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Sample records for alk positive patients

  1. Use of minimal disseminated disease and immunity to NPM-ALK antigen to stratify ALK-positive ALCL patients with different prognosis.

    PubMed

    Mussolin, L; Damm-Welk, C; Pillon, M; Zimmermann, M; Franceschetto, G; Pulford, K; Reiter, A; Rosolen, A; Woessmann, W

    2013-02-01

    We studied the prognostic value of minimal disseminated disease (MDD) and anti-ALK immune response in children with NPM-ALK-positive anaplastic-large cell lymphoma (ALCL) and evaluated their potential for risk stratification. NPM-ALK transcripts were analyzed by RT-PCR in bone marrow/peripheral blood of 128 ALCL patients at diagnosis, whereas ALK antibody titers in plasma were assessed using an immunocytochemical approach. MDD was positive in 59% of patients and 96% showed an anti-ALK response. Using MDD and antibody titer results, patients could be divided into three biological risk groups (bRG) with different prognosis: high risk (bHR): MDD-positive and antibody titer ≤ 1/750, 26/128 (20%); low risk (bLR): MDD negative and antibody titer >1/750, 40/128 (31%); intermediate risk (bIR): all remaining patients, 62/128 (48%). Progression-free survival was 28% (s.e., 9%), 68% (s.e., 6%) and 93% (s.e., 4%) for bHR, bIR and bLR, respectively (P<0.0001). Survival was 71% (s.e., 9%), 83% (s.e., 5%) and 98% (s.e., 2%) for bHR, bIR and bLR (P=0.02). Only bHR and histology other than common type were predictive of higher risk of failure (hazard ratio 4.9 and 2.7, respectively) in multivariate analysis. Stratification of ALCL patients based on MDD and anti-ALK titer should be considered in future ALCL trials to optimize treatment.

  2. Responses to crizotinib in patients with ALK-positive lung adenocarcinoma who tested immunohistochemistry (IHC)-positive and fluorescence in situ hybridization (FISH)-negative

    PubMed Central

    Yang, Lin; Mu, Xinlin; Wang, Yan; Zhao, Xinming; Li, Junling; Lin, Dongmei

    2016-01-01

    Although the Ventana immunohistochemistry (IHC) platform for detecting anaplastic lymphoma kinase gene (ALK) (D5F3) expression was recently approved by the US Food and Drugs Administration (FDA), fluorescence in situ hybridization (FISH) is still the “gold-standard” method recommended by the US National Comprehensive Cancer Network (NCCN) guideline for NSCLC. We evaluated 6 ALK-positive lung adenocarcinoma patients who tested Ventana IHC-positive and FISH-negative and assessed their clinical responses to the ALK tyrosine kinase inhibitor (TKI) crizotinib. Histologic and cytologic specimens from the 6 patients were stained with Ventana anti-ALK(D5F3) rabbit monoclonal primary antibody using the OptiView™ DAB IHC detection kit and OptiView™ amplification kit on a Ventana BenchMark XT processor. In addition, they were also tested by FISH, qRT-PCR, next-generation sequencing (NGS), and RNAscope ISH analysis. All patients received crizotinib treatment and their follow-up clinical data were recorded. The objective response rate achieved with crizotinib therapy was 66.7% (4/6 partial responses and 2/6 stable disease). One patient in whom a new fusion type (EML4->EXOC6B->ALK fusion) was identified obtained a partial response. These findings indicate that patients with ALK-positive lung adenocarcinoma who test Ventana IHC-positive and FISH-negative may still respond to crizotinib therapy. PMID:27418132

  3. Treatment patterns and survival in patients with ALK-positive non-small-cell lung cancer: a Canadian retrospective study

    PubMed Central

    Kayaniyil, S.; Hurry, M.; Wilson, J.; Wheatley-Price, P.; Melosky, B.; Rothenstein, J.; Cohen, V.; Koch, C.; Zhang, J.; Osenenko, K.; Liu, G.

    2016-01-01

    Background Crizotinib was the first agent approved for the treatment of anaplastic lymphoma kinase (ALK)–positive (+) non-small-cell lung cancer (nsclc), followed by ceritinib. However, patients eventually progress or develop resistance to crizotinib. With limited real-world data available, the objective of the present work was to evaluate treatment patterns and survival after crizotinib in patients with locally advanced or metastatic ALK+ nsclc in Canada. Methods In this retrospective study at 6 oncology centres across Canada, medical records of patients with locally advanced or metastatic ALK+ nsclc were reviewed. Demographic and clinical characteristics, treatments, and outcomes data were abstracted. Analyses focused on patients who discontinued crizotinib treatment. Results Of the 97 patients included, 9 were crizotinib-naïve, and 39 were still receiving crizotinib at study end. The 49 patients who discontinued crizotinib treatment were included in the analysis. Of those 49 patients, 43% received ceritinib at any time, 20% subsequently received systemic chemotherapy only (but never ceritinib), and 37% received no further treatment or died before receiving additional treatment. Median overall survival from crizotinib discontinuation was shorter in patients who did not receive ceritinib than in those who received ceritinib (1.7 months vs. 20.4 months, p < 0.001). In a multivariable analysis, factors associated with poorer survival included lack of additional therapies (particularly ceritinib), male sex, and younger age, but not smoking status; patients of Asian ethnicity showed a nonsignificant trend toward improved survival. Conclusions A substantial proportion of patients with ALK+ nsclc received no further treatment or died before receiving additional treatment after crizotinib. Treatment with systemic agents was associated with improved survival, with ceritinib use being associated with the longest survival. PMID:28050149

  4. Upregulation of PD-L1 by EML4-ALK fusion protein mediates the immune escape in ALK positive NSCLC: Implication for optional anti-PD-1/PD-L1 immune therapy for ALK-TKIs sensitive and resistant NSCLC patients.

    PubMed

    Hong, Shaodong; Chen, Nan; Fang, Wenfeng; Zhan, Jianhua; Liu, Qing; Kang, Shiyang; He, Xiaobo; Liu, Lin; Zhou, Ting; Huang, Jiaxing; Chen, Ying; Qin, Tao; Zhang, Yaxiong; Ma, Yuxiang; Yang, Yunpeng; Zhao, Yuanyuan; Huang, Yan; Zhang, Li

    2016-03-01

    Driver mutations were reported to upregulate programmed death-ligand 1 (PD-L1) expression. However, how PD-L1 expression and immune function was affected by ALK-TKIs and anti-PD-1/PD-L1 treatment in ALK positive non-small-cell lung cancer (NSCLC) remains poorly understood. In the present study, western-blot, real-time PCR, flow cytometry and immunofluorescence were employed to explore how PD-L1 was regulated by ALK fusion protein. ALK-TKIs and relevant inhibitors were used to identify the downstream signaling pathways involved in PD-L1 regulation. Cell apoptosis, viability and Elisa test were used to study the immune suppression by ALK activation and immune reactivation by ALK-TKIs and/or PD-1 blocking in tumor cells and DC-CIK cells co-culture system. We found that PD-L1 expression was associated with EGFR mutations and ALK fusion genes in NSCLC cell lines. Over-expression of ALK fusion protein increased PD-L1 expression. PD-L1 mediated by ALK fusion protein increased the apoptosis of T cells in tumor cells and DC-CIK cells co-culture system. Inhibiting ALK by sensitive TKIs could enhance the production of IFNγ. Anti-PD-1 antibody was effective in both crizotinib sensitive and resistant NSCLC cells. Synergistic tumor killing effects were not observed with ALK-TKIs and anti-PD-1 antibody combination in co-culture system. ALK-TKIs not only directly inhibited tumor viability but also indirectly enhanced the antitumor immunity via the downregulation of PD-L1. Anti-PD-1/PD-L1 antibodies could be an optional therapy for crizotinib sensitive, especially crizotinib resistant NSCLC patients with ALK fusion gene. Combination of ALK-TKIs and anti-PD-1/PD-L1 antibodies treatment for ALK positive NSCLC warrants more data before moving into clinical practice.

  5. Canadian consensus: inhibition of ALK-positive tumours in advanced non-small-cell lung cancer

    PubMed Central

    Melosky, B.; Agulnik, J.; Albadine, R.; Banerji, S.; Bebb, D.G.; Bethune, D.; Blais, N.; Butts, C.; Cheema, P.; Cheung, P.; Cohen, V.; Deschenes, J.; Ionescu, D.N.; Juergens, R.; Kamel-Reid, S.; Laurie, S.A.; Liu, G.; Morzycki, W.; Tsao, M.S.; Xu, Z.; Hirsh, V.

    2016-01-01

    Anaplastic lymphoma kinase (alk) is an oncogenic driver in non-small-cell lung cancer (nsclc). Chromosomal rearrangements involving the ALK gene occur in up to 4% of nonsquamous nsclc patients and lead to constitutive activation of the alk signalling pathway. ALK-positive nsclc is found in relatively young patients, with a median age of 50 years. Patients frequently have brain metastasis. Targeted inhibition of the alk pathway prolongs progression-free survival in patients with ALK-positive advanced nsclc. The results of several recent clinical trials confirm the efficacy and safety benefit of crizotinib and ceritinib in this population. Canadian oncologists support the following consensus statement: All patients with advanced nonsquamous nsclc (excluding pure neuroendocrine carcinoma) should be tested for the presence of an ALK rearrangement. If an ALK rearrangement is present, treatment with a targeted alk inhibitor in the first-line setting is recommended. As patients become resistant to first-generation alk inhibitors, other treatments, including second-generation alk inhibitors can be considered. PMID:27330348

  6. Achievements and future developments of ALK-TKIs in the management of CNS metastases from ALK-positive NSCLC

    PubMed Central

    Cappuzzo, Federico

    2016-01-01

    Non-small cell lung cancer (NSCLC) represents the paradigm of personalized treatment of human cancer. Several oncogenic druggable alterations have been so far identified, with anaplastic lymphoma kinase (ALK) gene rearrangements being one of the newest and most appealing. Presence of ALK fusions is associated with some particular clinical and pathological features, including a preferential seeding into the central nervous system (CNS). In addition, ALK rearrangements are recognized as the strongest predictor for benefit of anti-ALK therapy. Crizotinib, the first ALK inhibitor (ALK-I) licensed in clinical practice, is the standard of care for newly diagnosed patients. Unfortunately, within the first year of treatment the majority of patients become insensitive to crizotinib, with approximately one third of them developing brain metastases (BMs). Optimal management of BMs is one of the major challenges in treating ALK positive NSCLC. Several novel and highly CNS penetrant ALK-Is are currently under investigation and available data clearly indicated their ability in controlling intracranial disease. PMID:28149753

  7. Synergistic activity of ALK and mTOR inhibitors for the treatment of NPM-ALK positive lymphoma

    PubMed Central

    Redaelli, Sara; Ceccon, Monica; Antolini, Laura; Rigolio, Roberta; Pirola, Alessandra; Peronaci, Marco; Gambacorti-Passerini, Carlo; Mologni, Luca

    2016-01-01

    ALK-positive Anaplastic Large Cell Lymphoma (ALCL) represents a subset of Non-Hodgkin Lymphoma whose treatment benefited from crizotinib development, a dual ALK/MET inhibitor. Crizotinib blocks ALK-triggered pathways such as PI3K/AKT/mTOR, indispensable for survival of ALK-driven tumors. Despite the positive impact of targeted treatment in ALCL, resistant clones are often selected during therapy. Strategies to overcome resistance include the design of second generation drugs and the use of combined therapies that simultaneously target multiple nodes essential for cells survival. We investigated the effects of combined ALK/mTOR inhibition. We observed a specific synergistic effect of combining ALK inhibitors with an mTOR inhibitor (temsirolimus), in ALK+ lymphoma cells. The positive cooperation resulted in an increased inhibition of mTOR effectors, compared to single treatments, a block in G0/G1 phase and induction of apoptosis. The combination was able to prevent the selection of resistant clones, while long-term exposure to single agents led to the establishment of resistant cell lines, with either ALK inhibitor or temsirolimus. In vivo, mice injected with Karpas 299 cells and treated with low dose combination showed complete regression of tumors, while only partial inhibition was obtained in single agents-treated mice. Upon treatment stop the combination was able to significantly delay tumor relapses. Re-challenge of relapsed tumors at a higher dose led to full regression of xenografts in the combination group, but not in mice treated with lorlatinib alone. In conclusion, our data suggest that the combination of ALK and mTOR inhibitors could be a valuable therapeutic option for ALK+ ALCL patients. PMID:27662658

  8. Alectinib for choroidal metastasis in a patient with crizotinib-resistant ALK rearranged positive non-small cell lung cancer.

    PubMed

    Okuma, Yusuke; Tanaka, Yuichiro; Kamei, Tina; Hosomi, Yukio; Okamura, Tatsuru

    2015-01-01

    Choroidal metastasis is rare in cancer patients. Small molecules of molecular targeted agents for lung cancer with actionable mutations were reported to be palliated for symptoms caused by choroidal metastasis. Visual disturbance by choroidal metastasis significantly decreases quality of life during the patient's remaining lifespan; therefore, radiotherapy or laser photocoagulation is proposed with consensus. However, improvement in survival with matched molecular targeted agents for oncogenic driver mutations reminds us to also be concerned with late treatment toxicities. A 30-year-old female patient previously treated with crizotinib harboring ALK rearranged non-small cell lung cancer complained of visual disturbance, fever, and bone pains undergoing anti-PD-1 antibody treatment. A decreased proportion of ALK fusion was demonstrated by fluorescence in situ hybridization in liver metastasis compared to the primary site in a chemo-naïve state. She was diagnosed with low vision, choroidal metastasis and retinal detachment. Therefore, she started alectinib treatment and both her ocular and systemic symptoms were palliated in a week. Later, she temporarily discontinued alectinib because of skin rash although the choroidal metastasis and retinal detachment resolved and she regained low vision completely at 2 weeks. She obtained partial response with alectinib for more than 5 months after recovering from skin rash.

  9. Personalized treatment in advanced ALK-positive non-small cell lung cancer: from bench to clinical practice

    PubMed Central

    Passaro, Antonio; Lazzari, Chiara; Karachaliou, Niki; Spitaleri, Gianluca; Pochesci, Alessia; Catania, Chiara; Rosell, Rafael; de Marinis, Filippo

    2016-01-01

    The discovery of anaplastic lymphoma kinase (ALK) gene rearrangements and the development of tyrosine kinase inhibitors (TKI) that target them have achieved unprecedented success in the management of patients with ALK-positive non-small cell lung cancer (NSCLC). Despite the high efficacy of crizotinib, the first oral ALK TKI approved for the treatment of ALK-positive NSCLC, almost all patients inevitably develop acquired resistance, showing disease progression in the brain or in other parenchymal sites. Second- or third-generation ALK TKIs have shown to be active in crizotinib-pretreated or crizotinib-naïve ALK-positive patients, even in those with brain metastases. In this review, the current knowledge regarding ALK-positive NSCLC, focusing on the biology of the disease and the available therapeutic options are discussed. PMID:27799783

  10. Prospective and clinical validation of ALK immunohistochemistry: results from the phase I/II study of alectinib for ALK-positive lung cancer (AF-001JP study)

    PubMed Central

    Takeuchi, K.; Togashi, Y.; Kamihara, Y.; Fukuyama, T.; Yoshioka, H.; Inoue, A.; Katsuki, H.; Kiura, K.; Nakagawa, K.; Seto, T.; Maemondo, M.; Hida, T.; Harada, M.; Ohe, Y.; Nogami, N.; Yamamoto, N.; Nishio, M.; Tamura, T.

    2016-01-01

    Background Anaplastic lymphoma kinase (ALK) fusions need to be accurately and efficiently detected for ALK inhibitor therapy. Fluorescence in situ hybridization (FISH) remains the reference test. Although increasing data are supporting that ALK immunohistochemistry (IHC) is highly concordant with FISH, IHC screening needed to be clinically and prospectively validated. Patients and methods In the AF-001JP trial for alectinib, 436 patients were screened for ALK fusions through IHC (n = 384) confirmed with FISH (n = 181), multiplex RT-PCR (n = 68), or both (n = 16). IHC results were scored with iScore. Result ALK fusion was positive in 137 patients and negative in 250 patients. Since the presence of cancer cells in the samples for RT-PCR was not confirmed, ALK fusion negativity could not be ascertained in 49 patients. IHC interpreted with iScore showed a 99.4% (173/174) concordance with FISH. All 41 patients who had iScore 3 and were enrolled in phase II showed at least 30% tumor reduction with 92.7% overall response rate. Two IHC-positive patients with an atypical FISH pattern responded to ALK inhibitor therapy. The reduction rate was not correlated with IHC staining intensity. Conclusions Our study showed (i) that when sufficiently sensitive and appropriately interpreted, IHC can be a stand-alone diagnostic for ALK inhibitor therapies; (ii) that when atypical FISH patterns are accompanied by IHC positivity, the patients should be considered as candidates for ALK inhibitor therapies, and (iii) that the expression level of ALK fusion is not related to the level of response to ALK inhibitors and is thus not required for patient selection. Registration number JapicCTI-101264 (This study is registered with the Japan Pharmaceutical Information Center). PMID:26487585

  11. Proactive management strategies for potential gastrointestinal adverse reactions with ceritinib in patients with advanced ALK-positive non-small-cell lung cancer

    PubMed Central

    Schaefer, Eric S; Baik, Christina

    2016-01-01

    Anaplastic lymphoma kinase (ALK) gene fusions occur in 3%–7% of non-small-cell lung cancer (NSCLC) cases. Ceritinib, a once-daily, oral ALK inhibitor, has activity against crizotinib-resistant and crizotinib-naïve NSCLC, including brain metastases. Ceritinib (Zykadia™) was granted accelerated approval by the US Food and Drug Administration in 2014 for treating crizotinib-resistant ALK-positive NSCLC. Adverse events (AEs), particularly gastrointestinal (GI) AEs, are commonly experienced at the recommended dose of 750 mg/d and ∼38% of patients require dose interruption or reduction for GI AEs. This case study details our experience with the use of proactive GI AE management regimens in patients treated with ceritinib (750 mg/d) across two study sites. Proactive Regimens A and B were implemented in patients with metastatic ALK-positive NSCLC treated with ceritinib to manage drug-related GI AEs. Regimen A comprised ondansetron and diphenoxylate/atropine or loperamide, taken 30 minutes prior to ceritinib dose. Regimen B included dicyclomine (taken with the first ceritinib dose), ondansetron (taken 30 minutes prior to ceritinib dose for the first seven doses), and loperamide (taken as needed with the onset of diarrhea). The proactive medications were tapered off depending on patient tolerability to ceritinib. Nine patient cases are presented. Starting Regimens A or B before the first dose of ceritinib, or as soon as GI symptoms were encountered, prevented the need for dose reduction due to GI toxicity in eight of the nine patients. Using these regimens, 78% of patients were able to remain on 750 mg/d fasting. Two patients received 23 months and 16 months of therapy and remain on ceritinib 750 mg/d and 600 mg/d, respectively. Although not currently recommended or implemented in clinical studies, based on the patients evaluated here, upfront or proactive treatment plans that address AEs early on can allow the majority of patients to remain on the approved 750 mg

  12. Pooled Analysis of CNS Response to Alectinib in Two Studies of Pretreated Patients With ALK-Positive Non-Small-Cell Lung Cancer.

    PubMed

    Gadgeel, Shirish M; Shaw, Alice T; Govindan, Ramaswamy; Gandhi, Leena; Socinski, Mark A; Camidge, D Ross; De Petris, Luigi; Kim, Dong-Wan; Chiappori, Alberto; Moro-Sibilot, Denis L; Duruisseaux, Michael; Crino, Lucio; De Pas, Tommaso; Dansin, Eric; Tessmer, Antje; Yang, James Chih-Hsin; Han, Ji-Youn; Bordogna, Walter; Golding, Sophie; Zeaiter, Ali; Ou, Sai-Hong Ignatius

    2016-12-01

    Purpose Alectinib has shown activity in the CNS in phase I and II studies. To further evaluate this activity, we pooled efficacy and safety data from two single-arm phase II studies (NP28761 and NP28673; ClinicalTrials.gov identifiers: NCT01871805 and NCT01801111, respectively) in patients with ALK-positive non-small-cell lung cancer (NSCLC). Patients and Methods Both studies included patients with ALK-positive NSCLC who had previously received crizotinib; all patients received alectinib 600 mg twice per day. The primary end point in both studies was independent review committee (IRC)-assessed objective response rate (ORR; by Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1). Additional end points (all by IRC) included CNS ORR (CORR), CNS disease control rate (CDCR), and CNS duration of response (CDOR). Results One hundred thirty-six patients had baseline CNS metastases (60% of the overall study populations); 50 patients (37%) had measurable CNS disease at baseline. Ninety-five patients (70%) had prior CNS radiotherapy; 55 patients completed the CNS radiotherapy more than 6 months before starting alectinib. Median follow-up time was 12.4 months (range, 0.9 to 19.7 months). For patients with baseline measurable CNS disease, IRC CORR was 64.0% (95% CI, 49.2% to 77.1%), CDCR was 90.0% (95% CI, 78.2% to 96.7%), and median CDOR was 10.8 months (95% CI, 7.6 to 14.1 months). For patients with measurable and/or nonmeasurable baseline CNS disease, IRC CORR was 42.6% (95% CI, 34.2% to 51.4%), CDCR was 85.3% (95% CI, 78.2% to 90.8%), and median CDOR was 11.1 months (95% CI, 10.3 months to not evaluable). CORR was 35.8% (95% CI, 26.2% to 46.3%) for patients with prior radiotherapy (n = 95) and 58.5% (95% CI, 42.1% to 73.7%) for patients without prior radiotherapy (n = 41). As previously reported, alectinib was well tolerated, regardless of baseline CNS disease. Conclusion Alectinib showed good efficacy against CNS metastases, in addition to systemic activity

  13. ALK gene expression status in pleural effusion predicts tumor responsiveness to crizotinib in Chinese patients with lung adenocarcinoma

    PubMed Central

    Wang, Zheng; Wu, Xiaonan; Han, Xiaohong; Cheng, Gang; Mu, Xinlin; Zhang, Yuhui; Cui, Di; Liu, Chang; Liu, Dongge; Shi, Yuankai

    2016-01-01

    Objective The relationship between anaplastic lymphoma kinase (ALK) expression in malignant pleural effusion (MPE) samples detected only by Ventana immunohistochemistry (IHC) ALK (D5F3) and the efficacy of ALK-tyrosine kinase inhibitor therapy is uncertain. Methods Ventana anti-ALK (D5F3) rabbit monoclonal primary antibody testing was performed on 313 cell blocks of MPE samples from Chinese patients with advanced lung adenocarcinoma, and fluorescence in situ hybridization (FISH) was used to verify the ALK gene status in Ventana IHC ALK (D5F3)-positive samples. The follow-up clinical data on patients who received crizotinib treatment were recorded. Results Of the 313 MPE samples, 27 (8.6%) were confirmed as ALK expression-positive, and the Ventana IHC ALK (D5F3)-positive rate was 17.3% (27/156) in wild-type epidermal growth factor receptor (EGFR) MPE samples. Twenty-three of the 27 IHC ALK (D5F3)-positive samples were positive by FISH. Of the 11 Ventana IHC ALK (D5F3)-positive patients who received crizotinib therapy, 2 patients had complete response (CR), 5 had partial response (PR) and 3 had stable disease (SD). Conclusions The ALK gene expression status detected by the Ventana IHC ALK (D5F3) platform in MPE samples may predict tumor responsiveness to crizotinib in Chinese patients with advanced lung adenocarcinoma. PMID:28174489

  14. Spotlight on crizotinib in the first-line treatment of ALK-positive advanced non-small-cell lung cancer: patients selection and perspectives

    PubMed Central

    Leprieur, Etienne Giroux; Fallet, Vincent; Cadranel, Jacques; Wislez, Marie

    2016-01-01

    Around 4% of advanced non-small-cell lung cancers (NSCLCs) have an ALK rearrangement at the time of diagnosis. This molecular feature is more frequent in young patients, with no/light smoking habit and with adenocarcinoma pathological subtype. Crizotinib is a tyrosine kinase inhibitor, targeting ALK, ROS1, RON, and MET. The preclinical efficacy results led to a fast-track clinical development. The US Food and Drug Administration (FDA) approval was achieved after the Phase I clinical trial in 2011 in ALK-rearranged advanced NSCLC progressing after a first-line treatment. In 2013, the randomized Phase III trial PROFILE-1007 confirmed the efficacy of crizotinib in ALK-rearranged NSCLC, compared to cytotoxic chemotherapy, in second-line setting or more. In 2014, the PROFILE-1014 trial showed the superiority of crizotinib in the first-line setting compared to the pemetrexed platinum doublet chemotherapy. The response rate was 74%, and the progression-free survival was 10.9 months with crizotinib. Based on these results, crizotinib received approval from the FDA and European Medicines Agency for first-line treatment of ALK-rearranged NSCLC. The various molecular mechanisms at the time of the progression (ALK mutations or amplification, ALK-independent mechanisms) encourage performing re-biopsy at the time of progression under crizotinib. The best treatment strategy at the progression (crizotinib continuation beyond progression, switch to second-generation tyrosine kinase inhibitors, or cytotoxic chemotherapy) depends on the phenotype of the progression, the molecular status, and the physical condition of the patient. PMID:28210164

  15. Detection of ALK rearrangements in lung cancer patients using a homebrew PCR assay.

    PubMed

    Yu, Hui; Chang, JianHua; Liu, Fang; Wang, Qifeng; Lu, YongMing; Zhang, ZhuanXu; Shen, Jiabing; Zhai, Qing; Meng, Xia; Wang, Jialei; Ye, Xun

    2017-01-31

    Lung cancer patients with anaplastic lymphoma kinase (ALK) rearrangements are candidates for targeted therapeutics. However, patients must be tested with a companion diagnostic assay to realize their ALK rearrangement status. We analyzed the publicly available E-GEOD-31210 microarray dataset and identified a non-coding RNA, sweyjawbu, which is strongly associated with ALK rearrangements. We validated these results using quantitative real-time PCR in an independent cohort consisting of 4 cell lines and 83 clinical samples. We could differentiate between ALK rearrangement-positive and -negative lung cancer samples by comparing sweyjawbu expression. Additionally, ALK rearrangement status was determined by comparing the expression of the 5' and 3' regions of the ALK transcript or by detecting known ALK hybrid subtypes. Thus, using our homebrew PCR assay, we were able to accurately detect ALK rearrangements, which could be used for diagnostic screening of lung cancer patients. The prototype could potentially be transferred to an automatic multiplex PCR platform (FilmArray) to differentiate between ALK rearrangement-positive and -negative patients in point-of-care settings.

