of the neoadjuvant strategy in a prospective series of gliomas with favorable molecular status. Twenty-six consecutive cases of diffuse gliomas of WHO grade II or III with either 1p19q codeletion or MGMT methylation were treated with upfront chemotherapy following maximal safe removal. In cases of incomplete initial surgery, second-look resection was intended after tumor volume decrease by chemotherapy. Among 22 evaluable cases, chemotherapy led to a median change in the sum of the product of perpendicular diameters of -35 %, and 14 out of the 22 cases (64 %) showed objective response. Second-look resection after tumor volume decrease was performed in 12 out of 19 cases of incomplete initial surgery (GTR/STR 9, removal of residual methionine PET uptake 3). The median progression-free survival among the 22 patients with grade II tumors was 57 months, with some cases showing durable progression-free survival after second-look resection. MIB-1 indices of the second-look resected tumors were lower than those of the initial tumors, and the methylation status of the MGMT gene was unchanged. Neoadjuvant chemotherapy based on molecular guidance often produces significant volume decrease of incompletely resected gliomas. Radical second-look resection is an optional advantage of upfront chemotherapy for chemosensitive gliomas compared with initial radiotherapy.

Survival of elderly patients with multiple myeloma-Effect of upfront autologous stem cell transplantation.

PubMed

Merz, Maximilian; Jansen, Lina; Castro, Felipe A; Hillengass, Jens; Salwender, Hans; Weisel, Katja; Scheid, Christof; Luttmann, Sabine; Emrich, Katharina; Holleczek, Bernd; Katalinic, Alexander; Nennecke, Alice; Straka, Christian; Langer, Christian; Engelhardt, Monika; Einsele, Hermann; Kröger, Nicolaus; Beelen, Dietrich; Dreger, Peter; Brenner, Hermann; Goldschmidt, Hartmut

2016-07-01

The aim of this study was to determine the value of upfront autologous transplantation (ASCT) in elderly patients (60-79 years) with myeloma. We analysed relative survival (RS) of patients diagnosed in 1998-2011 and treated with ASCT within 12 months after diagnosis in Germany (n = 3591; German Registry of Stem Cell Transplantation) and compare RS with survival of myeloma patients diagnosed in the same years in Germany (n = 13,903; population-based German Cancer Registries). Utilisation of ASCT has increased rapidly between 2000-2002 and 2009-2011 (60-64years: 7.0-43.0%; 65-69 years: 6.6-23.7%; 70-79 years: 0.4-4.0%). Comparison of 5-year RS of patients from the general German myeloma population who have survived the first year after diagnosis with 5-year RS of patients treated with ASCT revealed higher survival for transplanted patients among all age groups (60-64: 59.2% versus 66.1%; 65-69: 57.4% versus 61.7%; 70-79: 51.0% versus 56.6%). RS increased strongly between 2003-2005 and 2009-2011 for the general German myeloma population (+8.5%) and for patients treated with ASCT (+11.8%). Differences in RS between these groups increased over time from +1.9% higher age-standardised survival in transplanted patients in 2003-2005 to 5.2% higher survival in 2009-2011. We conclude that upfront ASCT might be a major contributor to improved survival for elderly myeloma patients in Germany. Copyright © 2016 Elsevier Ltd. All rights reserved.

Tuberculosis, the Disrupted Immune-Endocrine Response and the Potential Thymic Repercussion As a Contributing Factor to Disease Physiopathology.

PubMed

D'Attilio, Luciano; Santucci, Natalia; Bongiovanni, Bettina; Bay, María L; Bottasso, Oscar

2018-01-01

Upon the pathogen encounter, the host seeks to ensure an adequate inflammatory reaction to combat infection but at the same time tries to prevent collateral damage, through several regulatory mechanisms, like an endocrine response involving the production of adrenal steroid hormones. Our studies show that active tuberculosis (TB) patients present an immune-endocrine imbalance characterized by an impaired cellular immunity together with increased plasma levels of cortisol, pro-inflammatory cytokines, and decreased amounts of dehydroepiandrosterone. Studies in patients undergoing specific treatment revealed that cortisol levels remained increased even after several months of initiating therapy. In addition to the well-known metabolic and immunological effects, glucocorticoids are involved in thymic cortical depletion with immature thymocytes being quite sensitive to such an effect. The thymus is a central lymphoid organ supporting thymocyte T-cell development, i.e., lineage commitment, selection events and thymic emigration. While thymic TB is an infrequent manifestation of the disease, several pieces of experimental and clinical evidence point out that the thymus can be infected by mycobacteria. Beyond this, the thymic microenvironment during TB may be also altered because of the immune-hormonal alterations. The thymus may be then an additional target of organ involvement further contributing to a deficient control of infection and disease immunopathology.

ADVANCES IN SALIVARY GLAND GENE THERAPY – ORAL AND SYSTEMIC IMPLICATIONS

PubMed Central

Baum, Bruce J.; Alevizos, Ilias; Chiorini, John A.; Cotrim, Ana P.; Zheng, Changyu

2016-01-01

Introduction Much research demonstrates the feasibility and efficacy of gene transfer to salivary glands. Recently, the first clinical trial targeting a salivary gland was completed, yielding positive safety and efficacy results. Areas covered There are two major disorders affecting salivary glands; radiation damage following treatment for head and neck cancers and Sjögren’s syndrome. Salivary gland gene transfer has also been employed in preclinical studies using transgenic secretory proteins for exocrine (upper gastrointestinal tract) and endocrine (systemic) applications. Expert opinion Salivary gland gene transfer is safe and can be beneficial in humans. Applications to treat and prevent radiation damage show considerable promise. A first-in-human clinical trial for the former was recently successfully completed. Studies on Sjögren’s syndrome suffer from an inadequate understanding of its etiology. Proof of concept in animal models has been shown for exocrine and endocrine disorders. Currently, the most promising exocrine application is for the management of obesity. Endocrine applications are limited, as it is currently impossible to predict if systemically required transgenic proteins will be efficiently secreted into the bloodstream. This results from not understanding of how secretory proteins are sorted. Future studies will likely employ ultrasound assisted and pseudotyped adenoassociated viral vector-mediated gene. PMID:26149284

Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline

PubMed Central

Nieman, Lynnette K.; Biller, Beverly M. K.; Findling, James W.; Murad, M. Hassan; Newell-Price, John; Savage, Martin O.; Tabarin, Antoine

2015-01-01

Objective: The objective is to formulate clinical practice guidelines for treating Cushing's syndrome. Participants: Participants include an Endocrine Society-appointed Task Force of experts, a methodologist, and a medical writer. The European Society for Endocrinology co-sponsored the guideline. Evidence: The Task Force used the Grading of Recommendations, Assessment, Development, and Evaluation system to describe the strength of recommendations and the quality of evidence. The Task Force commissioned three systematic reviews and used the best available evidence from other published systematic reviews and individual studies. Consensus Process: The Task Force achieved consensus through one group meeting, several conference calls, and numerous e-mail communications. Committees and members of The Endocrine Society and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines. Conclusions: Treatment of Cushing's syndrome is essential to reduce mortality and associated comorbidities. Effective treatment includes the normalization of cortisol levels or action. It also includes the normalization of comorbidities via directly treating the cause of Cushing's syndrome and by adjunctive treatments (eg, antihypertensives). Surgical resection of the causal lesion(s) is generally the first-line approach. The choice of second-line treatments, including medication, bilateral adrenalectomy, and radiation therapy (for corticotrope tumors), must be individualized to each patient. PMID:26222757