  16. A causal link from ALK to hexokinase II overexpression and hyperactive glycolysis in EML4-ALK-positive lung cancer

    PubMed Central

    Ma, Yibao; Yu, Chunrong; Mohamed, Esraa M.; Shao, Huanjie; Wang, Li; Sundaresan, Gobalakrishnan; Zweit, Jamal; Idowu, Michael; Fang, Xianjun

    2016-01-01

    A high rate of aerobic glycolysis is a hallmark of malignant transformation. Accumulating evidence suggests that diverse regulatory mechanisms mediate this cancer-associated metabolic change seen in a wide spectrum of cancer. The echinoderm microtubule associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion protein is found in approximately 3-7% of non-small cell lung carcinomas (NSCLC). Molecular evidence and therapeutic effectiveness of FDA-approved ALK inhibitors indicated that EML4-ALK is a driving factor of lung tumorigenesis. A recent clinical study showed that NSCLC harboring EML4-ALK rearrangements displayed higher glucose metabolism compared to EML4-ALK-negative NSCLC. In the current work, we presented evidence that EML4-ALK is coupled to overexpression of hexokinase II (HK2), one of the rate-limiting enzymes of the glycolytic pathway. The link from EML4-ALK to HK2 upregulation is essential for a high rate of glycolysis and proliferation of EML4-ALK-rearranged NSCLC cells. We identified hypoxia-inducible factor 1α (HIF1α) as a key transcription factor to drive HK2 gene expression in normoxia in these cells. EML4-ALK induced hypoxia-independent but glucose-dependent accumulation of HIF1α protein via both transcriptional activation of HIF1α mRNA and the PI3K-AKT pathway to enhance HIF1α protein synthesis. The EML4-ALK-mediated upregulation of HIF1α, HK2 and glycolytic metabolism was also highly active in vivo as demonstrated by FDG-PET imaging of xenografts grown from EML4-ALK-positive NSCLC cells. Our data reveal a novel EML4-ALK-HIF1α-HK2 cascade to enhance glucose metabolism in EML4-ALK-positive NSCLC. PMID:27132509

  17. Targeting autophagy enhances the anti-tumoral action of crizotinib in ALK-positive anaplastic large cell lymphoma

    PubMed Central

    Desquesnes, Aurore; Le Gonidec, Sophie; AlSaati, Talal; Beau, Isabelle; Lamant, Laurence; Meggetto, Fabienne; Espinos, Estelle; Codogno, Patrice; Brousset, Pierre; Giuriato, Sylvie

    2015-01-01

    Anaplastic Lymphoma Kinase-positive Anaplastic Large Cell Lymphomas (ALK+ ALCL) occur predominantly in children and young adults. Their treatment, based on aggressive chemotherapy, is not optimal since ALCL patients can still expect a 30% 2-year relapse rate. Tumor relapses are very aggressive and their underlying mechanisms are unknown. Crizotinib is the most advanced ALK tyrosine kinase inhibitor and is already used in clinics to treat ALK-associated cancers. However, crizotinib escape mechanisms have emerged, thus preventing its use in frontline ALCL therapy. The process of autophagy has been proposed as the next target for elimination of the resistance to tyrosine kinase inhibitors. In this study, we investigated whether autophagy is activated in ALCL cells submitted to ALK inactivation (using crizotinib or ALK-targeting siRNA). Classical autophagy read-outs such as autophagosome visualization/quantification by electron microscopy and LC3-B marker turn-over assays were used to demonstrate autophagy induction and flux activation upon ALK inactivation. This was demonstrated to have a cytoprotective role on cell viability and clonogenic assays following combined ALK and autophagy inhibition. Altogether, our results suggest that co-treatment with crizotinib and chloroquine (two drugs already used in clinics) could be beneficial for ALK-positive ALCL patients. PMID:26338968

  18. ALK gene rearranged lung adenocarcinomas: molecular genetics and morphology in cohort of patients from North India.

    PubMed

    Bal, Amanjit; Singh, Navneet; Agarwal, Parimal; Das, Ashim; Behera, Digambar

    2016-10-01

    ALK gene rearrangement in the lung adenocarcinomas is the second most common (1.6-11.7% of NSCLC) targetable genomic change after EGFR mutations. However, the prevalence and clinicopathological features of ALK-rearranged lung adenocarcinomas from North India are lacking. A total of 240 cases of lung adenocarcinoma were screened for EGFR mutations and for ALK expression. Smoking status, TNM stage, and treatment response were recorded in all cases. Out of 240 cases screened, 37 cases were positive for EGFR mutations and 17 cases (7.08%) showed ALK positivity with immunohistochemistry and break-apart FISH. On excluding 37 EGFR mutation-positive cases, the incidence of ALK-positive adenocarcinoma appears to be higher (17/203 cases, 8.03%). Eight were men and nine were women with mean age of 51.7 years. Majority (62.5%) were non-smokers and had unresectable disease (70.6% stage IV, 17.6% IIIB). The morphological patterns noted were solid (12 cases), papillary (four cases), and micropapillary (one case). Signet ring (two cases) and clear cell change (one cases) were noted. Out of five patients who received crizotinib, three had partial response and two had stable disease. ALK-rearranged lung adenocarcinomas account for a minor proportion of NSCLC with prevalence similar to that reported in literature. However, as contrast to published data in our series, patients were in older age group and had solid and papillary pattern on morphology with an aggressive course.

  19. A large, single-center, real-world study of clinicopathological characteristics and treatment in advanced ALK-positive non-small-cell lung cancer.

    PubMed

    Chen, Gang; Chen, Xi; Zhang, Yaxiong; Yan, Fang; Fang, Wenfeng; Yang, Yunpeng; Hong, Shaodong; Miao, Siyu; Wu, Manli; Huang, Xiaodan; Luo, Youli; Zhou, Cong; Gong, Run; Huang, Yan; Zhou, Ningning; Zhao, Hongyun; Zhang, Li

    2017-04-04

    Crizotinib has achieved astonishing success in advanced non-small-cell lung cancer (NSCLC) patients harboring anaplastic lymphoma kinase (ALK) rearrangement. However, no real-world studies described the clinicopathological characteristics and treatment of such patients in China. Patients were consecutively collected from Sun Yat-sen University Cancer Center. Chi-square test was applied to explore the relationship between ALK fusion status and metastasis sites. Kaplan-Meier methods and multivariable analyses were used to estimate progression-free survival (PFS). A total of 291 advanced NSCLC patients (ALK (+), N = 97; both ALK & epidermal growth factor receptor (EGFR) (-), N = 194) were enrolled. The occurrence of brain metastasis in ALK-positive patients was significantly higher than double-negative ones both at baseline (26.5% vs. 16.5%, P = 0.038) and during treatment (25.8% vs. 11.9%, P = 0.003), but opposite for pleural effusion (6.2% vs. 26.9%, P < 0.001 at baseline; 3.1% vs. 10.3%, P = 0.031 during treatment). ALK-positive patients of 53.6% used crizotinib, whereas others only received chemotherapy (37.1%) or supportive care (9.3%). Usage of crizotinib prolonged PFS compared with chemotherapy in ALK-positive patients (median PFS 17.6 m vs. 4.8 m, P < 0.001). ALK-positive NSCLC had more brain metastasis and less pleural effusion than double-negative ones. Crizotinib showed better PFS than chemotherapy in advanced ALK-positive NSCLC at any line. However, half advanced ALK-positive patients never received crizotinib, which was grim and need improving.

  20. An interaction map of small-molecule kinase inhibitors with anaplastic lymphoma kinase (ALK) mutants in ALK-positive non-small cell lung cancer.

    PubMed

    Ai, Xinghao; Shen, Shengping; Shen, Lan; Lu, Shun

    2015-05-01

    Human anaplastic lymphoma kinase (ALK) has become a well-established target for the treatment of ALK-positive non-small cell lung cancer (NSCLC). Here, we have profiled seven small-molecule inhibitors, including 2 that are approved drugs, against a panel of clinically relevant mutations in ALK tyrosine kinase (TK) domain, aiming at a comprehensive understanding of molecular mechanism and biological implication underlying inhibitor response to ALK TK mutation. We find that (i) the gatekeeper mutation L1196M causes crizotinib resistance by simultaneously increasing and decreasing the binding affinities of, respectively, ATP and inhibitor to ALK, whereas the secondary mutation C1156Y, which is located far away from the ATP-binding site of ALK TK domain, causes the resistance by inducing marked allosteric effect on the site, (ii) the 2nd and 3rd generation kinase inhibitors exhibit relatively high sensitivity towards ALK mutants as compared to 1st generation inhibitors, (iii) the pan-kinase inhibitor staurosporine is insensitive for most mutations due to its high structural compatibility, and (iv) ATP affinity to ALK is generally reduced upon most clinically relevant mutations. Furthermore, we also identify six novel mutation-inhibitor pairs that are potentially associated with drug resistance. In addition, the G1202R and C1156Y mutations are expected to generally cause resistance for many existing inhibitors, since they can address significant effect on the geometric shape and physicochemical property of ALK active pocket.

  1. Efficiency of Crizotinib on an ALK-Positive Inflammatory Myofibroblastic Tumor of the Central Nervous System: A Case Report

    PubMed Central

    Chennouf, Anas; Arslanian, Elizabeth; Roberge, David; Berthelet, France; Bojanowski, Michel; Bahary, Jean-Paul; Masucci, Laura; Belanger, Karl; Florescu, Marie

    2017-01-01

    Inflammatory myofibroblastic tumors (IMT) of the central nervous system (CNS) are rare entities that have a predilection for local recurrences. Approximately half of the inflammatory myofibroblastic tumors contain translocations that result in the over-expression of the anaplastic lymphoma kinase (ALK) gene. We hereby present the case of a patient diagnosed with a left parieto-occipital IMT that recurred after multiple surgeries and radiotherapy. Immuno-histochemical examination of the tumor demonstrated ALK overexpression and the presence of an ALK rearrangement observed in lung cancers. The patient was subsequently started on an ALK inhibitor. A response evaluation criteria in solid tumors (RECIST) partial response was observed by the seventh month of ALK inhibition and the tumor remained in control for 14 months. The current case reiterates the activity of ALK inhibitors within the CNS and suggests that radiotherapy may potentiate the permeability of ALK inhibitors in CNS tumors addicted to ALK signalling.

  2. ALK-positive anaplastic large cell lymphoma limited to the skin: clinical, histopathological and molecular analysis of 6 pediatric cases. A report from the ALCL99 study.

    PubMed

    Oschlies, Ilske; Lisfeld, Jasmin; Lamant, Laurence; Nakazawa, Atsuko; d'Amore, Emanuele S G; Hansson, Ulrika; Hebeda, Konnie; Simonitsch-Klupp, Ingrid; Maldyk, Jadwiga; Müllauer, Leonhard; Tinguely, Marianne; Stücker, Markus; Ledeley, Marie-Cecile; Siebert, Reiner; Reiter, Alfred; Brugières, Laurence; Klapper, Wolfram; Woessmann, Wilhelm

    2013-01-01

    Anaplastic large cell lymphomas are peripheral T-cell lymphomas that are characterized by a proliferation of large anaplastic blasts expressing CD30. In children, systemic anaplastic large cell lymphomas often present at advanced clinical stage and harbor translocations involving the anaplastic lymphoma kinase (ALK) gene leading to the expression of chimeric anaplastic lymphoma kinase (ALK)-fusion proteins. Primary cutaneous anaplastic large cell lymphoma is regarded as an ALK-negative variant confined to the skin and is part of the spectrum of primary cutaneous CD30-positive T-cell lymphoproliferative disorders. Thirty-three of 487 pediatric patients registered within the Anaplastic Large Cell Lymphoma-99 trial (1999 to 2006) presented with a skin limited CD30-positive lympho-proliferative disorder. In 23 of the 33 patients, material for international histopathological review was available, and the cases were studied for histopathological, immunophenotypical and clinical features as well as for breaks within the ALK gene. Five of 23 cases and one additional case (identified after closure of the trial) expressed ALK-protein. Complete staging excluded any other organ involvement in all children. Expression of ALK proteins was demonstrated by immunohistochemistry in all cases and the presence of breaks of the ALK gene was genetically confirmed in 5 evaluable cases. The histopathological and clinical picture of these skin-restricted ALK-positive lymphomas was indistinguishable from that of cutaneous anaplastic large cell lymphoma. Five children presented with a single skin lesion that was completely resected in 4 and incompletely resected in one. Three of these patients received no further therapy, 2 additional local radiotherapy, and one chemotherapy. All children remain in complete remission with a median follow up of seven years (range 1-8 years). We present 6 pediatric cases of ALK-positive primary cutaneous anaplastic large cell lymphomas. After thorough

  3. A patient previously treated with ALK inhibitors for central nervous system lesions from ALK rearranged lung cancer: a case report

    PubMed Central

    Kashima, Jumpei; Okuma, Yusuke; Hishima, Tsunekazu

    2016-01-01

    Background Patients with anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) are now preferentially treated with tyrosine kinase inhibitors (TKIs). However, patients treated with ALK inhibitors end up with acquired resistance. Case presentation We present a patient with recurrent ALK-rearranged NSCLC that developed multiple brain metastases and meningitis carcinomatosa after sequential treatment with several lines of cytotoxic chemotherapy, crizotinib, and alectinib. After the patient underwent retreatment with crizotinib as salvage therapy because of poor performance status, the intracranial metastatic foci and meningeal thickening were shrank within 1 week. Conclusion Our experience with this case suggests that alectinib may restore sensitivity to crizotinib or amplified pathway such as MET which bestowed alectinib resistance was inhibited with crizotinib. PMID:27785052

  4. Imaging Characteristics of Driver Mutations in EGFR, KRAS, and ALK among Treatment-Naïve Patients with Advanced Lung Adenocarcinoma

    PubMed Central

    Park, Jangchul; Kobayashi, Yoshihisa; Urayama, Kevin Y.; Yamaura, Hidekazu; Yatabe, Yasushi; Hida, Toyoaki

    2016-01-01

    This study aimed to identify the computed tomography characteristics of treatment-naïve patients with lung adenocarcinoma and known driver mutations in EGFR, KRAS, or ALK. Patients with advanced lung adenocarcinoma (stage IIIB–IV) and known mutations in EGFR, KRAS, or ALK were assessed. The radiological findings for the main tumor and intra-thoracic status were retrospectively analyzed in each group, and the groups’ characteristics were compared. We identified 265 treatment-naïve patients with non-small-cell carcinoma, who had EGFR mutations (n = 159), KRAS mutations (n = 55), or ALK rearrangements (n = 51). Among the three groups, we evaluated only patients with stage IIIB–IV lung adenocarcinoma who had EGFR mutations (n = 126), KRAS mutations (n = 35), or ALK rearrangements (n = 47). We found that ground-glass opacity at the main tumor was significantly more common among EGFR-positive patients, compared to ALK-positive patients (p = 0.009). Lymphadenopathy was significantly more common among ALK-positive patients, compared to EGFR-positive patients (p = 0.003). Extranodal invasion was significantly more common among ALK-positive patients, compared to EGFR-positive patients and KRAS-positive patients (p = 0.001 and p = 0.049, respectively). Lymphangitis was significantly more common among ALK-positive patients, compared to EGFR-positive patients (p = 0.049). Pleural effusion was significantly less common among KRAS-positive patients, compared to EGFR-positive patients and ALK-positive patients (p = 0.046 and p = 0.026, respectively). Lung metastases were significantly more common among EGFR-positive patients, compared to KRAS-positive patients and ALK-positive patients (p = 0.007 and p = 0.04, respectively). In conclusion, EGFR mutations were associated with ground-glass opacity, KRAS-positive tumors were generally solid and less likely to metastasize to the lung and pleura, and ALK-positive tumors tended to present with lymphadenopathy, extranodal

  5. Alectinib's activity against CNS metastases from ALK-positive non-small cell lung cancer: a single institution case series.

    PubMed

    Metro, Giulio; Lunardi, Gianluigi; Bennati, Chiara; Chiarini, Pietro; Sperduti, Isabella; Ricciuti, Biagio; Marcomigni, Luca; Costa, Cinzia; Crinò, Lucio; Floridi, Piero; Gori, Stefania; Chiari, Rita

    2016-09-01

    In the present study we assessed the activity of the next-generation anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (-TKI) alectinib, in patients with ALK-postive, advanced non-small cell lung cancer (NSCLC) and central nervous system (CNS) metastases. NSCLCs with ALK-positive disease, as assessed by fluorescence in situ hybridization, and CNS metastases were treated with alectinib 600 mg BID. Included patients were followed prospectively in order to evaluate the efficacy of the drug, with particular emphasis on activity in the CNS. Eleven consecutive patients were enrolled. The majority of them were pretreated with crizotinib (n = 10, 90.9 %), and cranial radiotherapy (n = 8, 72.7 %). Six of the seven patients with measurable CNS disease experienced a CNS response, including three patients who were naïve for cranial radiation. Median duration of response was 8 months. For the whole population, median CNS-progression-free survival (-PFS), systemic-PFS, overall-PFS, overall survival, and 1-year survival were 8, 11, 8, 13 months, and 31.1 %, respectively. Two patients experiencing a CNS response were assessed for alectinib's concentrations in serum and cerebro-spinal fluid (CSF), and showed a CSF-to-serum ratio ranging from 0.001 to 0.003 ng/mL. Alectinib is highly active against CNS metastases from ALK-positive NSCLCs, irrespective of prior treatment(s) with ALK-TKI(s) and/or cranial radiotherapy. The low CSF-to-serum ratio of alectinib suggests that measuring the concentrations of the drug in the CSF may not be a reliable surrogate of its distribution into the CNS.

  6. ALK: a tyrosine kinase target for cancer therapy

    PubMed Central

    Holla, Vijaykumar R.; Elamin, Yasir Y.; Bailey, Ann Marie; Johnson, Amber M.; Litzenburger, Beate C.; Khotskaya, Yekaterina B.; Sanchez, Nora S.; Zeng, Jia; Shufean, Md Abu; Shaw, Kenna R.; Mendelsohn, John; Mills, Gordon B.; Meric-Bernstam, Funda; Simon, George R.

    2017-01-01

    The anaplastic lymphoma kinase (ALK) gene plays an important physiologic role in the development of the brain and can be oncogenically altered in several malignancies, including non-small-cell lung cancer (NSCLC) and anaplastic large cell lymphomas (ALCL). Most prevalent ALK alterations are chromosomal rearrangements resulting in fusion genes, as seen in ALCL and NSCLC. In other tumors, ALK copy-number gains and activating ALK mutations have been described. Dramatic and often prolonged responses are seen in patients with ALK alterations when treated with ALK inhibitors. Three of these—crizotinib, ceritinib, and alectinib—are now FDA approved for the treatment of metastatic NSCLC positive for ALK fusions. However, the emergence of resistance is universal. Newer ALK inhibitors and other targeting strategies are being developed to counteract the newly emergent mechanism(s) of ALK inhibitor resistance. This review outlines the recent developments in our understanding and treatment of tumors with ALK alterations. PMID:28050598

  7. ALK Positive Anaplastic Large Cell Lymphoma Presenting as Extensive Bone Involvement

    PubMed Central

    Gajendra, Smeeta; Lipi, Lipika; Goel, Shalini; Misra, Ruchira

    2015-01-01

    Anaplastic lymphoma kinase (ALK) positive Anaplastic large cell lymphoma (ALCL) represents approximately 2% of all Non-Hodgkin’s lymphomas that commonly involves nodal as well as a wide variety of extra nodal sites, as skin, soft tissue, bones and lungs, although primary or secondary involvement of bone is rare. Herein, we report a case of 14-year-old female child presented as extensive bony involvement with a clinical diagnosis of bone tumour/ small round cell tumour, which was proved to be ALK positive ALCL on histopathological examination. PMID:25738071

  8. Alectinib induced CNS radiation necrosis in an ALK+NSCLC patient with a remote (7 years) history of brain radiation.

    PubMed

    Ou, Sai-Hong Ignatius; Weitz, Michael; Jalas, John R; Kelly, Daniel F; Wong, Vanessa; Azada, Michele C; Quines, Oliver; Klempner, Samuel J

    2016-06-01

    Alectinib is a second generation ALK inhibitor that has significant clinical activity in central nervous system (CNS) metastases in anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). Pseudoprogression (PsP) due to radiation necrosis during alecitnib treatment of central nervous system (CNS) metastases from ALK-rearranged NSCLC as been reported. Hence, distinguishing radiation-related PsP from alectinib-induced radiographic changes is important to avoid erroneous early trial discontinuation and abandonment of an effective treatment. However, it remains difficult to assess casuality of radiation necrosis is related to recent direct radiation or induced by alectinib treatment or both. It is also unknown how long from previous radiation can alectinib still induce radiation necrosis. Here we reported a crizotinib-refractory ALK-positive NSCLC patient who develop radiation necrosis in one of his metastatic CNS lesions after approximately 12 months of alectinib treatment who otherwise had on-going CNS response on alectinib. His most recent radiation to his CNS metastases was 7 years prior to the start of alectinib. This case illustrates that in the setting of pror CNS radiation, given the significant clinical activity of alectinib in CNS metastases in ALK-positive NSCLC patients the risk of CNS radiation necrosis remains long after previous radiation to the CNS metastases has been completed and can occur after durable response of treatment.

  9. Insights into brain metastasis in patients with ALK+ lung cancer: is the brain truly a sanctuary?

    PubMed

    Toyokawa, Gouji; Seto, Takashi; Takenoyama, Mitsuhiro; Ichinose, Yukito

    2015-12-01

    Anaplastic lymphoma kinase (ALK) has been identified to exert a potent transforming activity through its rearrangement in non-small cell lung cancer (NSCLC), and patients (pts) with ALK rearrangement can be treated more successfully with ALK inhibitors, such as crizotinib, alectinib, and ceritinib, than with chemotherapy. Despite the excellent efficacy of ALK inhibitors, resistance to these drugs is inevitably encountered in most ALK-rearranged pts. Cases of resistance are subtyped into three groups, i.e., systemic, oligo, and central nervous system (CNS) types, with the CNS being used to be considered a sanctuary. With regard to the management of CNS lesions in pts with ALK+ NSCLC, a growing body of evidence has gradually demonstrated the intracranial (IC) efficacy of ALK inhibitor (ALKi) in ALK+ NSCLC pts with brain metastases (BMs). Although the efficacy of crizotinib for the CNS lesions remains controversial, a recent retrospective investigation of ALK+ pts with BM enrolled in PROFILE 1005 and PROFILE 1007 demonstrated that crizotinib is associated with a high disease control rate for BM. However, BM comprises the most common site of progressive disease in pts with or without baseline BMs, which is a serious problem for crizotinib. Furthermore, alectinib can be used to achieve strong and long-lasting inhibitory effects on BM. In addition to alectinib, the IC efficacy of other next-generation ALK inhibitors, such as ceritinib, AP26113 and PF-06463922, has been demonstrated. In this article, we review the latest evidence regarding the BM and IC efficacy of ALK inhibitors in pts with ALK+ NSCLC.

  10. Novel ALK fusion partners in lung cancer.

    PubMed

    Iyevleva, Aglaya G; Raskin, Grigory A; Tiurin, Vladislav I; Sokolenko, Anna P; Mitiushkina, Natalia V; Aleksakhina, Svetlana N; Garifullina, Aigul R; Strelkova, Tatiana N; Merkulov, Valery O; Ivantsov, Alexandr O; Kuligina, Ekatherina Sh; Pozharisski, Kazimir M; Togo, Alexandr V; Imyanitov, Evgeny N

    2015-06-28

    Detection of ALK rearrangements in patients with non-small cell lung cancer (NSCLC) presents a significant technical challenge due to the existence of multiple translocation partners and break-points. To improve the performance of PCR-based tests, we utilized the combination of 2 assays, i.e. the variant-specific PCR for the 5 most common ALK rearrangements and the test for unbalanced 5'/3'-end ALK expression. Overall, convincing evidence for the presence of ALK translocation was obtained for 34/400 (8.5%) cases, including 14 EML4ex13/ALKex20, 12 EML4ex6/ALKex20, 3 EML4ex18/ALKex20, 2 EML4ex20/ALKex20 variants and 3 tumors with novel translocation partners. 386 (96.5%) out of 400 EGFR mutation-negative NSCLCs were concordant for both tests, being either positive (n = 26) or negative (n = 360) for ALK translocation; 49 of these samples (6 ALK+, 43 ALK-) were further evaluated by FISH, and there were no instances of disagreement. Among the 14 (3.5%) "discordant" tumors, 5 demonstrated ALK translocation by the first but not by the second PCR assay, and 9 had unbalanced ALK expression in the absence of known ALK fusion variants. 5 samples from the latter group were subjected to FISH, and the presence of translocation was confirmed in 2 cases. Next generation sequencing analysis of these 2 samples identified novel translocation partners, DCTN1 and SQSTM1; furthermore, the DCTN1/ALK fusion was also found in another NSCLC sample with unbalanced 5'/3'-end ALK expression, indicating a recurrent nature of this translocation. We conclude that the combination of 2 different PCR tests is a viable approach for the diagnostics of ALK rearrangements. Systematic typing of ALK fusions is likely to reveal new NSCLC-specific ALK partners.

  11. Three-Year Follow-Up of an Alectinib Phase I/II Study in ALK-Positive Non-Small-Cell Lung Cancer: AF-001JP.

    PubMed

    Tamura, Tomohide; Kiura, Katsuyuki; Seto, Takashi; Nakagawa, Kazuhiko; Maemondo, Makoto; Inoue, Akira; Hida, Toyoaki; Yoshioka, Hiroshige; Harada, Masao; Ohe, Yuichiro; Nogami, Naoyuki; Murakami, Haruyasu; Kuriki, Hiroshi; Shimada, Tadashi; Tanaka, Tomohiro; Takeuchi, Kengo; Nishio, Makoto

    2017-03-15

    Purpose Alectinib is an anaplastic lymphoma kinase (ALK) -specific kinase inhibitor that seems to be effective against non-small-cell lung cancer (NSCLC) with a variety of ALK mutations. The primary analysis of AF-001JP reported a promising overall response rate. To assess progression-free survival (PFS) and overall survival (OS), patients from the phase II part of AF-001JP were followed up for approximately 3 years. Patients and Methods Oral alectinib 300 mg was administered twice per day to patients with ALK inhibitor-naïve, ALK-positive NSCLC who had progressed after one or more regimens of previous chemotherapy. In this long-term follow-up, efficacy (PFS, OS), correlation between tumor shrinkage and PFS, safety of alectinib, and relief of cancer symptoms were evaluated. Results At the updated data cutoff (September 10, 2015; first patient in August 30, 2011, last patient in April 18, 2012), 25 of 46 phase II patients were still receiving alectinib. Disease progression was confirmed in 18 patients (39%); median PFS was not reached (3-year PFS rate, 62%; 95% CI, 45 to 75). Fourteen patients had brain metastases at baseline; of these, 6 remained in the study without CNS and systemic progression. Tumor shrinkage and PFS showed no correlation. The 3-year OS rate was 78% (13 events). The most common treatment-related adverse event (all grades) was increased blood bilirubin (36.2%). Most cancer symptoms were relieved early, and medication for symptoms was dramatically decreased during alectinib therapy. Conclusion Alectinib was effective in this 3-year follow-up with a favorable safety profile over a long administration period in ALK-positive NSCLC without previous ALK inhibitor treatment.

  12. A novel Patient Derived Tumorgraft model with TRAF1-ALK Anaplastic Large Cell Lymphoma translocation

    PubMed Central

    Abate, Francesco; Todaro, Maria; van der Krogt, Jo-Anne; Boi, Michela; Landra, Indira; Machiorlatti, Rodolfo; Tabbo’, Fabrizio; Messana, Katia; Barreca, Antonella; Novero, Domenico; Gaudiano, Marcello; Aliberti, Sabrina; Di Giacomo, Filomena; Tousseyn, Thomas; Lasorsa, Elena; Crescenzo, Ramona; Bessone, Luca; Ficarra, Elisa; Acquaviva, Andrea; Rinaldi, Andrea; Ponzoni, Maurilio; Longo, Dario Livio; Aime, Silvio; Cheng, Mangeng; Ruggeri, Bruce; Piccaluga, Pier Paolo; Pileri, Stefano; Tiacci, Enrico; Falini, Brunangelo; Pera-Gresely, Benet; Cerchietti, Leandro; Iqbal, Javeed; Chan, Wing C; Shultz, Leonard D.; Kwee, Ivo; Piva, Roberto; Wlodarska, Iwona; Rabadan, Raul; Bertoni, Francesco; Inghirami, Giorgio

    2016-01-01

    Although Anaplastic Large Cell Lymphomas (ALCL) carrying Anaplastic Lymphoma Kinase (ALK) have a relatively good prognosis, aggressive forms exist. We have identified a novel translocation, causing the fusion of the TRAF1 and ALK genes, in one patient who presented with a leukemic ALK+ ALCL (ALCL-11). To uncover the mechanisms leading to high-grade ALCL, we developed a human Patient Derived Tumorgraft (hPDT) line. Molecular characterization of primary and PDT cells demonstrated the activation of ALK and of NFkB pathways. Genomic studies of ALCL-11 showed the TP53 loss and the in vivo subclonal expansion of lymphoma cells lacking PRDM1/Blimp-1 and with c-MYC gene amplification. The treatment with proteasome inhibitors of TRAF1-ALK cells led to down-regulation of p50/p52 and lymphoma growth inhibition. Moreover a NFkB gene set classifier stratified ALCL in distinct subsets with different clinical outcome. Moreover, a selective ALK inhibitor (CEP28122) resulted in a significant clinical response of hPDT mice, but the disease could not be eradicated. These data indicate that the activation of NFkB signaling contributes to the neoplastic phenotype of TRAF1-ALK ALCL. ALCL hPDTs are invaluable to validate the role of druggable molecules, predict therapeutic responses and are helpful tools for the implementation of patient specific therapies. PMID:25533804

  13. Clinical outcomes of advanced non-small-cell lung cancer patients with EGFR mutation, ALK rearrangement and EGFR/ALK co-alterations

    PubMed Central

    Chen, Hua-Jun; Zhou, Qing; Yan, Li-Xu; Xie, Zhi; Su, Jian; Chen, Zhi-Hong; Tu, Hai-Yan; Yan, Hong-Hong; Wang, Zhen; Xu, Chong-Rui; Jiang, Ben-Yuan; Wang, Bin-Chao; Bai, Xiao-Yan; Zhong, Wen-Zhao; Wu, Yi-Long; Yang, Jin-Ji

    2016-01-01

    The co-occurrence of epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements constitutes a rare molecular subtype of non-small-cell lung cancer (NSCLC). Herein, we assessed the clinical outcomes and incidence of acquired resistance to tyrosine kinase inhibitors (TKIs) in this subtype. So we enrolled 118 advanced NSCLC treated with TKIs. EGFR mutations and ALK rearrangements were detected by DNA sequencing or Scorpion amplification refractory mutation system and fluorescence in situ hybridization respectively. Immunohistochemistry was used to evaluate the activation of associated proteins. We found that nine in ten patients with EGFR/ALK co-alterations had good response with first-line EGFR TKI, and the objective response rate (ORR) of EGFR TKIs was 80% (8/10) for EGFR/ALK co-altered and 65.5% (55/84) for EGFR-mutant (P = 0.57), with a median progression-free survival (PFS) of 11.2 and 13.2 months, (hazard ratio [HR]=0.95, 95% [CI], 0.49-1.84, P= 0.87). ORR of crizotinib was 40% (2/5) for EGFR/ALK co-altered and 73.9% (17/23) for ALK-rearranged (P= 0.29), with a median PFS of 1.9 and 6.9 months (hazard ratio [HR], 0.40; 95% [CI] 0.15-1.10, P = 0.08). The median overall survival (OS) was 21.3, 23.7, and 18.5 months in EGFR-mutant, ALK-rearranged, and EGFR/ALK co-altered (P= 0.06), and there existed a statistically significant difference in OS between ALK-rearranged and EGFR/ALK co-altered (P=0.03). Taken together, the first-line EGFR-TKI might be the reasonable care for advanced NSCLC harbouring EGFR/ALK co-alterations, whether or nor to use sequential crizotinib should be guided by the status of ALK rearrangement and the relative level of phospho-EGFR and phospho-ALK. PMID:27533086

  14. Uncommon features of surgically resected ALK-positive cavitary lung adenocarcinoma: a case report.

    PubMed

    Takamori, Shinkichi; Yamaguchi, Masafumi; Taguchi, Kenichi; Edagawa, Makoto; Shimamatsu, Shinichiro; Toyozawa, Ryo; Nosaki, Kaname; Hirai, Fumihiko; Seto, Takashi; Takenoyama, Mitsuhiro; Ichinose, Yukito

    2017-12-01

    Some features found on chest computed tomography (CT), such as central tumor location, large pleural effusion, and the absence of a pleural tail, and a patient age of less than 60 years, have been suggested to be useful in predicting anaplastic lymphoma kinase (ALK) rearrangement in patients with non-small cell lung cancer (NSCLC).A 68-year-old female patient with a history of gynecological treatment was found to have a cavitary mass in the right lower lobe on an annual chest roentgenogram. The tumor was located in the peripheral area with a pleural tail showing no pleural effusion. In addition, two pure ground-glass-opacity nodules (p-GGNs) in the right upper lobe of the lung were detected on consecutive chest CT scans. The patient underwent right lower lobectomy, partial resection of the right upper lobe, and hilar mediastinal lymph node dissection for complete resection of each tumor. The pathological diagnosis was invasive mucinous adenocarcinoma with signet-ring cells for the cavitary mass in the right lower lobe and invasive adenocarcinoma for the rest of the p-GGNs; subcarinal lymph node metastasis was also detected. The ALK rearrangement was detected by fluorescence in situ hybridization from the cavitary mass. The patient underwent four cycles of cisplatin and vinorelbine chemotherapy as standard adjuvant chemotherapy for pStage III NSCLC. The ALK fusion gene status of NSCLC with atypical CT features should also be investigated.

  15. The analysis of ALK gene rearrangement by fluorescence in situ hybridization in non-small cell lung cancer patients

    PubMed Central

    Krawczyk, Paweł Adam; Ramlau, Rodryg Adam; Szumiło, Justyna; Kozielski, Jerzy; Kalinka-Warzocha, Ewa; Bryl, Maciej; Knopik-Dąbrowicz, Alina; Spychalski, Łukasz; Szczęsna, Aleksandra; Rydzik, Ewelina; Milanowski, Janusz

    2013-01-01

    Introduction ALK gene rearrangement is observed in a small subset (3–7%) of non-small cell lung cancer (NSCLC) patients. The efficacy of crizotinib was shown in lung cancer patients harbouring ALK rearrangement. Nowadays, the analysis of ALK gene rearrangement is added to molecular examination of predictive factors. Aim of the study The frequency of ALK gene rearrangement as well as the type of its irregularity was analysed by fluorescence in situ hybridisation (FISH) in tissue samples from NSCLC patients. Material and methods The ALK gene rearrangement was analysed in 71 samples including 53 histological and 18 cytological samples. The analysis could be performed in 56 cases (78.87%), significantly more frequently in histological than in cytological materials. The encountered problem with ALK rearrangement diagnosis resulted from the scarcity of tumour cells in cytological samples, high background fluorescence noises and fragmentation of cell nuclei. Results The normal ALK copy number without gene rearrangement was observed in 26 (36.62%) patients ALK gene polysomy without gene rearrangement was observed in 25 (35.21%) samples while in 3 (4.23%) samples ALK gene amplification was found. ALK gene rearrangement was observed in 2 (2.82%) samples from males, while in the first case the rearrangement coexisted with ALK amplification. In the second case, signet-ring tumour cells were found during histopathological examination and this patient was successfully treated with crizotinib with partial remission lasting 16 months. Conclusions FISH is a useful technique for ALK gene rearrangement analysis which allows us to specify the type of gene irregularities. ALK gene examination could be performed in histological as well as cytological (cellblocks) samples, but obtaining a reliable result in cytological samples depends on the cellularity of examined materials. PMID:24592134

  16. Spectrum of EGFR gene mutations and ALK rearrangements in lung cancer patients in Turkey.

    PubMed

    Sag, Sebnem Ozemri; Gorukmez, Ozlem; Ture, Mehmet; Gorukmez, Orhan; Deligonul, Adem; Sahinturk, Serdar; Topak, Ali; Gulten, Tuna; Kurt, Ender; Yakut, Tahsin

    2016-01-01

    The EGFR gene and ALK rearrangements are two genetic drivers of non-small cell lung cancer (NSCLC). The frequency of EGFR mutations and ALK rearrangement varies according to not only ethnicity but also gender, smoking status and the histological type of NSCLC. In the present study, we demonstrated the distribution of EGFR mutations in 132 NSCLC patients by using a pyrosequencing technique and the distribution of ALK rearrangements in 51 NSCLC patients by using fluorescent in situ hybridization technique in Turkey. Additionally, we compared the clinicopathological data of NSCLC patients with the mutation status of EGFR in their cancerous tissues. Both EGFR mutations and ALK rearrangements were identified in 19 (14.39 %) and 1 (1.96 %) patients, respectively. We found EGFR mutations in codon 861, 719 and 858 with the ratios of 10.52 % (2/19), 10.52 % (2/19) and 31.58 % (6/19), respectively, and deletion of exon 19 in 47.37 % (9/19) of the patients. We found the frequency of EGFR mutations to be significantly higher in female patients and nonsmokers (p = 0.043, p = 0.027, respectively). Consequently, we found EGFR mutations to be more frequent in female patients and nonsmokers. Future studies on larger patient groups would provide more accurate data to exhibit the relationship between EGFR mutations and ALK rearrangements and the clinicopathological status.

  17. ALK positive Anaplastic Large Cell Lymphoma of the Thoracic Spine

    PubMed Central

    Abrego, Gabriela; García, Julio; Gilbert, Bruce; Forseen, Scott; Toscano, Michael

    2016-01-01

    Primary bone lymphoma (PBL) is an uncommon extra nodal disease that represents about 1–3% of lymphoma cases. Imaging findings are variable and non-specific. Computed tomography may demonstrate lytic lesions with sequestra and periosteal reaction. On magnetic resonance imaging, lesions are T1WI hypointense and T2WI hyperintense, related to peritumoral edema or bone marrow replacement. Rarely lesions may have associated fibrosis and show a more hypointense signal pattern on T2WI. After administration of contrast, PBL tends to enhance avidly. We present a case of a 24 years old African American female patient with history of back pain. Initial imaging examinations showed lesions involving the T12 and T11 vertebral bodies with initial negative biopsy results. One month later, the patient returned with worsening back pain, and the follow up studies depicted collapse of the T12 vertebral body. A diagnosis of anaplastic large cell lymphoma in T12 was made. A brief review of the literature, imaging and pathological findings, and treatment options are also discussed. PMID:27761194

  18. Fluorescence in situ hybridization analysis of the ALK gene in 2,045 non-small cell lung cancer patients from North-Western Spain (Galicia).

    PubMed

    Sánchez-Ares, María; Cameselle-Teijeiro, José M; Vázquez-Estévez, Sergio; Lázaro-Quintela, Martín; Vázquez-Boquete, Ángel; Afonso-Afonso, Francisco J; Casal-Rubio, Joaquín; González-Piñeiro, Ana L; Rico-Rodríguez, Yolanda; Fírvida-Pérez, José L; Ruíz-Bañobre, Juan; Couso, Elena; Santomé, Lucía; Pérez-Becerra, Raquel; García-Campelo, Rosario; Amenedo, Margarita; Azpitarte-Raposeiras, Cristina; Antúnez, José; Abdulkader, Ihab

    2016-08-01

    Identification of anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearrangements is a standard diagnostic test in patients with advanced non-small cell lung cancer (NSCLC). The current study describes the experience of ALK rearrangement detection of a referral center in the public health care system of Galicia in North-Western Spain. The fluorescence in situ hybridization (FISH) patterns of the ALK gene and the clinical and pathological features of these patients are reported. This study is also of interest for comparative purposes due to the relative geographical isolation of the area, which could have contributed to particular genetic features. A total of 2,045 tissue samples from NSCLC patients were collected between October 2010 and July 2015 and tested for ALK rearrangements by FISH. Examination of 1,686 paraffin-embedded tissue specimens and 395 cytological samples (306 cell block preparations and 53 cytological smears) was conducted, and any associations between the FISH results and clinicopathological features were assessed. The rate of successful evaluation was marginally higher in tissue samples than in cytological samples (92.9% vs. 84.1%); this difference was not significant. ALK rearrangements were identified in 82 patients(4%): 65 (79.3%) in tissue specimens, 15 (18.3%) in cell block samples and 2 (2.4%) in cytological smears. This genetic translocation appeared to be associated with a non-smoking history, younger age, female gender, stage IV and adenocarcinoma histological type. The findings demonstrate that ALK evaluation by FISH is feasible in tissue and cytological samples. The clinical and pathological features of the ALK-positive series of patients are similar to those previously reported in the literature.

  19. ALK Gene Copy Number Gain and Immunohistochemical Expression Status Using Three Antibodies in Neuroblastoma.

    PubMed

    Kim, Eun Kyung; Kim, Sewha

    2017-01-01

    Anaplastic lymphoma kinase ( ALK) gene aberrations-such as mutations, amplifications, and copy number gains-represent a major genetic predisposition to neuroblastoma (NB). This study aimed to evaluate the correlation between ALK gene copy number status, ALK protein expression, and clinicopathological parameters. We retrospectively retrieved 30 cases of poorly differentiated NB and constructed tissue microarrays (TMAs). ALK copy number changes were assessed by fluorescence in situ hybridization (FISH) assays, and ALK immunohistochemistry (IHC) testing was performed using three different antibodies (ALK1, D5F3, and 5A4 clones). ALK amplification and copy number gain were observed in 10% (3/30) and 53.3% (16/30) of the cohort, respectively. There were positive correlations between ALK copy number and IHC-positive rate in ALK1 and 5A4 antibodies ( P < 0.001 and P = 0.019, respectively). ALK1, D5F3, and 5A4 antibodies equally showed 100% sensitivity in detecting ALK amplification. However, the sensitivity for detecting copy number gain differed among the three antibodies, with 75% sensitivity in D5F3 and 0% sensitivity in ALK1. ALK-amplified NBs were correlated with synchronous MYCN amplification and chromosome 1p deletion. ALK IHC positivity was frequently observed in INSS stage IV and high-risk group patients. In conclusion, this study identified that an increase in the ALK copy number is a frequent genetic alteration in poorly differentiated NB. ALK-amplified NBs showed consistent ALK IHC positivity with all kinds of antibodies. In contrast, the detection performance of ALK copy number gain was antibody dependent, with the D5F3 antibody showing the best sensitivity.

  20. Deficient BIM Expression as a Mechanism of Intrinsic and Acquired Resistance to Targeted Therapies in EGFR-Mutant and ALK-Positive Lung Cancers

    DTIC Science & Technology

    2015-08-01

    EGFR- Mutant and ALK-Positive Lung Cancers PRINCIPAL INVESTIGATOR: Lecia Sequist MD. CONTRACTING ORGANIZATION: Massachusetts General Hospital Boston...and Acquired Resistance to Targeted Therapies in EGFR- Mutant and ALK-Positive Lung Cancers 5b. GRANT NUMBER W81XWH-13-1-0227 5c. PROGRAM ELEMENT...to a specific kinase, inhibition of that kinase often leads to cell growth arrest and apoptosis. For example, EGFR mutant and EML4-ALK lung cancers

  1. Deficient BIM Expression as a Mechanism of Intrinsic and Acquired Resistance to Targeted Therapies in EGFR-Mutant and ALK-Positive Lung Cancers

    DTIC Science & Technology

    2015-08-01

    EGFR- Mutant and ALK-Positive Lung Cancers PRINCIPAL INVESTIGATOR: Jeffrey Engelman MD PhD. CONTRACTING ORGANIZATION: Massachusetts General Hospital...Intrinsic and Acquired Resistance to Targeted Therapies in EGFR- Mutant and ALK-Positive Lung Cancers 5b. GRANT NUMBER W81XWH-13-1-0226 5c. PROGRAM...to a specific kinase, inhibition of that kinase often leads to cell growth arrest and apoptosis. For example, EGFR mutant and EML4-ALK lung cancers

  2. Activity of second-generation ALK inhibitors against crizotinib-resistant mutants in an NPM-ALK model compared to EML4-ALK

    PubMed Central

    Fontana, Diletta; Ceccon, Monica; Gambacorti-Passerini, Carlo; Mologni, Luca

    2015-01-01

    Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor involved in both solid and hematological tumors. About 80% of ALK-positive anaplastic large-cell lymphoma (ALCL) cases are characterized by the t(2;5)(p23;q35) translocation, encoding for the aberrant fusion protein nucleophosmin (NPM)-ALK, whereas 5% of non-small-cell lung cancer (NSCLC) patients carry the inv(2)(p21;p23) rearrangement, encoding for the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion. The ALK/c-MET/ROS inhibitor crizotinib successfully improved the treatment of ALK-driven diseases. However, several cases of resistance appeared in NSCLC patients, and ALK amino acid substitutions were identified as a leading cause of resistance to crizotinib. Second-generation ALK inhibitors have been developed in order to overcome crizotinib resistance. In this work, we profiled in vitro the activity of crizotinib, AP26113, ASP3026, alectinib, and ceritinib against six mutated forms of ALK associated with clinical resistance to crizotinib (C1156Y, L1196M, L1152R, G1202R, G1269A, and S1206Y) and provide a classification of mutants according to their level of sensitivity/resistance to the drugs. Since the biological activity of ALK mutations extends beyond the specific type of fusion, both NPM-ALK- and EML4-ALK-positive cellular models were used. Our data revealed that most mutants may be targeted by using different inhibitors. One relevant exception is represented by the G1202R substitution, which was highly resistant to all drugs (>10-fold increased IC50 compared to wild type) and may represent the most challenging mutation to overcome. These results provide a prediction of cross-resistance of known crizotinib-resistant mutations against all second-generation tyrosine kinase inhibitors (TKIs) clinically available, and therefore could be a useful tool to help clinicians in the management of crizotinib-resistance cases. PMID:25727400

  3. The ALK inhibitor PF-06463922 is effective as a single agent in neuroblastoma driven by expression of ALK and MYCN

    PubMed Central

    Guan, J.; Tucker, E. R.; Wan, H.; Chand, D.; Danielson, L. S.; Ruuth, K.; El Wakil, A.; Witek, B.; Jamin, Y.; Umapathy, G.; Robinson, S. P.; Johnson, T. W.; Smeal, T.; Martinsson, T.; Chesler, L.; Palmer, R. H.

    2016-01-01

    ABSTRACT The first-in-class inhibitor of ALK, c-MET and ROS1, crizotinib (Xalkori), has shown remarkable clinical efficacy in treatment of ALK-positive non-small cell lung cancer. However, in neuroblastoma, activating mutations in the ALK kinase domain are typically refractory to crizotinib treatment, highlighting the need for more potent inhibitors. The next-generation ALK inhibitor PF-06463922 is predicted to exhibit increased affinity for ALK mutants prevalent in neuroblastoma. We examined PF-06463922 activity in ALK-driven neuroblastoma models in vitro and in vivo. In vitro kinase assays and cell-based experiments examining ALK mutations of increasing potency show that PF-06463922 is an effective inhibitor of ALK with greater activity towards ALK neuroblastoma mutants. In contrast to crizotinib, single agent administration of PF-06463922 caused dramatic tumor inhibition in both subcutaneous and orthotopic xenografts as well as a mouse model of high-risk neuroblastoma driven by Th-ALKF1174L/MYCN. Taken together, our results suggest PF-06463922 is a potent inhibitor of crizotinib-resistant ALK mutations, and highlights an important new treatment option for neuroblastoma patients. PMID:27483357

  4. Phosphoproteomics reveals ALK promote cell progress via RAS/JNK pathway in neuroblastoma

    PubMed Central

    Xu, Guofeng; Zhang, Min; Wu, Yeming; Wu, Zhixiang

    2016-01-01

    Emerging evidence suggests receptor tyrosine kinase ALK as a promising therapeutic target in neuroblastoma. However, clinical trials reveal that a limited proportion of ALK-positive neuroblastoma patients experience clinical benefits from Crizotinib, a clinically approved specific inhibitor of ALK. The precise molecular mechanisms of aberrant ALK activity in neuroblastoma remain elusive, limiting the clinical application of ALK as a therapeutic target in neuroblastoma. Here, we describe a deep quantitative phosphoproteomic approach in which Crizotinib-treated neuroblastoma cell lines bearing aberrant ALK are used to investigate downstream regulated phosphoproteins. We identified more than 19,500—and quantitatively analyzed approximately 10,000—phosphorylation sites from each cell line, ultimately detecting 450–790 significantly-regulated phosphorylation sites. Multiple layers of bioinformatic analysis of the significantly-regulated phosphoproteins identified RAS/JNK as a downstream signaling pathway of ALK, independent of the ALK variant present. Further experiments demonstrated that ALK/JNK signaling could be inactivated by either ALK- or JNK-specific inhibitors, resulting in cell growth inhibition by induction of cell cycle arrest and cell apoptosis. Our study broadly defines the phosphoproteome in response to ALK inhibition and provides a resource for further clinical investigation of ALK as therapeutic target for the treatment of neuroblastoma. PMID:27732954

  5. Inhibition of Axl improves the targeted therapy against ALK-mutated neuroblastoma

    SciTech Connect

    Xu, Fei; Li, Hongling; Sun, Yong

    2014-11-28

    Highlights: • First reported Axl is co-expressed with ALK in neuroblastoma tissues and cell lines. • Axl activation promotes cell growth and impairs the efficiency of ALK inhibitor. • Further found silence of Axl leads to increased sensitivity to ALK inhibitors. • Axl inhibitor promotes the efficiency of targeted therapy in vitro and in vivo. • Axl activation should be considered in the clinical application of ALK inhibitors. - Abstract: Neuroblastoma (NB) patients harboring mutated ALK can be expected to potentially benefit from targeted therapy based on ALK tyrosine kinase inhibitor (TKI), such as crizotinib and ceritinib. However, the effect of the treatment varies with different individuals, although with the same genic changes. Axl receptor tyrosine kinase is expressed in a variety of human cancers, but little data are reported in NB, particularly in which carrying mutated ALK. In this study, we focus on the roles of Axl in ALK-mutated NB for investigating rational therapeutic strategy. We found that Axl is expressed in ALK-positive NB tissues and cell lines, and could be effectively activated by its ligand GAS6. Ligand-dependent Axl activation obviously rescued crizotinib-mediated suppression of cell proliferation in ALK-mutated NB cells. Genetic inhibition of Axl with specific small interfering RNA markedly increased the sensitivity of cells to ALK-TKIs. Furthermore, a small-molecule inhibitor of Axl significantly enhanced ALK-targeted therapy, as an increased frequency of apoptosis was observed in NB cells co-expressing ALK and Axl. Taken together, our results demonstrated that activation of Axl could lead to insensitivity to ALK inhibitors, and dual inhibition of ALK and Axl might be a potential therapeutic strategy against ALK-mutated NB.

  6. Development of potent ALK inhibitor and its molecular inhibitory mechanism against NSCLC harboring EML4-ALK proteins

    SciTech Connect

    Kang, Chung Hyo; Yun, Jeong In; Lee, Kwangho; Lee, Chong Ock; Lee, Heung Kyoung; Yun, Chang-Soo; Hwang, Jong Yeon; Cho, Sung Yun; Jung, Heejung; Kim, Pilho; Ha, Jae Du; Jeon, Jeong Hee; Choi, Sang Un; Jeong, Hye Gwang; Kim, Hyoung Rae; Park, Chi Hoon

    2015-08-28

    Here, we show the newly synthesized and potent ALK inhibitor having similar scaffold to KRCA-0008, which was reported previously, and its molecular mechanism against cancer cells harboring EML4-ALK fusion protein. Through ALK wild type enzyme assay, we selected two compounds, KRCA-0080 and KRCA-0087, which have trifluoromethyl instead of chloride in R2 position. We characterized these newly synthesized compounds by in vitro and in vivo assays. Enzyme assay shows that KRCA-0080 is more potent against various ALK mutants, including L1196M, G1202R, T1151-L1152insT, and C1156Y, which are seen in crizotinib-resistant patients, than KRCA-0008 is. Cell based assays demonstrate our compounds downregulate the cellular signaling, such as Akt and Erk, by suppressing ALK activity to inhibit the proliferation of the cells harboring EML4-ALK. Interestingly, our compounds induced strong G1/S arrest in H3122 cells leading to the apoptosis, which is proved by PARP-1 cleavage. In vivo H3122 xenograft assay, we found that KRCA-0080 shows significant reduction in tumor size compared to crizotinib and KRCA-0008 by 15–20%. Conclusively, we report a potent ALK inhibitor which shows significant in vivo efficacy as well as excellent inhibitory activity against various ALK mutants. - Highlights: • We synthesized KRCA-0008 derivatives having trifluoromethyl instead of chloride. • KRCA-0080 shows superior activity against several ALK mutants to KRCA-0008. • Cellular assays show our ALK inhibitors suppress only EML4-ALK positive cells. • Our ALK inhibitors induce G1/S arrest to lead apoptosis in H3122 cells. • KRCA-0080 has superior in vivo efficacy to crizotinib and KRCA-0008 by 15–20%.

  7. Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors

    PubMed Central

    Lindeman, Neal I.; Cagle, Philip T.; Beasley, Mary Beth; Chitale, Dhananjay Arun; Dacic, Sanja; Giaccone, Giuseppe; Jenkins, Robert Brian; Kwiatkowski, David J.; Saldivar, Juan-Sebastian; Squire, Jeremy; Thunnissen, Erik; Ladanyi, Marc

    2014-01-01

    Objective To establish evidence-based recommendations for the molecular analysis of lung cancers that are that are required to guide EGFR- and ALK-directed therapies, addressing which patients and samples should be tested, and when and how testing should be performed. Participants Three cochairs without conflicts of interest were selected, one from each of the 3 sponsoring professional societies: College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Writing and advisory panels were constituted from additional experts from these societies. Evidence Three unbiased literature searches of electronic databases were performed to capture articles published published from January 2004 through February 2012, yielding 1533 articles whose abstracts were screened to identify 521 pertinent articles that were then reviewed in detail for their relevance to the recommendations. Evidence was formally graded for each recommendation. Consensus Process Initial recommendations were formulated by the cochairs and panel members at a public meeting. Each guideline section was assigned to at least 2 panelists. Drafts were circulated to the writing panel (version 1), advisory panel (version 2), and the public (version 3) before submission (version 4). Conclusions The 37 guideline items address 14 subjects, including 15 recommendations (evidence grade A/B). The major recommendations are to use testing for EGFR mutations and ALK fusions to guide patient selection for therapy with an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) inhibitor, respectively, in all patients with advanced-stage adenocarcinoma, regardless of sex, race, smoking history, or other clinical risk factors, and to prioritize EGFR and ALK testing over other molecular predictive tests. As scientific discoveries and clinical practice outpace the completion of randomized clinical trials, evidence-based guidelines developed

  8. Analysis of nucleophosmin-anaplastic lymphoma kinase (NPM-ALK)-reactive CD8(+) T cell responses in children with NPM-ALK(+) anaplastic large cell lymphoma.

    PubMed

    K Singh, V; Werner, S; Hackstein, H; Lennerz, V; Reiter, A; Wölfel, T; Damm-Welk, C; Woessmann, W

    2016-10-01

    Cellular immune responses against the oncoantigen anaplastic lymphoma kinase (ALK) in patients with ALK-positive anaplastic large cell lymphoma (ALCL) have been detected using peptide-based approaches in individuals preselected for human leucocyte antigen (HLA)-A*02:01. In this study, we aimed to evaluate nucleophosmin (NPM)-ALK-specific CD8(+) T cell responses in ALCL patients ensuring endogenous peptide processing of ALK antigens and avoiding HLA preselection. We also examined the HLA class I restriction of ALK-specific CD8(+) T cells. Autologous dendritic cells (DCs) transfected with in-vitro-transcribed RNA (IVT-RNA) encoding NPM-ALK were used as antigen-presenting cells for T cell stimulation. Responder T lymphocytes were tested in interferon-gamma enzyme-linked immunospot (ELISPOT) assays with NPM-ALK-transfected autologous DCs as well as CV-1 in Origin with SV40 genes (COS-7) cells co-transfected with genes encoding the patients' HLA class I alleles and with NPM-ALK encoding cDNA to verify responses and define the HLA restrictions of specific T cell responses. NPM-ALK-specific CD8(+) T cell responses were detected in three of five ALK-positive ALCL patients tested between 1 and 13 years after diagnosis. The three patients had also maintained anti-ALK antibody responses. No reactivity was detected in samples from five healthy donors. The NPM-ALK-specific CD8(+) T cell responses were restricted by HLA-C-alleles (C*06:02 and C*12:02) in all three cases. This approach allowed for the detection of NPM-ALK-reactive T cells, irrespective of the individual HLA status, up to 9 years after ALCL diagnosis.

  9. Durable brain response with pulse-dose crizotinib and ceritinib in ALK-positive non-small cell lung cancer compared with brain radiotherapy.

    PubMed

    Dudnik, Elizabeth; Siegal, Tali; Zach, Leor; Allen, Aaron M; Flex, Dov; Yust-Katz, Shlomit; Limon, Dror; Hirsch, Fred R; Peled, Nir

    2016-04-01

    Crizotinib achieves excellent systemic control in anaplastic lymphoma kinase-rearranged (ALK+) non-small cell lung cancer (NSCLC); however, central nervous system (CNS) metastases frequently occur as an early event. Whole brain irradiation, the standard treatment, results in neurocognitive impairment. We present a case series of three ALK+ NSCLC patients with progressing CNS metastases who were treated with pulse-dose crizotinib followed by ceritinib. Three ALK+ NSCLC patients treated between 2011 and 2014 (two males, two never smokers, age range 20-54years, all echinoderm microtubule-associated protein-like 4/ALK rearrangement), were diagnosed with progressing cerebral disease while receiving crizotinib. Clinico-pathological characteristics, treatments, and outcomes were analyzed. In two patients the progression was limited to the CNS, and radiological evidence of leptomeningeal spread was present in one patient. Sequential use of crizotinib 500mg administered once daily (pulse-dose) followed by ceritinib on progression achieved control of the disease in the CNS for over 18 months and over 7 months in Patient 1 and Patient 2, respectively. This strategy provided durable CNS control after whole-brain radiotherapy failure in Patient 1, and allowed the whole-brain radiotherapy to be deferred in Patient 2. Limited CNS progression was documented in Patient 3 while he was on standard-dose/pulse-dose crizotinib for 15months; durable (over 7 months) complete remission was achieved with stereotactic radiotherapy and ceritinib. Manipulating the crizotinib schedule in ALK+ NSCLC patients with CNS metastases and using a novel ALK-inhibitor at the time of further progression may provide durable CNS control and allow brain radiotherapy to be deferred.

  10. Therapeutic efficacy of the bromodomain inhibitor OTX015/MK-8628 in ALK-positive anaplastic large cell lymphoma: an alternative modality to overcome resistant phenotypes

    PubMed Central

    Vurchio, Valentina; Yang, Shao Ning; Moon, John; Kwee, Ivo; Rinaldi, Andrea; Pan, Heng; Crescenzo, Ramona; Cheng, Mangeng; Cerchietti, Leandro; Elemento, Olivier; Riveiro, Maria E.; Cvitkovic, Esteban; Bertoni, Francesco; Inghirami, Giorgio

    2016-01-01

    Anaplastic large cell lymphomas (ALCL) represent a peripheral T-cell lymphoma subgroup, stratified based on the presence or absence of anaplastic lymphoma kinase (ALK) chimeras. Although ALK-positive ALCLs have a more favorable outcome than ALK-negative ALCL, refractory and/or relapsed forms are common and novel treatments are needed. Here we investigated the therapeutic potential of a novel bromodomain inhibitor, OTX015/MK-8628 in ALK-positive ALCLs. The effects of OTX015 on a panel of ALK+ ALCL cell lines was evaluated in terms of proliferation, cell cycle and downstream signaling, including gene expression profiling analyses. Synergy was tested with combination targeted therapies. Bromodomain inhibition with OTX015 led primarily to ALCL cell cycle arrest in a dose-dependent manner, along with downregulation of MYC and its downstream regulated genes. MYC overexpression did not compensate this OTX015-mediated phenotype. Transcriptomic analysis of OTX015-treated ALCL cells identified a gene signature common to various hematologic malignancies treated with bromodomain inhibitors, notably large cell lymphoma. OTX015-modulated genes included transcription factors (E2F2, NFKBIZ, FOS, JUNB, ID1, HOXA5 and HOXC6), members of multiple signaling pathways (ITK, PRKCH, and MKNK2), and histones (clusters 1-3). Combination of OTX015 with the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib led to cell cycle arrest then cell death, and combination with suboptimal doses of the ALK inhibitor CEP28122 caused cell cycle arrest. When OTX015 was associated with GANT61, a selective GLI1/2 inhibitor, C1156Y-resistant ALK ALCL growth was impaired. These findings support OTX015 clinical trials in refractory ALCL in combination with inhibitors of interleukin-2-inducible kinase or SHH/GLI1. PMID:27793034

  11. Treatment modalities for advanced ALK-rearranged non-small-cell lung cancer.

    PubMed

    Sullivan, Ivana; Planchard, David

    2016-04-01

    The ALK gene plays a key role in the pathogenesis of non-small-cell lung cancer (NSCLC). Patients with NSCLC harboring an ALK-rearrangement represent the second oncogene addiction to be identified in this disease. Crizotinib was the first ALK inhibitor showing pronounced clinical activity, and is now a reference treatment for ALK-positive NSCLC disease. However, despite initial impressive responses to crizotinib, acquired resistance almost invariably develops within 12 months. The pressing need for effective second-line agents has prompted the rapid development of next-generation ALK inhibitors. These agents, notably ceritinib and alectinib as the most developed, have a higher potency against ALK than crizotinib, along with activity against tumors harboring crizotinib-resistant mutations and potentially improved CNS penetration.

  12. ALK and ROS1 as a joint target for the treatment of lung cancer: a review.

    PubMed

    Puig de la Bellacasa, Raimon; Karachaliou, Niki; Estrada-Tejedor, Roger; Teixidó, Jordi; Costa, Carlota; Borrell, José I

    2013-04-01

    Rearrangements of the anaplastic lymphoma kinase (ALK) have been described in multiple malignancies, including non-small cell lung cancer (NSCLC). ALK fusions have gain of function properties while activating mutations in wild-type ALK can also occur within the tyrosine kinase domain. ALK rearrangements define a new molecular subtype of NSCLC that is exquisitely sensitive to ALK inhibition. Crizotinib, an orally available small molecule ATP-mimetic compound which was originally designed as a MET inhibitor, was recognized to have "off-target" anti-ALK activity and has been approved in the USA for the treatment of patients with ALK-positive NSCLC. Chromosomal rearrangements involving the ROS1 receptor tyrosine kinase have also been recently described in NSCLC, while crizotinib is currently under clinical trial in this molecular subset of NSCLC patients. The basic approaches of any computer aided drug design work in terms of structure and ligand based drug design. Details of each of these approaches should be covered with an emphasis on utilizing both in order to develop multi-targeted small-molecule kinase inhibitors. Such multi-targeted tyrosine kinase inhibitors can have antiproliferative activity against both ROS1and ALK rearranged NSCLC. Herein, we highlight the importance of targeting these proteins and the advances in optimizing more potent and selective ALK and ROS1 kinase inhibitors.

  13. ALK and ROS1 as a joint target for the treatment of lung cancer: a review

    PubMed Central

    Puig de la Bellacasa, Raimon; Karachaliou, Niki; Estrada-Tejedor, Roger; Teixidó, Jordi; Costa, Carlota

    2013-01-01

    Rearrangements of the anaplastic lymphoma kinase (ALK) have been described in multiple malignancies, including non-small cell lung cancer (NSCLC). ALK fusions have gain of function properties while activating mutations in wild-type ALK can also occur within the tyrosine kinase domain. ALK rearrangements define a new molecular subtype of NSCLC that is exquisitely sensitive to ALK inhibition. Crizotinib, an orally available small molecule ATP-mimetic compound which was originally designed as a MET inhibitor, was recognized to have “off-target” anti-ALK activity and has been approved in the USA for the treatment of patients with ALK-positive NSCLC. Chromosomal rearrangements involving the ROS1 receptor tyrosine kinase have also been recently described in NSCLC, while crizotinib is currently under clinical trial in this molecular subset of NSCLC patients. The basic approaches of any computer aided drug design work in terms of structure and ligand based drug design. Details of each of these approaches should be covered with an emphasis on utilizing both in order to develop multi-targeted small-molecule kinase inhibitors. Such multi-targeted tyrosine kinase inhibitors can have antiproliferative activity against both ROS1and ALK rearranged NSCLC. Herein, we highlight the importance of targeting these proteins and the advances in optimizing more potent and selective ALK and ROS1 kinase inhibitors. PMID:25806218

  14. Novel CAD-ALK gene rearrangement is drugable by entrectinib in colorectal cancer

    PubMed Central

    Amatu, Alessio; Somaschini, Alessio; Cerea, Giulio; Bosotti, Roberta; Valtorta, Emanuele; Buonandi, Pasquale; Marrapese, Giovanna; Veronese, Silvio; Luo, David; Hornby, Zachary; Multani, Pratik; Murphy, Danielle; Shoemaker, Robert; Lauricella, Calogero; Giannetta, Laura; Maiolani, Martina; Vanzulli, Angelo; Ardini, Elena; Galvani, Arturo; Isacchi, Antonella; Sartore-Bianchi, Andrea; Siena, Salvatore

    2015-01-01

    Background: Activated anaplastic lymphoma kinase (ALK) gene fusions are recurrent events in a small fraction of colorectal cancers (CRCs), although these events have not yet been exploited as in other malignancies. Methods: We detected ALK protein expression by immunohistochemistry and gene rearrangements by fluorescence in situ hybridisation in the ALKA-372-001 phase I study of the pan-Trk, ROS1, and ALK inhibitor entrectinib. One out of 487 CRCs showed ALK positivity with a peculiar pattern that prompted further characterisation by targeted sequencing using anchored multiplex PCR. Results: A novel ALK fusion with the carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) gene (CAD-ALK fusion gene) was identified. It resulted from inversion within chromosome 2 and the fusion of exons 1–35 of CAD with exons 20–29 of ALK. After failure of previous standard therapies, treatment of this patient with the ALK inhibitor entrectinib resulted in a durable objective tumour response. Conclusions: We describe the novel CAD-ALK rearrangement as an oncogene and provide the first evidence of its drugability as a new molecular target in CRC. PMID:26633560

  15. Fine-needle aspiration cytology yield as a basis for morphological, molecular, and cytogenetic diagnosis in alk-positive anaplastic large cell lymphoma with atypical clinical presentation.

    PubMed

    Bogdanic, Maja; Ostojic Kolonic, Slobodanka; Kaic, Gordana; Kardum Paro, Mirjana Mariana; Lasan Trcic, Ruzica; Kardum-Skelin, Ika

    2017-01-01

    ALK positive anaplastic large cell lymphoma is a T-cell lymphoma usually occurring in children and young adults. It frequently involves lymph nodes and extranodal sites and is associated with favorable prognosis. A 20-year old man was admitted for painful mass in the left axilla with overlying skin redness. Clinical presentation and US findings were highly suspicious for sarcoma. Definitive diagnosis was established cytolologically and using ancillary technologies from cytological samples. Fine needle aspiration cytology of tumor mass (lymph node conglomerate and surrounding tissue) show predominance of large, pleomorphic, atypical cells with large nuclei and vacuolised cytoplasm. Atypical cells immunocytochemically were positive for LCA, CD30, CD3, EMA, and ALK; negative for CD15 and CD56. NPM-ALK transcript was detected by reverse transcriptase-polymerase chain reaction (RT-PCT). Molecular analysis of TCRß and TCRγ genes demonstrated clonal TCR genes rearrangement. Complex karyotype with multiple numerical and structural changes was found on conventional cytogenetics. These findings excluded sarcoma and corroborated the diagnosis of ALK positive ALCL. Cutaneous involvement in ALCL can clinically mimic sarcoma, especially in cases with localized disease without B symptoms. In those cases, immunostaining, PCR, and conventional cytogenetics are helpful to exclude sarcoma. Diagn. Cytopathol. 2017;45:51-54. © 2016 Wiley Periodicals, Inc.

  16. Tackling ALK in non-small cell lung cancer: the role of novel inhibitors

    PubMed Central

    Facchinetti, Francesco; Di Maio, Massimo; Graziano, Paolo; Bria, Emilio; Rossi, Giulio; Novello, Silvia

    2016-01-01

    Crizotinib is an oral inhibitor of anaplastic lymphoma kinase (ALK) with remarkable clinical activity in patients suffering from ALK-rearranged non-small cell lung cancer (NSCLC), accounting to its superiority compared to chemotherapy. Unfortunately, virtually all ALK-rearranged tumors acquire resistance to crizotinib, frequently within one year since the treatment initiation. To date, therapeutic strategies to overcome crizotinib resistance have focused on the use of more potent and structurally different compounds. Second-generation ALK inhibitors such as ceritinib (LDK378), alectinib (CH5424802/RO5424802) and brigatinib (AP26113) have shown relevant clinical activity, consequently fostering their rapid clinical development and their approval by health agencies. The third-generation inhibitor lorlatinib (PF-06463922), selectively active against ALK and ROS1, harbors impressive biological potency; its efficacy in reversing resistance to crizotinib and to other ALK inhibitors is being proven by early clinical trials. The NTRK1-3 and ROS1 inhibitor entrectinib (RXDX-101) has been reported to act against NSCLC harboring ALK fusion proteins too. Despite the quick development of these novel agents, several issues remain to be discussed in the treatment of patients suffering from ALK-rearranged NSCLC. This position paper will discuss the development, the current evidence and approvals, as long as the future perspectives of new ALK inhibitors beyond crizotinib. Clinical behaviors of ALK-rearranged NSCLC vary significantly among patients and differential molecular events responsible of crizotinib resistance account for the most important quote of this heterogeneity. The precious availability of a wide range of active anti-ALK compounds should be approached in a critical and careful perspective, in order to develop treatment strategies tailored on the disease evolution of every single patient. PMID:27413712

  17. Primary central nervous system ALK-positive anaplastic large cell lymphoma in an adult

    PubMed Central

    Dong, Xiaoqin; Li, Jun; Huo, Na; Wang, Yan; Wu, Zhao; Lin, Xiaohong; Zhao, Hong

    2016-01-01

    Abstract Rationale: Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin lymphoma. It mostly invades lymph nodes with extranodal involvement observed in the soft tissue, bone, and skin. Patient concerns: We report a 34-year-old Chinese male patient who presented with headache, diplopia, and vomit. Cerebrospinal fluid (CSF) analysis via lumbar puncture showed elevated CSF pressure, elevated CSF protein concentrations, decreased CSF glucose and chloride concentration significantly, and pleocytosis of 68 to 350 × 106/L, in which lymphocytes and monocytes were predominant. These changes could be suggestive of tuberculous (TB) meningitis. Enhanced magnetic resonance imaging of spinal cord delineated multiple enhancing nodules in spinal cord, cauda equina, and cristae membrane, and multiple abnormal enhancing lesions in bilateral lumbar intervertebral foramen. Diagnoses: Spinal dura mater biopsy and paraffin pathology examination revealed anaplastic lymphoma kinase positive ALCL. Interventions: High-dose methotrexate, cytosine arabinoside craniospinal, and radiotherapy. Outcomes: Last follow-up on September 22, 2015 showed no evidence of tumor recurrence and the lower extremity muscle strength recovered to 4/5. Lessons: ALCL of primary central nervous system is an exceedingly rare tumor, which is usually misdiagnosed as meningitis (especially TB meningitis) according to clinical manifestation and laboratory examination. Thus closely monitoring patient's conditions and timely adjusting therapeutic regimen during treatment are necessary. PMID:27930548

  18. Crizotinib-Resistant Mutants of EML4-ALK Identified Through an Accelerated Mutagenesis Screen

    PubMed Central

    Zhang, Sen; Wang, Frank; Keats, Jeffrey; Zhu, Xiaotian; Ning, Yaoyu; Wardwell, Scott D; Moran, Lauren; Mohemmad, Qurish K; Anjum, Rana; Wang, Yihan; Narasimhan, Narayana I; Dalgarno, David; Shakespeare, William C; Miret, Juan J; Clackson, Tim; Rivera, Victor M

    2011-01-01

    Activating gene rearrangements of anaplastic lymphoma kinase (ALK) have been identified as driver mutations in non-small-cell lung cancer, inflammatory myofibroblastic tumors, and other cancers. Crizotinib, a dual MET/ALK inhibitor, has demonstrated promising clinical activity in patients with non-small-cell lung cancer and inflammatory myofibroblastic tumors harboring ALK translocations. Inhibitors of driver kinases often elicit kinase domain mutations that confer resistance, and such mutations have been successfully predicted using in vitro mutagenesis screens. Here, this approach was used to discover an extensive set of ALK mutations that can confer resistance to crizotinib. Mutations at 16 residues were identified, structurally clustered into five regions around the kinase active site, which conferred varying degrees of resistance. The screen successfully predicted the L1196M, C1156Y, and F1174L mutations, recently identified in crizotinib-resistant patients. In separate studies, we demonstrated that crizotinib has relatively modest potency in ALK-positive non-small-cell lung cancer cell lines. A more potent ALK inhibitor, TAE684, maintained substantial activity against mutations that conferred resistance to crizotinib. Our study identifies multiple novel mutations in ALK that may confer clinical resistance to crizotinib, suggests that crizotinib's narrow selectivity window may underlie its susceptibility to such resistance and demonstrates that a more potent ALK inhibitor may be effective at overcoming resistance. PMID:22034911

  19. CRKL mediates EML4-ALK signaling and is a potential therapeutic target for ALK-rearranged lung adenocarcinoma

    PubMed Central

    Voeller, Donna; Gower, Arjan; Kim, In-Kyu; Zhang, Yu-Wen; Giaccone, Giuseppe

    2016-01-01

    Anaplastic lymphoma kinase (ALK) gene rearrangements are oncogenic drivers in a small subset of patients with non-small-cell lung cancer (NSCLC). The ALK inhibitors are highly effective in NSCLC patients harboring ALK rearrangements; however, most patients acquire resistance to the therapy following an initial response. Mechanisms of acquired resistance are complex. We used LC-MS/MS-based phosphotyrosine-peptide profiling in the EML4-ALK rearranged H3122 and H2228 cells treated with ALK inhibitors, to identify downstream effectors of ALK. We then used Western blot, siRNA experiments, cell proliferation, viability and migration assays to validate our findings. We identified CRKL as a novel downstream effector of ALK signaling. We demonstrated that CRKL tyrosine phosphorylation was repressed by pharmacological inhibition or small interfering RNA (siRNA) knockdown of ALK in the ALK-rearranged cells. More importantly, CRKL knockdown attenuated their cell proliferation, viability, and migration, but it had no effect on ALK phosphorylation and expression in these cells. Furthermore, CRKL tyrosine phosphorylation was inhibited by dasatinib (an inhibitor of ABL and SRC kinases), which in combination with the ALK inhibitor crizotinib displayed a synergistic inhibitory effect in vitro. In conclusion, our study suggests that CRKL is a key downstream effector of ALK, and combined inhibition of ALK and CRKL may represent an effective strategy for treating ALK-rearranged NSCLC patients. PMID:27078848

  20. Detection of anaplastic lymphoma kinase (ALK) gene rearrangement in non-small cell lung cancer and related issues in ALK inhibitor therapy: a literature review.

    PubMed

    Yi, Eunhee S; Chung, Jin-Haeng; Kulig, Kimary; Kerr, Keith M

    2012-06-01

    Anaplastic lymphoma kinase (ALK) encodes a receptor tyrosine kinase, and ALK gene rearrangement (ALK+) is implicated in the oncogenesis of non-small cell lung carcinomas (NSCLCs), especially adenocarcinomas. The ALK inhibitor crizotinib was approved in August 2011 by the US Food and Drug Administration (FDA) for treating late-stage NSCLCs that are ALK+, with a companion fluorescent in situ hybridization (FISH) test using the Vysis ALK Break Apart FISH Probe Kit. This review covers pertinent issues in ALK testing, including approaches to select target patients for the test, pros and cons of different detection methods, and mechanisms as well as monitoring of acquired crizotinib resistance in ALK+ NSCLCs.

  1. Characterization of a CYP153 alkane hydroxylase gene in a Gram-positive Dietzia sp. DQ12-45-1b and its "team role" with alkW1 in alkane degradation.

    PubMed

    Nie, Yong; Liang, Jie-Liang; Fang, Hui; Tang, Yue-Qin; Wu, Xiao-Lei

    2014-01-01

    CYP153 and AlkB-like hydroxylases were recently discovered in Gram-positive alkane-degrading bacteria. However, it is unclear whether they cooperate with each other in alkane degradation as they do in Gram-negative bacteria. In this paper, we cloned the CYP153 gene from a representative Gram-positive alkane-degrading bacterium, Dietzia sp. DQ12-45-1b. The CYP153 gene transcription in Dietzia sp. DQ12-45-1b and heterologous expression in alkB gene knockout mutant strain Pseudomonas fluorescens KOB2∆1 both confirmed the functions of CYP153 on C6-C10 n-alkanes degradation, but not on longer chain-length n-alkanes. In addition, substrate-binding analysis of the purified CYP153 protein revealed different substrate affinities to C6-C16 n-alkanes, confirming n-alkanes binding to CYP153 protein. Along with AlkW1, an AlkB-like alkane hydroxylase in Dietzia sp. DQ12-45-1b, a teamwork pattern was found in n-alkane degradation, i.e. CYP153 was responsible for hydroxylating n-alkanes shorter than C10 while AlkW1 was responsible for those longer than C14. Further sequence analysis suggested that the high horizontal gene transfer (HGT) potential of CYP153 genes may be universal in Gram-positive alkane-degrading actinomycetes that contain both alkB and CYP153 genes.

  2. Alectinib: a novel second generation anaplastic lymphoma kinase (ALK) inhibitor for overcoming clinically-acquired resistance

    PubMed Central

    Song, Zilan; Wang, Meining; Zhang, Ao

    2015-01-01

    The development of inhibitors for the tyrosine anaplastic lymphoma kinase (ALK) has advanced rapidly, driven by biology and medicinal chemistry. The first generation ALK inhibitor crizotinib was granted US FDA approval with only four years of preclinical and clinical testing. Although this drug offers significant clinical benefit to the ALK-positive patients, resistance has been developed through a variety of mechanisms. In addition to ceritinib, alectinib is another second-generation ALK inhibitor launched in 2014 in Japan. This drug has a unique chemical structure bearing a 5H-benzo[b]carbazol-11(6H)-one structural scaffold with an IC50 value of 1.9 nmol/L, and is highly potent against ALK bearing the gatekeeper mutation L1196M with an IC50 of 1.56 nmol/L. In the clinic, alectinib is highly efficacious in treatment of ALK-positive non-small cell lung cancer (NSCLC), and retains potency to combat crizotinib-resistant ALK mutations L1196M, F1174L, R1275Q and C1156Y. PMID:26579422

  3. Chromoplectic TPM3–ALK rearrangement in a patient with inflammatory myofibroblastic tumor who responded to ceritinib after progression on crizotinib

    PubMed Central

    Mansfield, A. S.; Murphy, S. J.; Harris, F. R.; Robinson, S. I.; Marks, R. S.; Johnson, S. H.; Smadbeck, J. B.; Halling, G. C.; Yi, E. S.; Wigle, D.; Vasmatzis, G.; Jen, J.

    2016-01-01

    Background Inflammatory myofibroblastic tumors (IMTs) are rare sarcomas that can occur at any age. Surgical resection is the primary treatment for patients with localized disease; however, these tumors frequently recur. Less commonly, patients with IMTs develop or present with metastatic disease. There is no standard of care for these patients and traditional cytotoxic therapy is largely ineffective. Most IMTs are associated with oncogenic ALK, ROS1 or PDGFRβ fusions and may benefit from targeted therapy. Patient and methods We sought to understand the genomic abnormalities of a patient who presented for management of metastatic IMT after progression of disease on crizotinib and a significant and durable partial response to the more potent ALK inhibitor ceritinib. Results The residual IMT was resected based on the recommendations of a multidisciplinary tumor sarcoma tumor board and analyzed by whole-genome mate pair sequencing. Analysis of the residual, resected tumor identified a chromoplectic TPM3–ALK rearrangement that involved many other known oncogenes and was confirmed by rtPCR. Conclusions In our analysis of the treatment-resistant, residual IMT, we identified a complex pattern of genetic rearrangements consistent with chromoplexy. Although it is difficult to know for certain if these chromoplectic rearrangements preceded treatment, their presence suggests that chromoplexy has a role in the oncogenesis of IMTs. Furthermore, this patient's remarkable response suggests that ceritinib should be considered as an option after progression on crizotinib for patients with metastatic or unresectable IMT and ALK mutations. PMID:27742657

  4. Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK

    PubMed Central

    Katayama, Ryohei; Khan, Tahsin M.; Benes, Cyril; Lifshits, Eugene; Ebi, Hiromichi; Rivera, Victor M.; Shakespeare, William C.; Iafrate, A. John; Engelman, Jeffrey A.; Shaw, Alice T.

    2011-01-01

    The echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion oncogene represents a molecular target in a small subset of non-small cell lung cancers (NSCLCs). This fusion leads to constitutive ALK activation with potent transforming activity. In a pivotal phase 1 clinical trial, the ALK tyrosine kinase inhibitor (TKI) crizotinib (PF-02341066) demonstrated impressive antitumor activity in the majority of patients with NSCLC harboring ALK fusions. However, despite these remarkable initial responses, cancers eventually develop resistance to crizotinib, usually within 1 y, thereby limiting the potential clinical benefit. To determine how cancers acquire resistance to ALK inhibitors, we established a model of acquired resistance to crizotinib by exposing a highly sensitive EML4-ALK–positive NSCLC cell line to increasing doses of crizotinib until resistance emerged. We found that cells resistant to intermediate doses of crizotinib developed amplification of the EML4-ALK gene. Cells resistant to higher doses (1 μM) also developed a gatekeeper mutation, L1196M, within the kinase domain, rendering EML4-ALK insensitive to crizotinib. This gatekeeper mutation was readily detected using a unique and highly sensitive allele-specific PCR assay. Although crizotinib was ineffectual against EML4-ALK harboring the gatekeeper mutation, we observed that two structurally different ALK inhibitors, NVP-TAE684 and AP26113, were highly active against the resistant cancer cells in vitro and in vivo. Furthermore, these resistant cells remained highly sensitive to the Hsp90 inhibitor 17-AAG. Thus, we have developed a model of acquired resistance to ALK inhibitors and have shown that second-generation ALK TKIs or Hsp90 inhibitors are effective in treating crizotinib-resistant tumors harboring secondary gatekeeper mutations. PMID:21502504

  5. French multicentric validation of ALK rearrangement diagnostic in 547 lung adenocarcinomas.

    PubMed

    Lantuejoul, Sylvie; Rouquette, Isabelle; Blons, Hélène; Le Stang, Nolwenn; Ilie, Marius; Begueret, Hugues; Grégoire, Valerie; Hofman, Paul; Gros, Audrey; Garcia, Stephane; Monhoven, Nathalie; Devouassoux-Shisheboran, Mojgan; Mansuet-Lupo, Audrey; Thivolet, Françoise; Antoine, Martine; Vignaud, Jean-Michel; Penault-Llorca, Frederique; Galateau-Sallé, Françoise; McLeer-Florin, Anne

    2015-07-01

    Anaplastic lymphoma kinase (ALK) gene rearrangements in lung adenocarcinoma result in kinase activity targetable by crizotinib. Although fluorescence in situ hybridisation (FISH) is the reference diagnostic technique, immunohistochemistry (IHC) could be useful for pre-screening. Diagnostic yields of ALK IHC, FISH and quantitative reverse transcriptase PCR performed in 14 French pathology/molecular genetics platforms were compared. 547 lung adenocarcinoma specimens were analysed using 5A4 and D5F3 antibodies, two break-apart FISH probes and TaqMan kits. Clinicopathological data were recorded. 140 tumours were ALK rearranged (FISH with ≥15% of rearranged cells) and 400 were ALK FISH negative (<15%). FISH was not interpretable for seven cases. ALK patients were young (p=0.003), mostly females (p=0.007) and light/nonsmokers (p<0.0001). 13 cases were IHC negative but FISH ≥15%, including six cases with FISH between 15% and 20%; eight were IHC positive with FISH between 10% and 14%. Sensitivity and specificity for 5A4 and D5F3 were 87% and 92%, and 89% and 76%, respectively. False-negative IHC, observed in 2.4% of cases, dropped to 1.3% for FISH >20%. Variants were undetected in 36% of ALK tumours. Discordances predominated with FISH ranging from 10% to 20% of rearranged cells and were centre dependent. IHC remains a reliable pre-screening method for ALK rearrangement detection.

  6. ALK F1174V mutation confers sensitivity while ALK I1171 mutation confers resistance to alectinib. The importance of serial biopsy post progression.

    PubMed

    Ou, Sai-Hong; Milliken, Jeffrey C; Azada, Michele C; Miller, Vincent A; Ali, Siraj M; Klempner, Samuel J

    2016-01-01

    Many acquired resistant mutations to the anaplastic lymphoma kinase (ALK) gene have been identified during treatment of ALK-rearranged non-small cell lung cancer (NSCLC) patients with crizotinib, ceritinib, and alectinib. These various acquired resistant ALK mutations confer differential sensitivities to various ALK inhibitors and may provide guidance on how to sequence the use of many of the second generation ALK inhibitors. We described a patient who developed an acquired ALK F1174V resistant mutation on progression from crizotinib that responded to alectinib for 18 months but then developed an acquired ALK I1171S mutation to alectinib. Both tumor samples had essentially the same genomic profile by comprehensive genomic profiling otherwise. This is the first patient report that demonstrates ALK F1174V mutation is sensitive to alectinib and further confirms missense acquired ALK I1171 mutation is resistant to alectinib. Sequential tumor re-biopsy for comprehensive genomic profiling (CGP) is important to appreciate the selective pressure during treatment with various ALK inhibitors underpinning the evolution of the disease course of ALK+NSCLC patients while on treatment with the various ALK inhibitors. This approach will likely help inform the optimal sequencing strategy as more ALK inhibitors become available. This case report also validates the importance of developing structurally distinct ALK inhibitors for clinical use to overcome non-cross resistant ALK mutations.

  7. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer

    PubMed Central

    Koivunen, Jussi P.; Mermel, Craig; Zejnullahu, Kreshnik; Murphy, Carly; Lifshits, Eugene; Holmes, Alison J.; Choi, Hwan Geun; Kim, Jhingook; Chiang, Derek; Thomas, Roman; Lee, Jinseon; Richards, William G.; Sugarbaker, David J.; Ducko, Christopher; Lindeman, Neal; Marcoux, J. Paul; Engelman, Jeffrey A.; Gray, Nathanael S.; Lee, Charles; Meyerson, Matthew; Jänne, Pasi A.

    2011-01-01

    Purpose The EML4-ALK fusion gene has been detected in ~7% of Japanese non-small cell lung cancers (NSCLC). We determined the frequency of EML4-ALK in Caucasian NSCLCs and in NSCLC cell lines. We also determined whether TAE684, a specific ALK kinase inhibitor, would inhibit the growth of EML4-ALK containing cell lines in vitro and in vivo. Experimental Design We screened 305 primary NSCLCs (both US (n=138) and Korean (n=167) patients) and 83 NSCLC cell lines using RT-PCR and by exon array analyses. We evaluated the efficacy of TAE684 against NSCLC cell lines in vitro and in vivo. Results We detected 4 different variants, including two novel variants, of EML4-ALK using RT-PCR in 8/305 tumors (3%) and in 3/83 (3.6%) NSCLC cell lines. All EML4-ALK containing tumors and cell lines were adenocarcinomas. EML4-ALK was detected more frequently in NSCLC patients who were never or light (< 10 pack years) cigarette smokers compared to current/former smokers (6% vs. 1%; p=0.049). TAE684 inhibited the growth of 1 of 3 (H3122) EML4-ALK containing cell lines in vitro and in vivo, inhibited Akt phosphorylation and caused apoptosis. In another EML4-ALK cell line, DFCI032, TAE684 was ineffective due to co-activation of EGFR and ERBB2. The combination of TAE684 and CL-387,785 (EGFR/ERBB2 kinase inhibitor), inhibited growth and Akt phosphorylation and led to apoptosis in the DFCI032 cell line. Conclusions EML4-ALK is found in the minority of NSCLCs. ALK kinase inhibitors alone or in combination may nevertheless be clinically effective treatments for NSCLC patients whose tumors contain EML4-ALK. PMID:18594010

  8. Three Years Sustained Complete Remission Achieved in a Primary Refractory ALK-Positive Anaplastic T Large Cell Lymphoma Treated with Crizotinib

    PubMed Central

    Mahuad, Carolina Valeria; Repáraz, María de los Ángeles Vicente; Zerga, Marta E.; Aizpurua, María Florencia; Casali, Claudia; Garate, Gonzalo

    2016-01-01

    The prognosis of the primary refractory anaplastic lymphoma kinase (ALK+) anaplastic T large cell lymphoma is ominous. The identification of molecular targets with potential to drive oncogenesis remains a cornerstone for the designing of new selective cancer therapies. Crizotinib is a selective ATP-competitive inhibitor for ALK, approved for its use in lung cancer with rearrangements on ALK gene. The reported cases describe the use of crizotinib as a bridging strategy prior to allotransplantation; there are no reported prolonged survivals under monotherapy with Crizotinib. We report a case of a primary refractory ALK+ anaplastic large-cell lymphoma that sustains complete response after 3 years of crizotinib monotherapy. PMID:27441079

  9. Therapeutic strategies and mechanisms of drug resistance in Anaplastic Lymphoma Kinase (ALK)-rearranged lung cancer.

    PubMed

    Katayama, Ryohei

    2017-02-06

    Anaplastic lymphoma kinase (ALK) gene encoding the receptor tyrosine kinase ALK is expressed as a fusion gene in a variety of carcinomas. The expression of ALK is nearly undetectable in adults, and its activation is normally regulated by its ligands, FAM150A/B. However, ALK gene rearrangements result in different ALK fusion proteins that are constitutively expressed via the active promoter of fusion partner genes. ALK fusion proteins dimerize in a ligand-independent manner and lead to the dysregulation of cell proliferation via abnormal constitutive activation of ALK tyrosine kinase. Many ALK tyrosine kinase inhibitors (TKIs) have been developed to date, are three of which are currently in clinical use for the treatment of ALK-rearranged non-small cell lung cancer (NSCLC). ALK TKIs often achieve marked tumor regression in NSCLC patients with ALK rearrangements; however, ALK TKI-resistant tumors inevitably emerge within a few years in most cases. In this review, we summarize diverse ALK TKI resistance mechanisms identified in NSCLC with ALK rearrangements, and review potential therapeutic strategies to overcome ALK TKI resistance in these patients.

  10. The Utility of Thyroid Transcription Factor 1 (TTF-1), Napsin A, Excision Repair Cross-Complementing 1 (ERCC1), Anaplastic Lymphoma Kinase (ALK) and the Epidermal Growth Factor Receptor (EGFR) Expression in Small Biopsy in Prognosis of Patients with Lung Adenocarcinoma – A Retrograde Single-Center Study from Croatia

    PubMed Central

    Burazer, Marina Piljić; Mladinov, Suzana; Ćapkun, Vesna; Kuret, Sendi; Durdov, Merica Glavina

    2017-01-01

    Background The present study was carried out in order to evaluate our institutional experience with small biopsy in diagnosis and molecular testing of lung adenocarcinoma. Few specific and predictive markers have been evaluated and correlated with clinicopathologic characteristics and survival in patients with lung adenocarcinoma who received platinum-based chemotherapy. There have not been such reports from Croatia. Material/Methods A total of 142 cases of lung adenocarcinoma were retrospectively investigated in small biopsies for the immunohistochemical expression of TTF-1, napsin A, ERCC1, ALK, and the EGFR mutation by real-time polymerase chain reaction (rtPCR). Results TTF-1, napsin A, and ERCC1 expression was found in 81%, 78%, and 69% of patients, respectively, and the expressions were not significantly associated with subtype. Expression of ALK was found in 4% and EGFR mutation in 10% of patients. Exon 19 deletions were the most common. Longer survival was significantly associated with TTF-1 positivity (p=0.007) and napsin A positivity (p=0.026). Higher relative risk of death significantly correlated with positive expression of ERCC1 (p=0.041). Conclusions Positive TTF-1 and napsin A expressions in lung adenocarcinoma tissues were useful diagnostic and favorable prognostic parameters. Positive ERCC1 expression was identified as a negative prognostic marker in patients treated with platinum-based chemotherapy. The percentages of EGFR and ALK mutations corresponded to those in previously published reports for Caucasians. PMID:28128193

  11. ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project.

    PubMed

    Savage, Kerry J; Harris, Nancy Lee; Vose, Julie M; Ullrich, Fred; Jaffe, Elaine S; Connors, Joseph M; Rimsza, Lisa; Pileri, Stefano A; Chhanabhai, Mukesh; Gascoyne, Randy D; Armitage, James O; Weisenburger, Dennis D

    2008-06-15

    The International Peripheral T-Cell Lymphoma Project is a collaborative effort designed to gain better understanding of peripheral T-cell and natural killer (NK)/T-cell lymphomas (PTCLs). A total of 22 institutions in North America, Europe, and Asia submitted clinical and pathologic information on PTCLs diagnosed and treated at their respective centers. Of the 1314 eligible patients, 181 had anaplastic large-cell lymphoma (ALCL; 13.8%) on consensus review: One hundred fifty-nine had systemic ALCL (12.1%) and 22 had primary cutaneous ALCL (1.7%). Patients with anaplastic lymphoma kinase-positive (ALK(+)) ALCL had a superior outcome compared with those with ALK(-) ALCL (5-year failure-free survival [FFS], 60% vs 36%; P = .015; 5-year overall survival [OS], 70% vs 49%; P = .016). However, contrary to prior reports, the 5-year FFS (36% vs 20%; P = .012) and OS (49% vs 32%; P = .032) were superior for ALK(-) ALCL compared with PTCL, not otherwise specified (PTCL-NOS). Patients with primary cutaneous ALCL had a very favorable 5-year OS (90%), but with a propensity to relapse (5-year FFS, 55%). In summary, ALK(-) ALCL should continue to be separated from both ALK(+) ALCL and PTCL-NOS. Although the prognosis of ALK(-) ALCL appears to be better than that for PTCL-NOS, it is still unsatisfactory and better therapies are needed. Primary cutaneous ALCL is associated with an indolent course.

  12. Clinicopathological features and relation between anaplastic lymphoma kinase (ALK) mutation and histological subtype of lung adenocarcinoma in Eastern European Caucasian population

    PubMed Central

    Zaric, Bojan; Stojsic, Vladimir; Panjkovic, Milana; Tegeltija, Dragana; Stepanov, Vanesa; Kovacevic, Tomi; Sarcev, Tatjana; Radosavljevic, Davorin; Milovancev, Aleksandar; Adamidis, Vasilis; Zarogoulidis, Paul; Hohenforst-Schmidt, Wolfgang; Trakada, Georgia; Rapti, Aggeliki; Perin, Branislav

    2016-01-01

    Introduction: The incidence of echinoderm microtubule-associated protein-like4-anaplastic lymphoma kinase (EML4-ALK) mutation among surgically treated patients with adenocarcinoma of the lung of the Eastern European ethnicity is underreported. The aim of this trial was the determination of EML4-ALK mutation frequency in investigated population, and the evaluation of correlations between lung adenocarcinoma subtype and clinical characteristics with mutation status. Patients and methods: This was a prospective trial which included 195 patients with adenocarcinoma of the lung who underwent surgical treatment. ALK mutation screening was performed by immunohistochemistry (IHC). IHC scores of 2+ and 3+ were regarded as positive. Confirmatory FISH was performed in all IHC positive and in 2:1 ratio in negative patients. Results: Overall ALK mutation rate established by IHC was 6.2%, while FISH confirmed rate of 5.1%. The FISH confirmed ALK positivity in 7.6% Hungarians, 5.5% Serbians, and 6.6% Slovakians. Acinar subtype of adenocarcinoma of the lung was significantly (p=0.02) related to EML4-ALK positive mutation status. Most of the patients were males (56.9%), smokers (50.8%), or former smokers (28.7%) with acinar (55.4%) or solid (35.9%) adenocarcinoma of the lung. Sensitivity and specificity of IHC were 100% and 98.9% respectively. Conclusions: ALK mutation rate in surgically treated patients with adenocarcinoma of the lung was found to be 6.2% by IHC and 5.1% by FISH. Acinar subtype of the adenocarcinoma of the lung was significantly related to ALK positive mutation. PMID:27994656

  13. Anaplastic lymphoma kinase (ALK) inhibitors in the treatment of ALK-driven lung cancers.

    PubMed

    Roskoski, Robert

    2017-03-01

    Anaplastic lymphoma kinase is expressed in two-thirds of the anaplastic large-cell lymphomas as an NPM-ALK fusion protein. Physiological ALK is a receptor protein-tyrosine kinase within the insulin receptor superfamily of proteins that participates in nervous system development. The EML4-ALK fusion protein and four other ALK-fusion proteins play a fundamental role in the development in about 5% of non-small cell lung cancers. The amino-terminal portions of the ALK fusion proteins result in dimerization and subsequent activation of the ALK protein kinase domain that plays a key role in the pathogenesis of various tumors. Downstream signaling from the ALK fusion protein leads to the activation of the Ras/Raf/MEK/ERK1/2 cell proliferation module and the JAK/STAT cell survival pathways. Moreover, nearly two dozen ALK activating mutations are involved in the pathogenesis of childhood neuroblastomas. The occurrence of oncogenic ALK-fusion proteins, particularly in non-small cell lung cancer, has fostered considerable interest in the development of ALK inhibitors. Crizotinib was the first such inhibitor approved by the US Food and Drug Administration for the treatment of ALK-positive non-small cell lung cancer in 2011. The median time for the emergence of crizotinib drug resistance is 10.5 months after the initiation of therapy. Such resistance prompted the development of second-generation drugs including ceritinib and alectinib, which are approved for the treatment of non-small cell lung cancer. Unlike the single gatekeeper mutation that occurs in drug-resistant epidermal growth factor receptor in lung cancer, nearly a dozen different mutations in the catalytic domain of ALK fusion proteins have been discovered that result in crizotinib resistance. Crizotinib, ceritinib, and alectinib form a complex within the front cleft between the small and large lobes of an inactive ALK protein-kinase domain with a compact activation segment. These drugs are classified as type I½ B

  14. Comparison of small biopsy specimens and surgical specimens for the detection of EGFR mutations and EML4-ALK in non-small-cell lung cancer

    PubMed Central

    Xiao, DeSheng; Lu, Can; Zhu, Wei; He, QiuYan; Li, Yong; Fu, ChunYan; Zhou, JianHua; Liu, Shuang; Tao, YongGuang

    2016-01-01

    Epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) fusion genes represent novel oncogenes that are associated with non–small-cell lung cancers (NSCLC). The feasibility of detecting EGFR mutations and ALK fusion genes in small biopsy specimens or surgical specimens was determined. Of the 721 NSCLC patients, a total of 305 cases were positive for EGFR mutations (42.3%). The rate of EGFR mutations in women was significantly higher than that in men. Histologically, the EGFR mutation rate in adenocarcinomas was significantly higher than that in squamous cell carcinomas. No difference in the EGFR mutation rate was observed between surgical specimens (42.1%) and small biopsy specimens (42.4%), which indicated that the EGFR mutation ratios in surgical specimens and small biopsy specimens were not different. In 385 NSCLC patients, 26 cases were positive for EML4-ALK (6.8%). However, 11.7% of the surgical specimens were EML4-ALK-positive, whereas the positive proportion in the small biopsy specimens was only 4.7%, which indicated that EML4-ALK-positive rate in the surgical specimens was significantly higher than that in the small biopsy specimens. Detection of EGFR gene mutations was feasible in small biopsy specimens, and screening for EML4-ALK expression in small biopsy specimens can be used to guide clinical treatments. PMID:27322143

  15. Activated Alk triggers prolonged neurogenesis and Ret upregulation providing a therapeutic target in ALK-mutated neuroblastoma

    PubMed Central

    Cazes, Alex; Lopez-Delisle, Lucille; Tsarovina, Konstantina; Pierre-Eugène, Cécile; De Preter, Katleen; Peuchmaur, Michel; Nicolas, André; Provost, Claire; Louis-Brennetot, Caroline; Daveau, Romain; Kumps, Candy; Cascone, Ilaria; Schleiermacher, Gudrun; Prignon, Aurélie; Speleman, Frank; Rohrer, Hermann; Delattre, Olivier; Janoueix-Lerosey, Isabelle

    2014-01-01

    Activating mutations of the ALK (Anaplastic lymphoma Kinase) gene have been identified in sporadic and familial cases of neuroblastoma, a cancer of early childhood arising from the sympathetic nervous system (SNS). To decipher ALK function in neuroblastoma predisposition and oncogenesis, we have characterized knock-in (KI) mice bearing the two most frequent mutations observed in neuroblastoma patients. A dramatic enlargement of sympathetic ganglia is observed in AlkF1178L mice from embryonic to adult stages associated with an increased proliferation of sympathetic neuroblasts from E14.5 to birth. In a MYCN transgenic context, the F1178L mutation displays a higher oncogenic potential than the R1279Q mutation as evident from a shorter latency of tumor onset. We show that tumors expressing the R1279Q mutation are sensitive to ALK inhibition upon crizotinib treatment. Furthermore, our data provide evidence that activated ALK triggers RET upregulation in mouse sympathetic ganglia at birth as well as in murine and human neuroblastoma. Using vandetanib, we show that RET inhibition strongly impairs tumor growth in vivo in both MYCN/KI AlkR1279Q and MYCN/KI AlkF1178L mice. Altogether, our findings demonstrate the critical role of activated ALK in SNS development and pathogenesis and identify RET as a therapeutic target in ALK mutated neuroblastoma. PMID:24811913

  16. PF-06463922, an ALK/ROS1 inhibitor, overcomes resistance to 1st and 2nd generation ALK inhibitors in pre-clinical models

    PubMed Central

    Zou, Helen Y.; Friboulet, Luc; Kodack, David P.; Engstrom, Lars D.; Li, Qiuhua; West, Melissa; Tang, Ruth W.; Wang, Hui; Tsaparikos, Konstantinos; Wang, Jinwei; Timofeevski, Sergei; Katayama, Ryohei; Dinh, Dac M.; Lam, Hieu; Lam, Justine L.; Yamazaki, Shinji; Hu, Wenyue; Patel, Bhushankumar; Bezwada, Divya; Frias, Rosa L.; Lifshits, Eugene; Mahmood, Sidra; Gainor, Justin F.; Affolter, Timothy; Lappin, Patrick B.; Gukasyan, Hovhannes; Lee, Nathan; Deng, Shibing; Jain, Rakesh K; Johnson, Ted W.; Shaw, Alice T.; Fantin, Valeria R.; Smeal, Tod

    2015-01-01

    SUMMARY We report the preclinical evaluation of PF-06463922, a potent and brain penetrant ALK/ROS1 inhibitor. Compared to other clinically available ALK inhibitors, PF-06463922 displayed superior potency against all known clinically acquired ALK mutations, including the highly resistant G1202R mutant. Furthermore, PF-06463922 treatment led to regression of EML4-ALK driven brain metastases, leading to prolonged mouse survival, in a superior manner. Finally, PF-06463922 demonstrated high selectivity and safety margins in a variety of preclinical studies. These results suggest that PF-06463922 will be highly effective for the treatment of patients with ALK-driven lung cancers, including those who relapsed on clinically available ALK inhibitors due to secondary ALK kinase domain mutations and/or due to the failed control of brain metastases. PMID:26144315

  17. Reversal of microRNA-150 silencing disadvantages crizotinib-resistant NPM-ALK(+) cell growth

    PubMed Central

    Hoareau-Aveilla, Coralie; Valentin, Thibaud; Daugrois, Camille; Quelen, Cathy; Mitou, Géraldine; Quentin, Samuel; Jia, Jinsong; Spicuglia, Salvatore; Ferrier, Pierre; Ceccon, Monica; Giuriato, Sylvie; Gambacorti-Passerini, Carlo; Brousset, Pierre; Lamant, Laurence; Meggetto, Fabienne

    2015-01-01

    The regulatory microRNA miR-150 is involved in the development of hemopathies and is downregulated in T-lymphomas, such as anaplastic large-cell lymphoma (ALCL) tumors. ALCL is defined by the presence or absence of translocations that activate the anaplastic lymphoma kinase (ALK), with nucleophosmin-ALK (NPM-ALK) fusions being the most common. Here, we compared samples of primary NPM-ALK(+) and NPM-ALK(–) ALCL to investigate the role of miR-150 downstream of NPM-ALK. Methylation of the MIR150 gene was substantially elevated in NPM-ALK(+) biopsies and correlated with reduced miR-150 expression. In NPM-ALK(+) cell lines, DNA hypermethylation–mediated miR-150 repression required ALK-dependent pathways, as ALK inhibition restored miR-150 expression. Moreover, epigenetic silencing of miR-150 was due to the activation of STAT3, a major downstream substrate of NPM-ALK, in cooperation with DNA methyltransferase 1 (DNMT1). Accordingly, miR-150 repression was turned off following treatment with the DNMT inhibitor, decitabine. In murine NPM-ALK(+) xenograft models, miR-150 upregulation induced antineoplastic activity. Treatment of crizotinib-resistant NPM-ALK(+) KARPAS-299-CR06 cells with decitabine or ectopic miR-150 expression reduced viability and growth. Altogether, our results suggest that hypomethylating drugs, alone or in combination with other agents, may benefit ALK(+) patients harboring tumors resistant to crizotinib and other anti-ALK tyrosine kinase inhibitors (TKIs). Moreover, these results support further work on miR-150 in these and other ALK(+) malignancies. PMID:26258416

  18. Pharmacologic study (JP28927) of alectinib in Japanese patients with ALK+ non-small-cell lung cancer with or without prior crizotinib therapy.

    PubMed

    Hida, Toyoaki; Nakagawa, Kazuhiko; Seto, Takashi; Satouchi, Miyako; Nishio, Makoto; Hotta, Katsuyuki; Takahashi, Toshiaki; Ohe, Yuichiro; Takeda, Koji; Tatsuno, Masahiro; Asakawa, Takashi; Shimada, Tadashi; Tanaka, Tomohiro; Tamura, Tomohide

    2016-11-01

    We report pharmacokinetics, efficacy and safety data for a new 150-mg alectinib capsule in ALK+ non-small-cell lung cancer in a multicenter, open-label pharmacologic study (JP28927). Eligible patients (≥20 years, locally advanced/metastatic ALK+ disease, ALK inhibitor-naïve and -pretreated [including crizotinib refractory]) were randomized 1:1 to receive one of two sequences of alectinib 300 mg twice daily (comprising different schedules of 20/40-mg and 150-mg capsules) until investigator-determined lack of clinical benefit. Co-primary endpoints were: bioequivalence of alectinib 20/40 mg vs 150 mg; food effect with 150 mg; and safety. Thirty-five patients were enrolled; median treatment duration was 13.1 months (range 1.1-15.0). Under fasting conditions, exposure of the two formulations was similar; mean AUClast  ± standard deviation 3230 ± 914 h·ng/mL vs 3710 ± 1040 h·ng/mL, respectively, for 150-mg vs 20/40-mg capsules. Food effect with 150 mg alectinib was negligible. Treatment-related adverse events in >20% of patients were constipation (31.4%), dysgeusia (25.7%), and decreased white blood cell and neutrophil count (22.9% each). No treatment-related grade 4/5 events occurred. Median time to response was 1.2 months (95% CI 1.1-2.1). For the full analysis set (n = 35) and crizotinib-failure subpopulations (n = 23), the overall response rate was 70.0% (95% CI 50.6-85.3) and 65.0% (95% CI 40.8-84.6), and median progression-free survival was 13.9 months (95% CI 11.1-not reached) and 12.9 months (95% CI 3.9-not reached), respectively. The 150-mg capsule had a similar exposure profile to 20/40-mg capsules. Alectinib demonstrated promising efficacy and was well tolerated.

  19. Efficacy of ALK5 inhibition in myelofibrosis

    PubMed Central

    Zhao, Wanke; Ho, Wanting Tina; Han, Ying; Murdun, Cem; Mailloux, Adam W.; Zhang, Ling; Wang, Xuefeng; Budhathoki, Anjali; Pradhan, Kith; Rapaport, Franck; Wang, Huaquan; Shao, Zonghong; Ren, Xiubao; Steidl, Ulrich; Levine, Ross L.; Zhao, Zhizhuang Joe; Verma, Amit; Epling-Burnette, Pearlie K.

    2017-01-01

    Myelofibrosis (MF) is a bone marrow disorder characterized by clonal myeloproliferation, aberrant cytokine production, extramedullary hematopoiesis, and bone marrow fibrosis. Although somatic mutations in JAK2, MPL, and CALR have been identified in the pathogenesis of these diseases, inhibitors of the Jak2 pathway have not demonstrated efficacy in ameliorating MF in patients. TGF-β family members are profibrotic cytokines and we observed significant TGF-β1 isoform overexpression in a large cohort of primary MF patient samples. Significant overexpression of TGF-β1 was also observed in murine clonal MPLW515L megakaryocytic cells. TGF-β1 stimulated the deposition of excessive collagen by mesenchymal stromal cells (MSCs) by activating the TGF-β receptor I kinase (ALK5)/Smad3 pathway. MSCs derived from MPLW515L mice demonstrated sustained overproduction of both collagen I and collagen III, effects that were abrogated by ALK5 inhibition in vitro and in vivo. Importantly, use of galunisertib, a clinically active ALK5 inhibitor, significantly improved MF in both MPLW515L and JAK2V617F mouse models. These data demonstrate the role of malignant hematopoietic stem cell (HSC)/TGF-β/MSC axis in the pathogenesis of MF, and provide a preclinical rationale for ALK5 blockade as a therapeutic strategy in MF.

  20. Decoding Tumor Phenotypes for ALK, ROS1, and RET Fusions in Lung Adenocarcinoma Using a Radiomics Approach.

    PubMed

    Yoon, Hyun Jung; Sohn, Insuk; Cho, Jong Ho; Lee, Ho Yun; Kim, Jae-Hun; Choi, Yoon-La; Kim, Hyeseung; Lee, Genehee; Lee, Kyung Soo; Kim, Jhingook

    2015-10-01

    Quantitative imaging using radiomics can capture distinct phenotypic differences between tumors and may have predictive power for certain phenotypes according to specific genetic mutations. We aimed to identify the clinicoradiologic predictors of tumors with ALK (anaplastic lymphoma kinase), ROS1 (c-ros oncogene 1), or RET (rearranged during transfection) fusions in patients with lung adenocarcinoma.A total of 539 pathologically confirmed lung adenocarcinomas were included in this retrospective study. The baseline clinicopathologic characteristics were retrieved from the patients' medical records and the ALK/ROS1/RET fusion status was reviewed. Quantitative computed tomography (CT) and positron emission tomography imaging characteristics were evaluated using a radiomics approach. Significant features for the fusion-positive tumor prediction model were extracted from all of the clinicoradiologic features, and were used to calculate diagnostic performance for predicting 3 fusions' positivity. The clinicoradiologic features were compared between ALK versus ROS1/RET fusion-positive tumors to identify the clinicoradiologic similarity between the 2 groups.The fusion-positive tumor prediction model was a combination of younger age, advanced tumor stage, solid tumor on CT, higher values for SUV(max) and tumor mass, lower values for kurtosis and inverse variance on 3-voxel distance than those of fusion-negative tumors (sensitivity and specificity, 0.73 and 0.70, respectively). ALK fusion-positive tumors were significantly different in tumor stage, central location, SUV(max), homogeneity on 1-, 2-, and 3-voxel distances, and sum mean on 2-voxel distance compared with ROS1/RET fusion-positive tumors.ALK/ROS1/RET fusion-positive lung adenocarcinomas possess certain clinical and imaging features that enable good discrimination of fusion-positive from fusion-negative lung adenocarcinomas.

  1. Management of crizotinib therapy for ALK-rearranged non-small cell lung carcinoma: an expert consensus.

    PubMed

    Cappuzzo, Federico; Moro-Sibilot, Denis; Gautschi, Oliver; Boleti, Ekaterini; Felip, Enriqueta; Groen, Harry J M; Germonpré, Paul; Meldgaard, Peter; Arriola, Edurne; Steele, Nicola; Fox, Jesme; Schnell, Patrick; Engelsberg, Arne; Wolf, Jürgen

    2015-02-01

    Within 4 years of the discovery of anaplastic lymphoma kinase (ALK) rearrangements in non-small cell lung cancer (NSCLC), the ALK inhibitor crizotinib gained US and European approval for the treatment of advanced ALK-positive NSCLC. This was due to the striking response data observed with crizotinib in phase I and II trials in patients with ALK-positive NSCLC, as well as the favorable tolerability and safety profile observed. Recently published phase III data established crizotinib as a new standard of care for this NSCLC molecular subset. A consequence of such rapid approval, however, is the limited clinical experience and relative paucity of information concerning optimal therapy management. In this review, we discuss the development of crizotinib and the clinical relevance of its safety profile, examining crizotinib-associated adverse events in detail and making specific management recommendations. Crizotinib-associated adverse events were mostly mild to moderate in severity in clinical studies, and appropriate monitoring and supportive therapies are considered effective in avoiding the need for dose interruption or reduction in most cases. Therapy management of patients following disease progression on crizotinib is also discussed. Based on available clinical data, it is evident that patients may have prolonged benefit from crizotinib after Response Evaluation Criteria in Solid Tumors-defined disease progression, and crizotinib should be continued for as long as the patient derives benefit.

  2. Deficient BIM Expression as a Mechanism of Intrinsic and Acquired Resistance to Targeted Therapies in EGFR-Mutant and ALK-Positive Lung Cancers

    DTIC Science & Technology

    2014-08-01

    depressed   in  patients’  specimens  following  acquired...second-­‐generation  ALK  inhibitors.   2C.  Current  objectives:  Determine  if  BIM  levels  are   depressed  (or  BIM  has...whether  resistant  lines  have  a   depressed  apoptotic  response  to  second-­‐line  targeted   therapies  by

  3. Screening for ALK abnormalities in central nervous system metastases of non-small-cell lung cancer: ALK abnormalities in CNS metastases of NSCLC.

    PubMed

    Nicoś, Marcin; Jarosz, Bożena; Krawczyk, Paweł; Wojas-Krawczyk, Kamila; Kucharczyk, Tomasz; Sawicki, Marek; Pankowski, Juliusz; Trojanowski, Tomasz; Milanowski, Janusz

    2016-11-23

    Anaplastic lymphoma kinase (ALK) gene rearrangement was reported in 3-7% of primary non-small-cell lung cancer (NSCLC) and its presence is commonly associated with adenocarcinoma (AD) type and non-smoking history. ALK tyrosine kinase inhibitors (TKIs) such as crizotinib, alectinib and ceritinib showed efficiency in patients with primary NSCLC harboring ALK gene rearrangement. Moreover, response to ALK TKIs was observed in central nervous system (CNS) metastatic lesions of NSCLC. However, there are no reports concerning the frequency of ALK rearrangement in CNS metastases. We assessed the frequency of ALK abnormalities in 145 formalin fixed paraffin embedded (FFPE) tissue samples from CNS metastases of NSCLC using immunohistochemical (IHC) automated staining (BenchMark GX, Ventana, USA) and fluorescence in situ hybridization (FISH) technique (Abbot Molecular, USA). The studied group was heterogeneous in terms of histopathology and smoking status. ALK abnormalities were detected in 4.8% (7/145) of CNS metastases. ALK abnormalities were observed in six AD (7.5%; 6/80) and in single patients with adenosuqamous lung carcinoma. Analysis of clinical and demographic factors indicated that expression of abnormal ALK was significantly more frequently observed (p=0.0002; χ(2) =16.783) in former-smokers. Comparison of IHC and FISH results showed some discrepancies, which were caused by unspecific staining of macrophages and glial/nerve cells, which constitute the background of CNS tissues. Our results indicate high frequency of ALK gene rearrangement in CNS metastatic sites of NSCLC that are in line with prior studies concerning evaluation of the presence of ALK abnormalities in such patients. However, we showed that assessment of ALK by IHC and FISH methods in CNS tissues require additional standardizations. This article is protected by copyright. All rights reserved.

  4. Decoding Tumor Phenotypes for ALK, ROS1, and RET Fusions in Lung Adenocarcinoma Using a Radiomics Approach

    PubMed Central

    Yoon, Hyun Jung; Sohn, Insuk; Cho, Jong Ho; Lee, Ho Yun; Kim, Jae-Hun; Choi, Yoon-La; Kim, Hyeseung; Lee, Genehee; Lee, Kyung Soo; Kim, Jhingook

    2015-01-01

    Abstract Quantitative imaging using radiomics can capture distinct phenotypic differences between tumors and may have predictive power for certain phenotypes according to specific genetic mutations. We aimed to identify the clinicoradiologic predictors of tumors with ALK (anaplastic lymphoma kinase), ROS1 (c-ros oncogene 1), or RET (rearranged during transfection) fusions in patients with lung adenocarcinoma. A total of 539 pathologically confirmed lung adenocarcinomas were included in this retrospective study. The baseline clinicopathologic characteristics were retrieved from the patients’ medical records and the ALK/ROS1/RET fusion status was reviewed. Quantitative computed tomography (CT) and positron emission tomography imaging characteristics were evaluated using a radiomics approach. Significant features for the fusion-positive tumor prediction model were extracted from all of the clinicoradiologic features, and were used to calculate diagnostic performance for predicting 3 fusions’ positivity. The clinicoradiologic features were compared between ALK versus ROS1/RET fusion-positive tumors to identify the clinicoradiologic similarity between the 2 groups. The fusion-positive tumor prediction model was a combination of younger age, advanced tumor stage, solid tumor on CT, higher values for SUVmax and tumor mass, lower values for kurtosis and inverse variance on 3-voxel distance than those of fusion-negative tumors (sensitivity and specificity, 0.73 and 0.70, respectively). ALK fusion-positive tumors were significantly different in tumor stage, central location, SUVmax, homogeneity on 1-, 2-, and 3-voxel distances, and sum mean on 2-voxel distance compared with ROS1/RET fusion-positive tumors. ALK/ROS1/RET fusion-positive lung adenocarcinomas possess certain clinical and imaging features that enable good discrimination of fusion-positive from fusion-negative lung adenocarcinomas. PMID:26469915

  5. New therapeutic strategies in neuroblastoma: combined targeting of a novel tyrosine kinase inhibitor and liposomal siRNAs against ALK

    PubMed Central

    Di Paolo, Daniela; Yang, D.; Pastorino, Fabio; Emionite, Laura; Cilli, Michele; Daga, Antonio; Destefanis, Elisa; Di Fiore, Annarita; Piaggio, Francesca; Brignole, Chiara; Xu, Xiaobao; Liang, Chris; Gibbons, James

    2015-01-01

    Many different aberrations in the Anaplastic Lymphoma Kinase (ALK) were found to be oncogenic drivers in several cancers including neuroblastoma (NB), therefore ALK is now considered a critical player in NB oncogenesis and a promising therapeutic target. The ALK-inhibitor crizotinib has a limited activity against the various ALK mutations identified in NB patients. We tested: the activity of the novel ALK-inhibitor X-396 administered alone or in combination with Targeted Liposomes carrying ALK-siRNAs (TL[ALK-siRNA]) that are active irrespective of ALK gene mutational status; the pharmacokinetic profiles and the biodistribution of X-396; the efficacy of X-396 versus crizotinib treatment in NB xenografts; whether the combination of X-396 with the TL[ALK-siRNA] could promote long-term survival in NB mouse models. X-396 revealed good bioavailability, moderate half-life, high mean plasma and tumor concentrations. X-396 was more effective than crizotinib in inhibiting in vitro cell proliferation of NB cells and in reducing tumor volume in subcutaneous NB models in a dose-dependent manner. In orthotopic NB xenografts, X-396 significantly increased life span independently of the ALK mutation status. In combination studies, all effects were significantly improved in the mice treated with TL[ALK-siRNA] and X-396 compared to mice receiving the single agents. Our findings provide a rational basis to design innovative molecular-based treatment combinations for clinical application in ALK-driven NB tumors. PMID:26299615

  6. New therapeutic strategies in neuroblastoma: combined targeting of a novel tyrosine kinase inhibitor and liposomal siRNAs against ALK.

    PubMed

    Di Paolo, Daniela; Yang, D; Pastorino, Fabio; Emionite, Laura; Cilli, Michele; Daga, Antonio; Destafanis, Elisa; Di Fiore, Annarita; Piaggio, Francesca; Brignole, Chiara; Xu, Xiaobao; Liang, Chris; Gibbons, James; Ponzoni, Mirco; Perri, Patrizia

    2015-10-06

    Many different aberrations in the Anaplastic Lymphoma Kinase (ALK) were found to be oncogenic drivers in several cancers including neuroblastoma (NB), therefore ALK is now considered a critical player in NB oncogenesis and a promising therapeutic target. The ALK-inhibitor crizotinib has a limited activity against the various ALK mutations identified in NB patients. We tested: the activity of the novel ALK-inhibitor X-396 administered alone or in combination with Targeted Liposomes carrying ALK-siRNAs (TL[ALK-siRNA]) that are active irrespective of ALK gene mutational status; the pharmacokinetic profiles and the biodistribution of X-396; the efficacy of X-396 versus crizotinib treatment in NB xenografts; whether the combination of X-396 with the TL[ALK-siRNA] could promote long-term survival in NB mouse models. X-396 revealed good bioavailability, moderate half-life, high mean plasma and tumor concentrations. X-396 was more effective than crizotinib in inhibiting in vitro cell proliferation of NB cells and in reducing tumor volume in subcutaneous NB models in a dose-dependent manner. In orthotopic NB xenografts, X-396 significantly increased life span independently of the ALK mutation status. In combination studies, all effects were significantly improved in the mice treated with TL[ALK-siRNA] and X-396 compared to mice receiving the single agents. Our findings provide a rational basis to design innovative molecular-based treatment combinations for clinical application in ALK-driven NB tumors.

  7. Profile of Ventana ALK (D5F3) companion diagnostic assay for non-small-cell lung carcinomas.

    PubMed

    Conde, Esther; Hernandez, Susana; Prieto, Mario; Martinez, Rebeca; Lopez-Rios, Fernando

    2016-06-01

    The development of several ALK inhibitors means that the importance of accurately identifying ALK-positive lung cancer has never been greater. Therefore, it is crucial that ALK testing assays become more standardized. The aim of this review is to comment on the recently FDA-approved VENTANA ALK (D5F3) Companion Diagnostic (CDx) Assay. This kit provides high sensitivity and specificity for the detection of ALK rearrangements and seamless integration into the laboratory workflow, with a fully automated analytical phase and fast interpretation. The use of controls increases the sensitivity and specificity and a dichotomous scoring approach enhances reproducibility.

  8. Alk1 controls arterial endothelial cell migration in lumenized vessels.

    PubMed

    Rochon, Elizabeth R; Menon, Prahlad G; Roman, Beth L

    2016-07-15

    Heterozygous loss of the arterial-specific TGFβ type I receptor, activin receptor-like kinase 1 (ALK1; ACVRL1), causes hereditary hemorrhagic telangiectasia (HHT). HHT is characterized by development of fragile, direct connections between arteries and veins, or arteriovenous malformations (AVMs). However, how decreased ALK1 signaling leads to AVMs is unknown. To understand the cellular mis-steps that cause AVMs, we assessed endothelial cell behavior in alk1-deficient zebrafish embryos, which develop cranial AVMs. Our data demonstrate that alk1 loss has no effect on arterial endothelial cell proliferation but alters arterial endothelial cell migration within lumenized vessels. In wild-type embryos, alk1-positive cranial arterial endothelial cells generally migrate towards the heart, against the direction of blood flow, with some cells incorporating into endocardium. In alk1-deficient embryos, migration against flow is dampened and migration in the direction of flow is enhanced. Altered migration results in decreased endothelial cell number in arterial segments proximal to the heart and increased endothelial cell number in arterial segments distal to the heart. We speculate that the consequent increase in distal arterial caliber and hemodynamic load precipitates the flow-dependent development of downstream AVMs.

  9. Alk1 and Alk5 inhibition by Nrp1 controls vascular sprouting downstream of Notch

    PubMed Central

    Aspalter, Irene Maria; Gordon, Emma; Dubrac, Alexandre; Ragab, Anan; Narloch, Jarek; Vizán, Pedro; Geudens, Ilse; Collins, Russell Thomas; Franco, Claudio Areias; Abrahams, Cristina Luna; Thurston, Gavin; Fruttiger, Marcus; Rosewell, Ian; Eichmann, Anne; Gerhardt, Holger

    2015-01-01

    Sprouting angiogenesis drives blood vessel growth in healthy and diseased tissues. Vegf and Dll4/Notch signalling cooperate in a negative feedback loop that specifies endothelial tip and stalk cells to ensure adequate vessel branching and function. Current concepts posit that endothelial cells default to the tip-cell phenotype when Notch is inactive. Here we identify instead that the stalk-cell phenotype needs to be actively repressed to allow tip-cell formation. We show this is a key endothelial function of neuropilin-1 (Nrp1), which suppresses the stalk-cell phenotype by limiting Smad2/3 activation through Alk1 and Alk5. Notch downregulates Nrp1, thus relieving the inhibition of Alk1 and Alk5, thereby driving stalk-cell behaviour. Conceptually, our work shows that the heterogeneity between neighbouring endothelial cells established by the lateral feedback loop of Dll4/Notch utilizes Nrp1 levels as the pivot, which in turn establishes differential responsiveness to TGF-β/BMP signalling. PMID:26081042

  10. The enzymatic activity of 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase is enhanced by NPM-ALK: new insights in ALK-mediated pathogenesis and the treatment of ALCL.

    PubMed

    Boccalatte, Francesco E; Voena, Claudia; Riganti, Chiara; Bosia, Amalia; D'Amico, Lucia; Riera, Ludovica; Cheng, Mangeng; Ruggeri, Bruce; Jensen, Ole N; Goss, Valerie L; Lee, Kimberly; Nardone, Julie; Rush, John; Polakiewicz, Roberto D; Comb, Michael J; Chiarle, Roberto; Inghirami, Giorgio

    2009-03-19

    Anaplastic large cell lymphoma represents a subset of neoplasms caused by translocations that juxtapose the anaplastic lymphoma kinase (ALK) to dimerization partners. The constitutive activation of ALK fusion proteins leads to cellular transformation through a complex signaling network. To elucidate the ALK pathways sustaining lymphomagenesis and tumor maintenance, we analyzed the tyrosine-kinase protein profiles of ALK-positive cell lines using 2 complementary proteomic-based approaches, taking advantage of a specific ALK RNA interference (RNAi) or cell-permeable inhibitors. A well-defined set of ALK-associated tyrosine phosphopeptides, including metabolic enzymes, kinases, ribosomal and cytoskeletal proteins, was identified. Validation studies confirmed that vasodilator-stimulated phosphoprotein and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (ATIC) associated with nucleophosmin (NPM)-ALK, and their phosphorylation required ALK activity. ATIC phosphorylation was documented in cell lines and primary tumors carrying ALK proteins and other tyrosine kinases, including TPR-Met and wild type c-Met. Functional analyses revealed that ALK-mediated ATIC phosphorylation enhanced its enzymatic activity, dampening the methotrexate-mediated transformylase activity inhibition. These findings demonstrate that proteomic approaches in well-controlled experimental settings allow the definition of informative proteomic profiles and the discovery of novel ALK downstream players that contribute to the maintenance of the neoplastic phenotype. Prediction of tumor responses to methotrexate may justify specific molecular-based chemotherapy.

  11. Targeted Disruption of ALK Reveals a Potential Role in Hypogonadotropic Hypogonadism

    PubMed Central

    Nord, Christoffer; Ahlgren, Ulf; Eriksson, Maria; Vernersson-Lindahl, Emma; Helland, Åslaug; Alexeyev, Oleg A.; Hallberg, Bengt; Palmer, Ruth H.

    2015-01-01

    Mice lacking ALK activity have previously been reported to exhibit subtle behavioral phenotypes. In this study of ALK of loss of function mice we present data supporting a role for ALK in hypogonadotropic hypogonadism in male mice. We observed lower level of serum testosterone at P40 in ALK knock-out males, accompanied by mild disorganization of seminiferous tubules exhibiting decreased numbers of GATA4 expressing cells. These observations highlight a role for ALK in testis function and are further supported by experiments in which chemical inhibition of ALK activity with the ALK TKI crizotinib was employed. Oral administration of crizotinib resulted in a decrease of serum testosterone levels in adult wild type male mice, which reverted to normal levels after cessation of treatment. Analysis of GnRH expression in neurons of the hypothalamus revealed a significant decrease in the number of GnRH positive neurons in ALK knock-out mice at P40 when compared with control littermates. Thus, ALK appears to be involved in hypogonadotropic hypogonadism by regulating the timing of pubertal onset and testis function at the upper levels of the hypothalamic-pituitary gonadal axis. PMID:25955180

  12. Identification of the transforming STRN-ALK fusion as a potential therapeutic target in the aggressive forms of thyroid cancer

    PubMed Central

    Kelly, Lindsey M.; Barila, Guillermo; Liu, Pengyuan; Evdokimova, Viktoria N.; Trivedi, Sumita; Panebianco, Federica; Gandhi, Manoj; Carty, Sally E.; Hodak, Steven P.; Luo, Jianhua; Dacic, Sanja; Yu, Yan P.; Nikiforova, Marina N.; Ferris, Robert L.; Altschuler, Daniel L.; Nikiforov, Yuri E.

    2014-01-01

    Thyroid cancer is a common endocrine malignancy that encompasses well-differentiated as well as dedifferentiated cancer types. The latter tumors have high mortality and lack effective therapies. Using a paired-end RNA-sequencing approach, we report the discovery of rearrangements involving the anaplastic lymphoma kinase (ALK) gene in thyroid cancer. The most common of these involves a fusion between ALK and the striatin (STRN) gene, which is the result of a complex rearrangement involving the short arm of chromosome 2. STRN-ALK leads to constitutive activation of ALK kinase via dimerization mediated by the coiled-coil domain of STRN and to a kinase-dependent, thyroid-stimulating hormone–independent proliferation of thyroid cells. Moreover, expression of STRN-ALK transforms cells in vitro and induces tumor formation in nude mice. The kinase activity of STRN-ALK and the ALK-induced cell growth can be blocked by the ALK inhibitors crizotinib and TAE684. In addition to well-differentiated papillary cancer, STRN-ALK was found with a higher prevalence in poorly differentiated and anaplastic thyroid cancers, and it did not overlap with other known driver mutations in these tumors. Our data demonstrate that STRN-ALK fusion occurs in a subset of patients with highly aggressive types of thyroid cancer and provide initial evidence suggesting that it may represent a therapeutic target for these patients. PMID:24613930

  13. Uterine ALK3 is essential during the window of implantation

    PubMed Central

    Monsivais, Diana; Clementi, Caterina; Peng, Jia; Titus, Mary M.; Barrish, James P.; Creighton, Chad J.; Lydon, John P.; DeMayo, Francesco J.; Matzuk, Martin M.

    2016-01-01

    The window of implantation is defined by the inhibition of uterine epithelial proliferation, structural epithelial cell remodeling, and attenuated estrogen (E2) response. These changes occur via paracrine signaling between the uterine epithelium and stroma. Because implantation defects are a major cause of infertility in women, identifying these signaling pathways will improve infertility interventions. Bone morphogenetic proteins (BMPs) are TGF-β family members that regulate the postimplantation and midgestation stages of pregnancy. In this study, we discovered that signaling via activin-like kinase 3 (ALK3/BMPR1A), a BMP type 1 receptor, is necessary for blastocyst attachment. Conditional knockout (cKO) of ALK3 in the uterus was obtained by producing Alk3flox/flox-Pgr-cre–positive females. Alk3 cKO mice are sterile and have defects in the luminal uterine epithelium, including increased microvilli density and maintenance of apical cell polarity. Moreover, Alk3 cKO mice exhibit an elevated uterine E2 response and unopposed epithelial cell proliferation during the window of implantation. We determined that dual transcriptional regulation of Kruppel-like factor 15 (Klf15), by both the transforming growth factor β (TGF-β) transcription factor SMAD family member 4 (SMAD4) and progesterone receptor (PR), is necessary to inhibit uterine epithelial cell proliferation, a key step for embryo implantation. Our findings present a convergence of BMP and steroid hormone signaling pathways in the regulation of uterine receptivity. PMID:26721398

  14. ALK-negative anaplastic large cell lymphoma with urinary bladder involvement diagnosed in urine cytology: A case report and literature review.

    PubMed

    Lobo, João; Henrique, Rui; Monteiro, Paula; Lobo, Cláudia

    2017-04-01

    Anaplastic large cell lymphoma is an aggressive T-cell neoplasm. It rarely involves the urinary bladder, with just twelve cases reported thus far and only one being ALK-negative. Immunophenotyping (particularly for ALK) is mandatory, both for prognostic and therapeutic reasons. Herein, we report the case of a patient with an ALK-negative anaplastic large cell lymphoma involving the bladder which was diagnosed and fully characterized by immunocytochemistry in urine cytology. The patient underwent a cystoscopy and the urine sample disclosed tumor diathesis background and aggregates of atypical cells, with evidence of multinucleation and mitotic figures. Immunocytochemistry revealed strong membrane/Golgi positivity for CD30 and negativity for ALK. The patient was submitted to transurethral resection for therapeutic purposes, which confirmed the diagnosis. To the best of our knowledge, this represents only the third case of anaplastic large cell lymphoma with bladder involvement diagnosed in urine cytology and the very first with diagnostic findings allowing for immunophenotyping of the disease in a bladder wash. The present report reinforces the role of urine cytology as a suitable method for establishing an earlier diagnosis and characterization of the disease, avoiding submitting patients to invasive procedures like transurethral resections. Diagn. Cytopathol. 2017;45:354-358. © 2016 Wiley Periodicals, Inc.

  15. Targeting stemness is an effective strategy to control EML4-ALK+ non-small cell lung cancer cells.

    PubMed

    Oh, Se Jin; Noh, Kyung Hee; Lee, Young-Ho; Hong, Soon-Oh; Song, Kwon-Ho; Lee, Hyo-Jung; Kim, Soyeon; Kim, Tae Min; Jeon, Ju-Hong; Seo, Jae Hong; Kim, Dong-Wan; Kim, Tae Woo

    2015-11-24

    The fusion between anaplastic lymphoma kinase (ALK) and echinoderm microtubule-associated protein-like 4 (EML4) is a causative factor in a unique subset of patients with non-small cell lung carcinoma (NSCLC). Although the inhibitor crizotinib, as it blocks the kinase activity of the resulting EML4-ALK fusion protein, displays remarkable initial responses, a fraction of NSCLC cases eventually become resistant to crizotinib by acquiring mutations in the ALK domain or activating bypass pathways via EGFR, KIT, or KRAS. Cancer stem cell (CSC) theory provides a plausible explanation for acquisition of tumorigenesis and resistance. However, the question as to whether EML4-ALK-driven tumorigenesis is linked with the stem-like property and whether the stemness is an effective target in controlling EML4-ALK+ NSCLC including crizotinib-resistant NSCLC cells has not been addressed. Here, we report that stem-like properties stem from ALK activity in EML4-ALK+ NSCLC cells. Notably, treatment with rapamycin, a CSC targeting agent, attenuates stem-like phenotypes of the EML4-ALK+ cells, which increased capability of tumor formation and higher expression of stemness-associated molecules such as ALDH, NANOG, and OCT4. Importantly, combinational treatment with rapamycin and crizotinib leads to synergistic anti-tumor effects on EML4-ALK+ NSCLC cells as well as on those resistant to crizotinib. Thus, we provide a proof of principle that targeting stemness would be a novel strategy to control intractable EML4-ALK+ NSCLC.

  16. ALK and ROS1 as targeted therapy paradigms and clinical implications to overcome crizotinib resistance.

    PubMed

    Ye, Mingxiang; Zhang, Xinxin; Li, Nan; Zhang, Yong; Jing, Pengyu; Chang, Ning; Wu, Jianxiong; Ren, Xinling; Zhang, Jian

    2016-03-15

    During the past decade, more than 10 targetable oncogenic driver genes have been validated in non-small cell lung cancer (NSCLC). Anaplastic lymphoma kinase (ALK) and ROS1 kinase are two new driver genes implicated in ALK- and ROS1-rearranged NSCLC. Inhibition of ALK and ROS1 by crizotinib has been reported to be highly effective and well tolerated in these patients. However, resistance to crizotinib emerges years after treatment, and increasing efforts have been made to overcome this issue. Here, we review the biology of ALK and ROS1 and their roles in cancer progression. We also summarize the ongoing and completed clinical trials validating ALK and ROS1 as targets for cancer treatment. In the last section of the review, we will discuss the molecular mechanisms of crizotinib resistance and focus approaches to overcome it. This review describes an exciting new area of research and may provide new insights for targeted cancer therapies.

  17. RANBP2-ALK fusion combined with monosomy 7 in acute myelomonocytic leukemia.

    PubMed

    Lim, Ji-Hun; Jang, Seongsoo; Park, Chan-Jeoung; Cho, Young-Uk; Lee, Je-Hwan; Lee, Kyoo-Hyung; Lee, Jin-Ok; Shin, Jong-Yeon; Kim, Jong-Il; Huh, Jooryung; Seo, Eul-Ju

    2014-01-01

    Anaplastic lymphoma receptor tyrosine kinase (ALK) is located on chromosome 2p23; the chromosomal rearrangements of this gene are common genetic alterations, resulting in the creation of multiple fusion genes involved in tumorigenesis. However, the presence of an ALK fusion in myeloid malignancies is extremely rare. We report a case of acute myelomonocytic leukemia in a 31-year-old woman with an unusual rearrangement between RAN-binding protein 2 (RANBP2) and ALK and a karyotype of 45,XX,inv(2)(p23q21),-7[20]. We detected an ALK rearrangement using fluorescence in situ hybridization, identified the ALK fusion partner by using RNA transcriptome sequencing, and demonstrated the RANBP2-ALK fusion transcript by reverse transcriptase--PCR and Sanger sequencing. Immunohistochemistry for ALK showed strong staining of the nuclear membrane in leukemic cells. The patient had an unfavorable clinical course. Our results, together with a literature review, suggest the RANBP2-ALK fusion combined with monosomy 7 may be related to a unique clonal hematologic disorder of childhood and adolescence, characterized by myelomonocytic leukemia and a poor prognosis.

  18. EML4-ALK induces epithelial–mesenchymal transition consistent with cancer stem cell properties in H1299 non-small cell lung cancer cells

    SciTech Connect

    Guo, Fuchun; Liu, Xiaoke Qing, Qin Sang, Yaxiong Feng, Chengjun Li, Xiaoyu Jiang, Li Su, Pei Wang, Yongsheng

    2015-04-10

    The echinoderm microtubule-associated protein-like 4(EML4) – anaplastic lymphoma kinase (ALK) fusion gene has been identified as a driver mutation in non-small-cell lung cancer (NSCLC). However, the role of EML4-ALK in malignant transformation is not entirely clear. Here, for the first time, we showed that H1299 NSCLC cells stably expressing EML4-ALK acquire EMT phenotype, associated with enhanced invasive migration and increased expression of EMT-inducing transcription factors. H1299-EML4-ALK cells also displayed cancer stem cell-like properties with a concomitant up-regulation of CD133 and enhanced ability of mammospheres formation. Moreover, we found that inhibition of ERK1/2 reversed EMT induced by EML4-ALK in H1299 cells. Taken together, these results suggested that EML4-ALK induced ERK activation is mechanistically associated with EMT phenotype. Thus, inhibition of ERK signaling pathway could be a potential strategy in treatment of NSCLC patients with EML4-ALK translocation. - Highlights: • EML4-ALK induced epithelial–mesenchymal transition in H1299 cells. • Expression of EML4-ALK promotes invasion and migration in vitro. • EML4-ALK enhanced sphere formation and stem cell-like properties in H1299 cells. • Blockage of ERK1/2 reverse Epithelial–Mesenchymal transition induced by EML4-ALK.

  19. Automation of ALK gene rearrangement testing with fluorescence in situ hybridization (FISH): a feasibility study.

    PubMed

    Zwaenepoel, Karen; Merkle, Dennis; Cabillic, Florian; Berg, Erica; Belaud-Rotureau, Marc-Antoine; Grazioli, Vittorio; Herelle, Olga; Hummel, Michael; Le Calve, Michele; Lenze, Dido; Mende, Stefanie; Pauwels, Patrick; Quilichini, Benoit; Repetti, Elena

    2015-02-01

    In the past several years we have observed a significant increase in our understanding of molecular mechanisms that drive lung cancer. Specifically in the non-small cell lung cancer sub-types, ALK gene rearrangements represent a sub-group of tumors that are targetable by the tyrosine kinase inhibitor Crizotinib, resulting in significant reductions in tumor burden. Phase II and III clinical trials were performed using an ALK break-apart FISH probe kit, making FISH the gold standard for identifying ALK rearrangements in patients. FISH is often considered a labor and cost intensive molecular technique, and in this study we aimed to demonstrate feasibility for automation of ALK FISH testing, to improve laboratory workflow and ease of testing. This involved automation of the pre-treatment steps of the ALK assay using various protocols on the VP 2000 instrument, and facilitating automated scanning of the fluorescent FISH specimens for simplified enumeration on various backend scanning and analysis systems. The results indicated that ALK FISH can be automated. Significantly, both the Ikoniscope and BioView system of automated FISH scanning and analysis systems provided a robust analysis algorithm to define ALK rearrangements. In addition, the BioView system facilitated consultation of difficult cases via the internet.

  20. U.S. Food and Drug Administration approval: crizotinib for treatment of advanced or metastatic non-small cell lung cancer that is anaplastic lymphoma kinase positive.

    PubMed

    Malik, Shakun M; Maher, Virginia Ellen; Bijwaard, Karen E; Becker, Robert L; Zhang, Lijun; Tang, Shenghui W; Song, Pengfei; Liu, Qi; Marathe, Anshu; Gehrke, Brenda; Helms, Whitney; Hanner, Diane; Justice, Robert; Pazdur, Richard

    2014-04-15

    On August 26, 2011, the U.S. Food and Drug Administration (FDA) approved crizotinib (XALKORI Capsules, Pfizer Inc.) for treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK) positive as detected by an FDA-approved test. The Vysis ALK Break-Apart FISH Probe Kit (Abbott Molecular, Inc.) was approved concurrently. In two multicenter, single-arm trials, patients with locally advanced or metastatic ALK-positive NSCLC previously treated with one or more systemic therapies received crizotinib orally at a dose of 250 mg twice daily. In 119 patients with ALK-positive NSCLC by local trial assay, the objective response rate (ORR) was 61% [95% confidence intervals (CI), 52%-70%] with a median response duration of 48 weeks. In 136 patients with ALK-positive NSCLC by the to-be-marketed test, the ORR was 50% (95% CI, 42%-59%) with a median response duration of 42 weeks. The most common adverse reactions (≥25%) were vision disorder, nausea, diarrhea, vomiting, edema, and constipation. Accelerated approval was granted on the basis of the high ORRs and durable responses. On November 20, 2013, crizotinib received full approval based on an improvement in progression-free survival in patients with metastatic ALK-positive NSCLC previously treated with one platinum-based chemotherapy regimen.

  1. Resensitization to Crizotinib by the Lorlatinib ALK Resistance Mutation L1198F.

    PubMed

    Shaw, Alice T; Friboulet, Luc; Leshchiner, Ignaty; Gainor, Justin F; Bergqvist, Simon; Brooun, Alexei; Burke, Benjamin J; Deng, Ya-Li; Liu, Wei; Dardaei, Leila; Frias, Rosa L; Schultz, Kate R; Logan, Jennifer; James, Leonard P; Smeal, Tod; Timofeevski, Sergei; Katayama, Ryohei; Iafrate, A John; Le, Long; McTigue, Michele; Getz, Gad; Johnson, Ted W; Engelman, Jeffrey A

    2016-01-07

    In a patient who had metastatic anaplastic lymphoma kinase (ALK)-rearranged lung cancer, resistance to crizotinib developed because of a mutation in the ALK kinase domain. This mutation is predicted to result in a substitution of cysteine by tyrosine at amino acid residue 1156 (C1156Y). Her tumor did not respond to a second-generation ALK inhibitor, but it did respond to lorlatinib (PF-06463922), a third-generation inhibitor. When her tumor relapsed, sequencing of the resistant tumor revealed an ALK L1198F mutation in addition to the C1156Y mutation. The L1198F substitution confers resistance to lorlatinib through steric interference with drug binding. However, L1198F paradoxically enhances binding to crizotinib, negating the effect of C1156Y and resensitizing resistant cancers to crizotinib. The patient received crizotinib again, and her cancer-related symptoms and liver failure resolved. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT01970865.).

  2. ALK oncoproteins in atypical inflammatory myofibroblastic tumours: novel RRBP1-ALK fusions in epithelioid inflammatory myofibroblastic sarcoma.

    PubMed

    Lee, Jen-Chieh; Li, Chien-Feng; Huang, Hsuan-Ying; Zhu, Mei-Jun; Mariño-Enríquez, Adrián; Lee, Chung-Ta; Ou, Wen-Bin; Hornick, Jason L; Fletcher, Jonathan A

    2017-02-01

    ALK oncogenic activation mechanisms were characterized in four conventional spindle-cell inflammatory myofibroblastic tumours (IMT) and five atypical IMT, each of which had ALK genomic perturbations. Constitutively activated ALK oncoproteins were purified by ALK immunoprecipitation and electrophoresis, and were characterized by mass spectrometry. The four conventional IMT had TPM3/4-ALK fusions (two cases) or DCTN1-ALK fusions (two cases), whereas two atypical spindle-cell IMT had TFG-ALK and TPM3-ALK fusion in one case each, and three epithelioid inflammatory myofibroblastic sarcomas had RANBP2-ALK fusions in two cases, and a novel RRBP1-ALK fusion in one case. The epithelioid inflammatory myofibroblastic sarcoma with RRBP1-ALK fusion had cytoplasmic ALK expression with perinuclear accentuation, different from the nuclear membranous ALK localization in epithelioid inflammatory myofibroblastic sarcomas with RANBP2-ALK fusions. Evaluation of three additional uncharacterized epithelioid inflammatory myofibroblastic sarcomas with ALK cytoplasmic/perinuclear- accentuation expression demonstrated RRBP1-ALK fusion in two cases. These studies show that atypical spindle-cell IMT can utilize the same ALK fusion mechanisms described previously in conventional IMT, whereas in clinically aggressive epithelioid inflammatory myofibroblastic sarcoma we identify a novel recurrent ALK oncogenic mechanism, resulting from fusion with the RRBP1 gene. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  3. Analysis of clinical characteristics and prognosis of patients with anaplastic lymphoma kinase‐positive and surgically resected lung adenocarcinoma

    PubMed Central

    Tao, Hong; Cai, Yiran; Shi, Liang; Tang, Junfang; Liu, Zhidong; Wang, Zitong; Bai, Lianqi

    2016-01-01

    Background Recent research into lung cancer‐related driver genes has identified a distinctive molecular subtype of non‐small cell lung cancer (NSCLC) – anaplastic lymphoma kinase (ALK)‐positive NSCLC. We evaluated the clinical features and survival rates of ALK‐positive lung adenocarcinoma patients who had undergone surgery but had not received ALK inhibitor therapy, along with the characteristics of patients with distant metastases. Methods Clinical data of 40 patients with ALK‐positive, postsurgical lung adenocarcinoma were retrospectively analyzed. Relationships between the patients’ clinical characteristics, distant metastases, and their disease‐free survival (DFS) and overall survival (OS) rates were assessed. Results Most patients were relatively young, never‐smokers, had peripheral tumors, and the tumors were either moderately or poorly differentiated. The most common organ of distant metastases was the brain. The median time from surgery to brain metastasis was 17.2 months. The median OS following brain metastasis was 9.4 months. DFS in patients with early stage disease, peripheral tumors, no lymph node metastases, and treated with adjuvant therapy was significantly longer than for those with late stage disease (P = 0.015), central tumors (P = 0.000), lymph node metastases (P = 0.026), and not treated with adjuvant therapy (P = 0.000). Patients with early stage disease, peripheral tumors, and treated with adjuvant therapy obtained markedly longer OS than those with late stage disease (P = 0.021), central tumors (P = 0.003), and not treated with adjuvant therapy (P = 0.006). Conclusion Patients with ALK‐positive surgically resected lung adenocarcinoma have distinctive clinical characteristics. The brain is the most common site of extrapulmonary metastasis. Survival is associated with stage, tumor location, and the administration of adjuvant therapy. PMID:27779369

  4. Internalization and Down-Regulation of the ALK Receptor in Neuroblastoma Cell Lines upon Monoclonal Antibodies Treatment

    PubMed Central

    Mazot, Pierre; Cazes, Alex; Dingli, Florent; Degoutin, Joffrey; Irinopoulou, Théano; Boutterin, Marie-Claude; Lombard, Bérangère; Loew, Damarys; Hallberg, Bengt; Palmer, Ruth Helen; Delattre, Olivier

    2012-01-01

    Recently, activating mutations of the full length ALK receptor, with two hot spots at positions F1174 and R1275, have been characterized in sporadic cases of neuroblastoma. Here, we report similar basal patterns of ALK phosphorylation between the neuroblastoma IMR-32 cell line, which expresses only the wild-type receptor (ALKWT), and the SH-SY5Y cell line, which exhibits a heterozygous ALK F1174L mutation and expresses both ALKWT and ALKF1174L receptors. We demonstrate that this lack of detectable increased phosphorylation in SH-SY5Y cells is a result of intracellular retention and proteasomal degradation of the mutated receptor. As a consequence, in SH-SY5Y cells, plasma membrane appears strongly enriched for ALKWT whereas both ALKWT and ALKF1174L were present in intracellular compartments. We further explored ALK receptor trafficking by investigating the effect of agonist and antagonist mAb (monoclonal antibodies) on ALK internalization and down-regulation, either in SH-SY5Y cells or in cells expressing only ALKWT. We observe that treatment with agonist mAbs resulted in ALK internalization and lysosomal targeting for receptor degradation. In contrast, antagonist mAb induced ALK internalization and recycling to the plasma membrane. Importantly, we correlate this differential trafficking of ALK in response to mAb with the recruitment of the ubiquitin ligase Cbl and ALK ubiquitylation only after agonist stimulation. This study provides novel insights into the mechanisms regulating ALK trafficking and degradation, showing that various ALK receptor pools are regulated by proteasome or lysosome pathways according to their intracellular localization. PMID:22479414

  5. ALK Signaling and Target Therapy in Anaplastic Large Cell Lymphoma

    PubMed Central

    Tabbó, Fabrizio; Barreca, Antonella; Piva, Roberto; Inghirami, Giorgio

    2012-01-01

    The discovery by Morris et al. (1994) of the genes contributing to the t(2;5)(p23;q35) translocation has laid the foundation for a molecular based recognition of anaplastic large cell lymphoma and highlighted the need for a further stratification of T-cell neoplasia. Likewise the detection of anaplastic lymphoma kinase (ALK) genetic lesions among many human cancers has defined unique subsets of cancer patients, providing new opportunities for innovative therapeutic interventions. The objective of this review is to appraise the molecular mechanisms driving ALK-mediated transformation, and to maintain the neoplastic phenotype. The understanding of these events will allow the design and implementation of novel tailored strategies for a well-defined subset of cancer patients. PMID:22649787

  6. Application of AlkBGT and AlkL from Pseudomonas putida GPo1 for Selective Alkyl Ester ω-Oxyfunctionalization in Escherichia coli

    PubMed Central

    Eggink, Gerrit; Weusthuis, Ruud A.

    2016-01-01

    ABSTRACT The enzyme system AlkBGT from Pseudomonas putida GPo1 can efficiently ω-functionalize fatty acid methyl esters. Outer membrane protein AlkL boosts this ω-functionalization. In this report, it is shown that whole cells of Escherichia coli expressing the AlkBGT system can also ω-oxidize ethyl nonanoate (NAEE). Coexpression of AlkBGT and AlkL resulted in 1.7-fold-higher ω-oxidation activity on NAEE. With this strain, initial activity on NAEE was 70 U/g (dry weight) of cells (gcdw), 67% of the initial activity on methyl nonanoate. In time-lapse conversions with 5 mM NAEE the main product was 9-hydroxy NAEE (3.6 mM), but also 9-oxo NAEE (0.1 mM) and 9-carboxy NAEE (0.6 mM) were formed. AlkBGT also ω-oxidized ethyl, propyl, and butyl esters of fatty acids ranging from C6 to C10. Increasing the length of the alkyl chain improved the ω-oxidation activity of AlkBGT on esters of C6 and C7 fatty acids. From these esters, application of butyl hexanoate resulted in the highest ω-oxidation activity, 82 U/gcdw. Coexpression of AlkL only had a positive effect on ω-functionalization of substrates with a total length of C11 or longer. These findings indicate that AlkBGT(L) can be applied as a biocatalyst for ω-functionalization of ethyl, propyl, and butyl esters of medium-chain fatty acids. IMPORTANCE Fatty acid esters are promising renewable starting materials for the production of ω-hydroxy fatty acid esters (ω-HFAEs). ω-HFAEs can be used to produce sustainable polymers. Chemical conversion of the fatty acid esters to ω-HFAEs is challenging, as it generates by-products and needs harsh reaction conditions. Biocatalytic production is a promising alternative. In this study, biocatalytic conversion of fatty acid esters toward ω-HFAEs was investigated using whole cells. This was achieved with recombinant Escherichia coli cells that produce the AlkBGT enzymes. These enzymes can produce ω-HFAEs from a wide variety of fatty acid esters. Medium-chain-length acids (C

  7. Concurrent EGFR Mutation and ALK Translocation in Non-Small Cell Lung Cancer

    PubMed Central

    Thomas, Sachdev; Bank, Bruce; Fishkin, Paul; Mooney, Colin; Salgia, Ravi

    2016-01-01

    Epidermal growth factor receptor (EGFR) mutations and anaplastic large-cell lymphoma kinase (ALK) rearrangements are now routine biomarkers that have been incorporated into the practice of managing non-small cell lung cancer (NSCLC). Historically, the two molecular alterations have been viewed as mutually exclusive, but recent identified cases suggest otherwise. In this report, we describe cases of lung cancer with concurrent EGFR mutation and ALK rearrangement and identify their clinical characteristics. Non-small cell lung cancer patients with multiple molecular alterations were retrospectively analyzed from an academic referral center from 2011–2013. An additional review was conducted of reported cases with dual alterations. Four cases of NSCLC with alterations in both EGFR and ALK were identified and evaluated with 16 published cases for a total of 20 cases. The age of patients ranged from 37 to 77 years. Nine patients were never smokers. The disease control rates in patients treated with EGFR inhibitors and ALK inhibitors were 46% (6/13) and 71% (5/7), respectively. This series highlights the importance of comprehensive molecular profiling of newly diagnosed lung cancer, as NSCLC may be driven by concurrent molecular alterations. EGFR- and ALK-targeted therapies appear to have modest activity in patients with tumors possessing both alterations. Dual-altered NSCLC patients may have distinct clinical characteristics warranting further study. Combination targeted therapy or novel multi-targeted tyrosine kinase inhibitors may prove important in these patients, though necessary studies remain ongoing. PMID:27026837

  8. Patient positioning in the proton radiotherapy era

    PubMed Central

    2010-01-01

    The main hindrance to the diffusion of proton therapy facilities is the high cost for gantry installations. An alternative technical option is provided by fixed-beam treatment rooms, where the patient is rotated and translated in space with a robotic arm solution to enable beam incidence from various angles. The technological efforts based on robotic applications made up to now for patient positioning in proton beam facilities are described here, highlighting their limitations and perspectives. PMID:20465816

  9. Activin A Stimulates Aromatase via the ALK4-Smad Pathway in Endometriosis

    PubMed Central

    Zheng, Juan; Qu, Juan; Lu, Pinhong; Mao, Yundong; Qi, Xiaochen; Ji, Hui; Liu, Jiayin

    2016-01-01

    Endometriosis is an estrogen-dependent disease. We previously found that the expression of Activin A was upregulated in the peritoneal fluid of patients with endometriosis. The results of the present study indicated that Activin A induced estradiol secretion and P450arom expression in endometrial stromal cells (ESCs) derived from endometriosis patients. The mechanism of estrogenic synthesis was regulated by the Activin-Smad pathway in endometrial lesions. The data showed that the effect of Activin A on ESCs was partially abrogated by pretreatment with an inhibitor of ALK4 (the type I receptor, ActRIB) and Smad4-siRNA. Cumulatively, these data suggest that Activin A promotes the secretion of estradiol from ESCs by increasing the expression of P450arom via the ALK4-Smad pathway. These findings indicate the ALK4-Smad pathway may promote ectopic lesion survival and development. PMID:27833918

  10. L1198F Mutation Resensitizes Crizotinib to ALK by Altering the Conformation of Inhibitor and ATP Binding Sites

    PubMed Central

    Li, Jian; Sun, Rong; Wu, Yuehong; Song, Mingzhu; Li, Jia; Yang, Qianye; Chen, Xiaoyi; Bao, Jinku; Zhao, Qi

    2017-01-01

    The efficacy of anaplastic lymphoma kinase (ALK) positive non-small-cell lung cancer (NSCLC) treatment with small molecule inhibitors is greatly challenged by acquired resistance. A recent study reported the newest generation inhibitor resistant mutation L1198F led to the resensitization to crizotinib, which is the first Food and Drug Administration (FDA) approved drug for the treatment of ALK-positive NSCLC. It is of great importance to understand how this extremely rare event occurred for the purpose of overcoming the acquired resistance of such inhibitors. In this study, we exploited molecular dynamics (MD) simulation to dissect the molecular mechanisms. Our MD results revealed that L1198F mutation of ALK resulted in the conformational change at the inhibitor site and altered the binding affinity of ALK to crizotinib and lorlatinib. L1198F mutation also affected the autoactivation of ALK as supported by the identification of His1124 and Tyr1278 as critical amino acids involved in ATP binding and phosphorylation. Our findings are valuable for designing more specific and potent inhibitors for the treatment of ALK-positive NSCLC and other types of cancer. PMID:28245558

  11. Renal transplantation in a HIV positive patient

    PubMed Central

    Mann, A.; Soundararajan, P.; Shroff, S.

    2009-01-01

    Historically HIV positive patients were considered a contraindication for renal transplant. After the year 1996, with the introduction of HAART the retropositive patients live longer and therefore end stage organ disease is now an increasingly important cause of mortality and morbidity in these patients. Here we report our experience for the first time in India. A forty nine year old hypertensive female from Africa who was diagnosed chronic kidney disease and retropositive status, progressed to end stage renal disease and underwent live related renal transplant at our centre. PMID:20436733

  12. Atypical Carcinoid Tumor with Anaplastic Lymphoma Kinase (ALK) Rearrangement Successfully Treated by an ALK Inhibitor.

    PubMed

    Nakajima, Masayuki; Uchiyama, Naoki; Shigemasa, Rie; Matsumura, Takeshi; Matsuoka, Ryota; Nomura, Akihiro

    This is the first report in which crizotinib, an anaplastic lymphoma kinase (ALK) inhibitor, reduced an atypical carcinoid tumor with ALK rearrangement. A 70-year-old man developed a tumor in the left lung and multiple metastases to the lung and brain. The pathology of transbronchial biopsied specimens demonstrated an atypical carcinoid pattern. Combined with immunohistochemical findings, we diagnosed the tumor as atypical carcinoid. ALK gene rearrangement was observed by both immunohistochemical (IHC) and fluorescence in situ hybridization. He was treated with chemotherapy as first-line therapy, however, the tumor did not respond to chemotherapy. Thereafter, he was treated with crizotinib, which successfully reduced the tumors.

  13. Kinetic mechanism for the excision of hypoxanthine by Escherichia coli AlkA and evidence for binding to DNA ends.

    PubMed

    Zhao, Boyang; O'Brien, Patrick J

    2011-05-24

    The Escherichia coli 3-methyladenine DNA glycosylase II protein (AlkA) recognizes a broad range of oxidized and alkylated base lesions and catalyzes the hydrolysis of the N-glycosidic bond to initiate the base excision repair pathway. Although the enzyme was one of the first DNA repair glycosylases to be discovered more than 25 years ago and there are multiple crystal structures, the mechanism is poorly understood. Therefore, we have characterized the kinetic mechanism for the AlkA-catalyzed excision of the deaminated purine, hypoxanthine. The multiple-turnover glycosylase assays are consistent with Michaelis-Menten kinetics. However, under single-turnover conditions that are commonly employed for studying other DNA glycosylases, we observe an unusual biphasic protein saturation curve. Initially, the observed rate constant for excision increases with an increasing level of AlkA protein, but at higher protein concentrations, the rate constant decreases. This behavior can be most easily explained by tight binding to DNA ends and by crowding of multiple AlkA protamers on the DNA. Consistent with this model, crystal structures have shown the preferential binding of AlkA to DNA ends. By varying the position of the lesion, we identified an asymmetric substrate that does not show inhibition at higher concentrations of AlkA, and we performed pre-steady state and steady state kinetic analysis. Unlike the situation in other glycosylases, release of the abasic product is faster than N-glycosidic bond cleavage. Nevertheless, AlkA exhibits significant product inhibition under multiple-turnover conditions, and it binds approximately 10-fold more tightly to an abasic site than to a hypoxanthine lesion site. This tight binding could help protect abasic sites when the adaptive response to DNA alkylation is activated and very high levels of AlkA protein are present.

  14. Alk1 and Alk2 are two new cell cycle-regulated haspin-like proteins in budding yeast.

    PubMed

    Nespoli, Alessandro; Vercillo, Raffaella; di Nola, Lisa; Diani, Laura; Giannattasio, Michele; Plevani, Paolo; Muzi-Falconi, Marco

    2006-07-01

    Haspin is a protein kinase identified in mouse and human cells, and genes coding for haspin-like proteins are present in virtually all eukaryotic genomes sequenced so far. Two haspin homologues, called Alk1 and Alk2, are present in the yeast Saccharomyces cerevisiae. Both Alk1 and Alk2 exhibit a weak auto-kinase activity in vitro, are phosphoproteins in vivo and are hyperphosphorylated in response to DNA damage. The amount and modification of the two proteins is greatly regulated during the cell cycle. In fact, Alk1 and Alk2 levels peak in mitosis and late-S/G2, respectively, and phosphorylation of both proteins is maximal in mitosis. Control of protein stability plays a major role in Alk2 regulation. The half-life of Alk2 is particularly short in G1; mutagenesis and genetic analysis indicate that its degradation is controlled by the APC pathway. Overexpression of ALK2, but not of ALK1, causes a mitotic arrest, which is correlated to the kinase activity of the protein. This finding, together with its cell cycle regulation, suggests a role for Alk2 in the control of mitosis.

  15. Beyond ALK-RET, ROS1 and other oncogene fusions in lung cancer

    PubMed Central

    Nakaoku, Takashi; Tsuta, Koji; Tsuchihara, Katsuya; Matsumoto, Shingo; Yoh, Kiyotaka; Goto, Koichi

    2015-01-01

    Fusions of the RET and ROS1 protein tyrosine kinase oncogenes with several partner genes were recently identified as new targetable genetic aberrations in cases of non-small cell lung cancer (NSCLC) lacking activating EGFR, KRAS, ALK, BRAF, or HER2 oncogene aberrations. RET and ROS1 fusion-positive tumors are mainly observed in young, female, and/or never smoking patients. Studies based on in vitro and in vivo (i.e., mouse) models and studies of several fusion-positive patients indicate that inhibiting the kinase activity of the RET and ROS1 fusion proteins is a promising therapeutic strategy. Accordingly, there are several ongoing clinical trials aimed at examining the efficacy of tyrosine kinase inhibitors (TKIs) against RET and ROS1 proteins in patients with fusion-positive lung cancer. Other gene fusions (NTRK1, NRG1, and FGFR1/2/3) that are targetable by existing TKIs have also been identified in NSCLCs. Options for personalized lung cancer therapy will be increased with the help of multiplex diagnosis systems able to detect multiple druggable gene fusions. PMID:25870798

  16. Patient position verification using CT images.

    PubMed

    Kress, J; Minohara, S; Endo, M; Debus, J; Kanai, T

    1999-06-01

    The use of ions in the radiotherapy of cancer patients requires an accurate patient positioning in order to exploit its potential benefits. Using CT images as the basis for the setup verification offers the advantage of a high in-plane resolution in combination with a geometrically accurate, volumetric information. Before each fraction a single CT slice is acquired at the isocenter level after the positioning procedure. This single slice is registered to the planning CT cube using automated image registration algorithms. Thus any erreonous translation or rotation can be detected and quantified. The registration process involves the interpolation of the volumetric data, the calculation of an energy function, and the minimization of this energy function. Several data interpolation functions as well as minimization algorithms were compared. CT studies with a head phantom were performed in which defined translations and rotations were simulated by moving a motor-driven treatment chair. Different slice thicknesses and anatomical sites were studied to investigate their potential influence on the registration accuracy. The accuracy of the registration was found to be a fraction of a voxel size for suitable combinations of algorithms (typically better than 0.16 mm/deg). A significant dependancy of the registration accuracy on the CT slice thickness and the anatomical site was found (the accuracy ranges from 0.05 mm/deg to 0.16 mm/deg depending on the site). The calculation time is dependant on the used algorithms and the magnitude of the setup error. For the standard combination of algorithms as proposed by the authors (Downhill Simplex minimization with Trilinear interpolation) the typical calculation time is about 20 s for a Sun UltraSPARC processor. Taking into account the mechanical accuracy of the setup device (motor-driven chair) the registration of CT images is thus a useful tool for detecting and quantifying any significant error in the patient position.

  17. Basic Knee Arthroscopy Part 1: Patient Positioning

    PubMed Central

    Ward, Benjamin D.; Lubowitz, James H.

    2013-01-01

    Knee arthroscopy is an important diagnostic and therapeutic tool in the management of disorders of the knee. In a series of 4 articles, the basics of knee arthroscopy are reviewed. In this article (part 1), patient positioning, tourniquet placement, and draping are reviewed. Meticulous attention to these details allows surgical access to the compartments of the knee. A circumferential leg holder or a lateral post allows the application of varus and valgus forces to open the medial and lateral compartments of the knee. PMID:24892015

  18. An Unusual Case of Systemic Inflammatory Myofibroblastic Tumor with Successful Treatment with ALK-Inhibitor

    PubMed Central

    Jacob, Sanjivini V.; Reith, John D.; Kojima, Angerika Y.; Williams, William D.; Liu, Chen; Vila Duckworth, Lizette

    2014-01-01

    Systemic inflammatory myofibroblastic tumor is an exceedingly rare entity. A 45-year-old Hispanic female presented with a 6-month history of left-sided thigh pain, low back pain, and generalized weakness. PET/CT scan revealed abnormal activity in the liver, adrenal gland, and pancreas. MRI of the abdomen demonstrated two 6-7 cm masses in the liver. MRI of the lumbar spine demonstrated lesions in the L2 to L4 spinous processes, paraspinal muscles, and subcutaneous tissues, as well as an 8 mm enhancing intradural lesion at T11, all thought to be metastatic disease. A biopsy of the liver showed portal tract expansion by a spindle cell proliferation rich in inflammation. Tumor cells showed immunoreactivity for smooth muscle actin and anaplastic lymphoma kinase 1 (ALK1). Tissue from the L5 vertebra showed a process histologically identical to that seen in the liver. FISH analysis of these lesions demonstrated an ALK (2p23) gene rearrangement. The patient was successfully treated with an ALK-inhibitor, Crizotinib, and is now in complete remission. We present the first reported case, to our knowledge, of inflammatory myofibroblastic tumor with systemic manifestations and ALK translocation. This case is a prime example of how personalized medicine has vastly improved patient care through the use of molecular-targeted therapy. PMID:25045570

  19. Concurrent progress of reprogramming and gene correction to overcome therapeutic limitation of mutant ALK2-iPSC

    PubMed Central

    Kim, Bu-Yeo; Jeong, SangKyun; Lee, Seo-Young; Lee, So Min; Gweon, Eun Jeong; Ahn, Hyunjun; Kim, Janghwan; Chung, Sun-Ku

    2016-01-01

    Fibrodysplasia ossificans progressiva (FOP) syndrome is caused by mutation of the gene ACVR1, encoding a constitutive active bone morphogenetic protein type I receptor (also called ALK2) to induce heterotopic ossification in the patient. To genetically correct it, we attempted to generate the mutant ALK2-iPSCs (mALK2-iPSCs) from FOP-human dermal fibroblasts. However, the mALK2 leads to inhibitory pluripotency maintenance, or impaired clonogenic potential after single-cell dissociation as an inevitable step, which applies gene-correction tools to induced pluripotent stem cells (iPSCs). Thus, current iPSC-based gene therapy approach reveals a limitation that is not readily applicable to iPSCs with ALK2 mutation. Here we developed a simplified one-step procedure by simultaneously introducing reprogramming and gene-editing components into human fibroblasts derived from patient with FOP syndrome, and genetically treated it. The mixtures of reprogramming and gene-editing components are composed of reprogramming episomal vectors, CRISPR/Cas9-expressing vectors and single-stranded oligodeoxynucleotide harboring normal base to correct ALK2 c.617G>A. The one-step-mediated ALK2 gene-corrected iPSCs restored global gene expression pattern, as well as mineralization to the extent of normal iPSCs. This procedure not only helps save time, labor and costs but also opens up a new paradigm that is beyond the current application of gene-editing methodologies, which is hampered by inhibitory pluripotency-maintenance requirements, or vulnerability of single-cell-dissociated iPSCs. PMID:27256111

  20. A malignant inflammatory myofibroblastic tumor of the hypopharynx harboring the 3a/b variants of the EML4-ALK fusion gene

    PubMed Central

    Muscarella, Lucia Anna; Rossi, Giulio; Trombetta, Domenico; La Torre, Annamaria; Di Candia, Leonarda; Mengoli, Maria Cecilia; Sparaneo, Angelo; Fazio, Vito Michele; Graziano, Paolo

    2017-01-01

    Inflammatory myofibroblastic tumors (IMT) in the head and neck region are rare neoplasms that generally mimic benign/low-grade neoplasms. Overexpression of anaplastic lymphoma kinase (ALK) has been reported in 50% of IMT cases, secondary to ALK activation by structural rearrangements in the ALK gene, which results in a fusion protein with echinoderm microtubule associated protein like 4 (EML4) in ~20% of cases. The present study describes a case of a 74-year-old woman with a malignant IMT in the right posterior hypopharynx harboring a previously unreported chromosomal rearrangement resulting in EML4 and ALK gene fusion. Strong ALK immunoreactivity was observed in neoplastic cells, while fluorescent in situ hybridization combined with fluorescent fragment analysis and direct sequencing identified the first case of the 3a/b variants of the EML4-ALK fusion gene in IMT. The results of the current study highlight the uncommon occurrence of ALK-positive IMT in the head/neck region and demonstrate the importance of integrating different molecular methodologies to identify unequivocal gene fusion characterization. PMID:28356934

  1. 21 CFR 868.6820 - Patient position support.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Patient position support. 868.6820 Section 868...) MEDICAL DEVICES ANESTHESIOLOGY DEVICES Miscellaneous § 868.6820 Patient position support. (a) Identification. A patient position support is a device intended to maintain the position of an...

  2. Economic Analysis of Alternative Strategies for Detection of ALK Rearrangements in Non Small Cell Lung Cancer

    PubMed Central

    Doshi, Shivang; Ray, David; Stein, Karen; Zhang, Jie; Koduru, Prasad; Fogt, Franz; Wellman, Axel; Wat, Ricky; Mathews, Charles

    2016-01-01

    Identification of alterations in ALK gene and development of ALK-directed therapies have increased the need for accurate and efficient detection methodologies. To date, research has focused on the concordance between the two most commonly used technologies, fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC). However, inter-test concordance reflects only one, albeit important, aspect of the diagnostic process; laboratories, hospitals, and payors must understand the cost and workflow of ALK rearrangement detection strategies. Through literature review combined with interviews of pathologists and laboratory directors in the U.S. and Europe, a cost-impact model was developed that compared four alternative testing strategies—IHC only, FISH only, IHC pre-screen followed by FISH confirmation, and parallel testing by both IHC and FISH. Interviews were focused on costs of reagents, consumables, equipment, and personnel. The resulting model showed that testing by IHC alone cost less ($90.07 in the U.S., $68.69 in Europe) than either independent or parallel testing by both FISH and IHC ($441.85 in the U.S. and $279.46 in Europe). The strategies differed in cost of execution, turnaround time, reimbursement, and number of positive results detected, suggesting that laboratories must weigh the costs and the clinical benefit of available ALK testing strategies. PMID:26838801

  3. EML4-ALK induces epithelial-mesenchymal transition consistent with cancer stem cell properties in H1299 non-small cell lung cancer cells.

    PubMed

    Guo, Fuchun; Liu, Xiaoke; Qing, Qin; Sang, Yaxiong; Feng, Chengjun; Li, Xiaoyu; Jiang, Li; Su, Pei; Wang, Yongsheng

    2015-04-10

    The echinoderm microtubule-associated protein-like 4(EML4)--anaplastic lymphoma kinase (ALK) fusion gene has been identified as a driver mutation in non-small-cell lung cancer (NSCLC). However, the role of EML4-ALK in malignant transformation is not entirely clear. Here, for the first time, we showed that H1299 NSCLC cells stably expressing EML4-ALK acquire EMT phenotype, associated with enhanced invasive migration and increased expression of EMT-inducing transcription factors. H1299-EML4-ALK cells also displayed cancer stem cell-like properties with a concomitant up-regulation of CD133 and enhanced ability of mammospheres formation. Moreover, we found that inhibition of ERK1/2 reversed EMT induced by EML4-ALK in H1299 cells. Taken together, these results suggested that EML4-ALK induced ERK activation is mechanistically associated with EMT phenotype. Thus, inhibition of ERK signaling pathway could be a potential strategy in treatment of NSCLC patients with EML4-ALK translocation.

  4. Effects of different compost amendments on the abundance and composition of alkB harboring bacterial communities in a soil under industrial use contaminated with hydrocarbons

    PubMed Central

    Wallisch, Stefanie; Gril, Tjasa; Dong, Xia; Welzl, Gerd; Bruns, Christian; Heath, Ester; Engel, Marion; Suhadolc, Marjetka; Schloter, Michael

    2014-01-01

    Alkane degrading microorganisms play an important role for the bioremediation of petrogenic contaminated environments. In this study, we investigated the effects of compost addition on the abundance and diversity of bacteria harboring the alkane monooxygenase gene (alkB) in an oil-contaminated soil originated from an industrial zone in Celje, Slovenia (Technosol). Soil without any amendments (control soil) and soil amended with two composts differing in their maturation stage and nutrient availability, were incubated under controlled conditions in a microcosm experiment and sampled after 0, 6, 12, and 36 weeks of incubation. As expected the addition of compost stimulated the degradation of alkanes in the investigated soil shortly after the addition. By using quantitative real-time PCR higher number of alkB genes were detected in soil samples amended with compost compared to the control soils. To get an insight into the composition of alkB harboring microbial communities, we performed next generation sequencing of amplicons of alkB gene fragment. Richness and diversity of alkB gene harboring prokaryotes was higher in soil mixed with compost compared to control soils with stronger effects of the less maturated, nutrient poor compost. The phylogenetic analysis of communities suggested that the addition of compost stimulated the abundance of alkB harboring Actinobacteria during the experiment independent from the maturation stage of the compost. AlkB harboring γ-proteobacteria like Shewanella or Hydrocarboniphaga as well as α-proteobacteria of the genus Agrobacterium responded also positively to the addition of compost to soil. The amendment of the less maturated, nutrient poor compost resulted in addition in a large increase of alkB harboring bacteria of the Cytophaga group (Microscilla) mainly at the early sampling time points. Our data indicates that compost amendments significantly change abundance and diversity pattern of alkB harboring microbes in Technosol and

  5. Effects of different compost amendments on the abundance and composition of alkB harboring bacterial communities in a soil under industrial use contaminated with hydrocarbons.

    PubMed

    Wallisch, Stefanie; Gril, Tjasa; Dong, Xia; Welzl, Gerd; Bruns, Christian; Heath, Ester; Engel, Marion; Suhadolc, Marjetka; Schloter, Michael

    2014-01-01

    Alkane degrading microorganisms play an important role for the bioremediation of petrogenic contaminated environments. In this study, we investigated the effects of compost addition on the abundance and diversity of bacteria harboring the alkane monooxygenase gene (alkB) in an oil-contaminated soil originated from an industrial zone in Celje, Slovenia (Technosol). Soil without any amendments (control soil) and soil amended with two composts differing in their maturation stage and nutrient availability, were incubated under controlled conditions in a microcosm experiment and sampled after 0, 6, 12, and 36 weeks of incubation. As expected the addition of compost stimulated the degradation of alkanes in the investigated soil shortly after the addition. By using quantitative real-time PCR higher number of alkB genes were detected in soil samples amended with compost compared to the control soils. To get an insight into the composition of alkB harboring microbial communities, we performed next generation sequencing of amplicons of alkB gene fragment. Richness and diversity of alkB gene harboring prokaryotes was higher in soil mixed with compost compared to control soils with stronger effects of the less maturated, nutrient poor compost. The phylogenetic analysis of communities suggested that the addition of compost stimulated the abundance of alkB harboring Actinobacteria during the experiment independent from the maturation stage of the compost. AlkB harboring γ-proteobacteria like Shewanella or Hydrocarboniphaga as well as α-proteobacteria of the genus Agrobacterium responded also positively to the addition of compost to soil. The amendment of the less maturated, nutrient poor compost resulted in addition in a large increase of alkB harboring bacteria of the Cytophaga group (Microscilla) mainly at the early sampling time points. Our data indicates that compost amendments significantly change abundance and diversity pattern of alkB harboring microbes in Technosol and

  6. Reduced mural cell coverage and impaired vessel integrity after angiogenic stimulation in the Alk1-deficient brain

    PubMed Central

    Chen, Wanqiu; Guo, Yi; Walker, Espen J.; Shen, Fanxia; Jun, Kristine; Oh, S. Paul; Degos, Vincent; Lawton, Michael T.; Tihan, Tarik; Davalos, Dimitrios; Akassoglou, Katerina; Nelson, Jeffrey; Pile-Spellman, John; Su, Hua; Young, William L.

    2013-01-01

    Objective Vessels in brain arteriovenous malformations (bAVM) are prone to rupture. The underlying pathogenesis is not clear. Hereditary hemorrhagic telangiectasia type 2 (HHT2) patients with activin receptor-like kinase 1 (Alk1) mutation have a higher incidence of bAVM than the general population. We tested the hypothesis that vascular endothelial growth factor (VEGF) impairs vascular integrity in the Alk1-deficient brain through reduction of mural cell-coverage. Methods and Results Adult Alk11f/2f mice (loxP sites flanking exons 4-6) and wild-type (WT) mice were injected with 2×107 PFU Ad-Cre and 2×109 genome copies of AAV-VEGF to induce focal homozygous Alk1 deletion (in Alk11f/2f mice) and angiogenesis. Brain vessels were analyzed eight weeks later. Compared to WT mice, the Alk1-deficient brain had more fibrin (99±30×103 pixels/mm2 vs. 40±13×103, P=0.001), iron deposition (508±506 pixels/mm2 vs. 6 ±49, P=0.04), and Iba1+ microglia/macrophage infiltration (888±420 Iba1+ cells/mm2 vs. 240±104 Iba1+, P=0.001) after VEGF stimulation. In the angiogenic foci, the Alk1-deficient brain had more α-SMA- vessels (52±9% vs. 12±7%, P<0.001), fewer vascular associated pericytes (503±179/mm2 vs. 931±115, P<0.001), and reduced PDGFR-β expression (26±9%, P<0.001). Conclusion Reduction of mural cell coverage in response to VEGF stimulation is a potential mechanism for the impairment of vessel wall integrity in HHT2-associated bAVM. PMID:23241407

  7. Rearranged Anaplastic Lymphoma Kinase (ALK) Gene in Adult-Onset Papillary Thyroid Cancer Amongst Atomic Bomb Survivors

    PubMed Central

    Mukai, Mayumi; Takahashi, Keiko; Hayashi, Yuzo; Nakachi, Kei; Kusunoki, Yoichiro

    2012-01-01

    Background We previously noted that among atomic bomb survivors (ABS), the relative frequency of cases of adult papillary thyroid cancer (PTC) with chromosomal rearrangements (mainly RET/PTC) was significantly greater in those with relatively higher radiation exposure than those with lower radiation exposure. In contrast, the frequency of PTC cases with point mutations (mainly BRAFV600E) was significantly lower in patients with relatively higher radiation exposure than those with lower radiation exposure. We also found that among ABS, the frequency of PTC cases with no detectable gene alterations in RET, neurotrophic tyrosine kinase receptor 1 (NTRK1), BRAF, or RAS was significantly higher in patients with relatively higher radiation exposure than those with lower radiation exposure. However, in ABS with PTC, the relationship between the presence of the anaplastic lymphoma kinase (ALK) gene fused with other gene partners and radiation exposure has received little study. In this study, we tested the hypothesis that the relative frequency of rearranged ALK in ABS with PTC, and with no detectable gene alterations in RET, NTRK1, BRAF, or RAS, would be greater in those having relatively higher radiation exposures. Methods The 105 subjects in the study were drawn from the Life Span Study cohort of ABS of Hiroshima and Nagasaki who were diagnosed with PTC between 1956 and 1993. Seventy-nine were exposed (>0 mGy), and 26 were not exposed to A-bomb radiation. In the 25 ABS with PTC, and with no detectable gene alterations in RET, NTRK1, BRAF, or RAS, we examined archival, formalin-fixed, paraffin-embedded PTC specimens for rearrangement of ALK using reverse transcription–polymerase chain reaction and 5′ rapid amplification of cDNA ends (5′ RACE). Results We found rearranged ALK in 10 of 19 radiation-exposed PTC cases, but none among 6 patients with PTC with no radiation exposure. In addition, solid/trabecular-like architecture in PTC was closely associated with ALK

  8. A New Protein Architecture for Processing Alkylation Damaged DNA: The Crystal Structure of DNA Glycosylase AlkD

    SciTech Connect

    Rubinson, Emily H.; Metz, Audrey H.; O'Quin, Jami; Eichman, Brandt F.

    2008-12-15

    DNA glycosylases safeguard the genome by locating and excising chemically modified bases from DNA. AlkD is a recently discovered bacterial DNA glycosylase that removes positively charged methylpurines from DNA, and was predicted to adopt a protein fold distinct from from those of other DNA repair proteins. The crystal structure of Bacillus cereus AlkD presented here shows that the protein is composed exclusively of helical HEAT-like repeats, which form a solenoid perfectly shaped to accommodate a DNA duplex on the concave surface. Structural analysis of the variant HEAT repeats in AlkD provides a rationale for how this protein scaffolding motif has been modified to bind DNA. We report 7mG excision and DNA binding activities of AlkD mutants, along with a comparison of alkylpurine DNA glycosylase structures. Together, these data provide important insight into the requirements for alkylation repair within DNA and suggest that AlkD utilizes a novel strategy to manipulate DNA in its search for alkylpurine bases.

  9. Insertion element analysis and mapping of the Pseudomonas plasmid alk regulon.

    PubMed Central

    Fennewald, M; Benson, S; Oppici, M; Shapiro, J

    1979-01-01

    We characterized and mapped new mutations of the alk (alkane utilization) genes found on Pseudomonas plasmids of the Inc P-2 group. These mutations were isolated after (i) nitrosoguanidine mutagenesis, (ii) transposition of the Tn7 trimethoprim and streptomycin resistance determinant, and (iii) reversion of polarity effects of alk::Tn7 insertion mutations. Our results indicate the existence of two alk loci not previously described--alkD, whose product is required for synthesis of membrane alkane-oxidizing activities, and alkE, whose product is required for synthesis of inducible membrane alcohol dehydrogenase activity. Polarity of alk::Tn7 insertion mutations indicates the existence of an alkBAE operon. Mapping of alk loci by transduction in P. aeruginosa shows that there are at least three alk clusters in the CAM-OCT plasmid--alkRD, containing regulatory genes; alkBAE, containing genes for specific biochemical activities; and alkC, containing one or more genes needed for normal synthesis of membrane alcohol dehydrogenase. The alkRD and alkBAE clusters are linked but separated by about 42 kilobases. The alkC cluster is not linked to either of the other two alk regions. Altogether, these results indicate a complex genetic control of the alkane utilization phenotype in P. putida and P. aeruginosa involving at least six separate genes. Images PMID:479111

  10. Sensitivity Analysis of the NPM-ALK Signalling Network Reveals Important Pathways for Anaplastic Large Cell Lymphoma Combination Therapy

    PubMed Central

    Buetti-Dinh, Antoine; O’Hare, Thomas

    2016-01-01

    A large subset of anaplastic large cell lymphoma (ALCL) patients harbour a somatic aberration in which anaplastic lymphoma kinase (ALK) is fused to nucleophosmin (NPM) resulting in a constitutively active signalling fusion protein, NPM-ALK. We computationally simulated the signalling network which mediates pathological cell survival and proliferation through NPM-ALK to identify therapeutically targetable nodes through which it may be possible to regain control of the tumourigenic process. The simulations reveal the predominant role of the VAV1-CDC42 (cell division control protein 42) pathway in NPM-ALK-driven cellular proliferation and of the Ras / mitogen-activated ERK kinase (MEK) / extracellular signal-regulated kinase (ERK) cascade in controlling cell survival. Our results also highlight the importance of a group of interleukins together with the Janus kinase 3 (JAK3) / signal transducer and activator of transcription 3 (STAT3) signalling in the development of NPM-ALK derived ALCL. Depending on the activity of JAK3 and STAT3, the system may also be sensitive to activation of protein tyrosine phosphatase-1 (SHP1), which has an inhibitory effect on cell survival and proliferation. The identification of signalling pathways active in tumourigenic processes is of fundamental importance for effective therapies. The prediction of alternative pathways that circumvent classical therapeutic targets opens the way to preventive approaches for countering the emergence of cancer resistance. PMID:27669408

  11. Fatal Haemoptysis Associated with Dramatic Response to Crizotinib in an ALK-Rearranged Lung Adenocarcinoma

    PubMed Central

    Mussat, Elodie; Giraud, Violaine; Julie, Catherine; Chinet, Thierry

    2016-01-01

    The presence of an ALK (Anaplastic Lymphoma Kinase) rearrangement is a rare molecular feature in Non-Small Cell Lung Carcinoma (NSCLC), and concerns mainly non- or light smokers, young patients, with adenocarcinoma histological type. These tumours are particularly sensitive to Alk-targeted therapies, as crizotinib. Crizotinib is usually well-tolerated. We report a case of fatal haemoptysis associated with dramatic response to crizotinib in a patient with an ALK-rearranged lung adenocarcinoma. The patient presented a mediastinal invasion with tracheal involvement and compression of the right pulmonary artery. The initial evolution under crizotinib was good with tumour response. At 6 weeks of crizotinib the patient presented a massive haemoptysis with a tracheobronchial fistula and pneumomediastinum. She died of acute respiratory failure. Our case is the first to report a fatal effect of crizotinib associated with tumour necrosis and good tumour response on a massive mediastinal infiltration. Precautions are recommended with the use of crizotinib in proximal lung tumours with vascular invasion. PMID:27134984

  12. Activation of the orphan receptor tyrosine kinase ALK by zinc.

    PubMed

    Bennasroune, Aline; Mazot, Pierre; Boutterin, Marie-Claude; Vigny, Marc

    2010-08-06

    Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase essentially and transiently expressed during development of the central and peripheral nervous system. The nature of the cognate ligand of this receptor in Vertebrates is still a matter of debate. During synaptic transmission the release of ionic zinc found in vesicles of certain glutamatergic and gabaergic terminals may act as a neuromodulator by binding to pre- or post-synaptic receptors. Recently, zinc has been shown to activate the receptor tyrosine kinase, TrkB, independently of neurotrophins. This activation occurs via increasing the Src family kinase activity. In the present study, we investigated whether the ALK activity could be modulated by extracellular zinc. We first showed that zinc alone rapidly activates ALK. This activation is dependent of ALK tyrosine kinase activity and dimerization of the receptor but is independent of Src family kinase activity. In contrast, addition of sodium pyrithione, a zinc ionophore, led to a further activation of ALK. This stronger activation is dependent of Src family kinase but independent of ALK activity and dimerization. In conclusion, zinc could constitute an endogenous ligand of ALK in vertebrates.

  13. Prevalence of positive autoimmune biomarkers in the brucellosis patients.

    PubMed

    Ahmadinejad, Zahra; Abdollahi, Alireza; Ziaee, Vahid; Domiraei, Zeinab; Najafizadeh, Seyed-Reza; Jafari, Sirus; Ahmadinejad, Mahdi

    2016-10-01

    Brucellosis is a chronic infectious disease with articular involvement. Discrimination between brucellosis and rheumatologic disorders is difficult in regions endemic for brucellosis. There are few studies about the rate of positive autoantibodies as rheumatologic biomarkers in brucellosis, and the prevalence is variable. In this study, the rheumatologic tests were studied in brucellosis patients. This cross sectional study was performed in two teaching hospitals in Tehran, Iran. Forty-nine patients with brucella infection and 42 healthy participants were enrolled in this study. Brucellosis was diagnosed on the basis of the clinical symptoms and positive serology for brucellosis. Rheumatic factor (RF) and antinuclear antibodies (ANA) were evaluated in all patients. Cyclic citrullinated peptides antibody (ACPA) and anti-double strand DNA (anti-dsDNA) were checked in all patients and control groups. Out of 49 patients, 15 (30.6 %) were RF positive and 4 (8.2 %) were ANA positive. Anti-dsDNA was concurrently positive with ANA in 1 patient (2 %) but ACPA titer was positive in 8 patients (16.3 %). None of the patients with positive autoantibody biomarkers fulfilled the criteria for rheumatologic disorders. The rate of positive RF in healthy people was significantly lower than patient group (2.4 vs. 30.6 %), but the positiveness rate of other biomarkers did not have significant difference in two groups. Sixty percent of the patients with positive RF and 75 % with positive ACPA had skeletal involvement (P < 0.05). Autoantibody biomarkers can be positive in brucellosis. Rheumatologists should be aware of brucellosis in patients with musculoskeletal involvement and positive autoantibody biomarkers in endemic regions.

  14. Prevalence of unrecognized benign paroxysmal positional vertigo in older patients.

    PubMed

    van der Zaag-Loonen, H J; van Leeuwen, R B; Bruintjes, Tj D; van Munster, B C

    2015-06-01

    Dizziness is a relatively common complaint which occurs more often with increasing age. Benign paroxysmal positional vertigo (BPPV) is an important cause which can easily be treated but is frequently not recognized by professionals. The aim of this study was to assess the prevalence of unrecognized BPPV in older patients. Patients ≥70 years of age (n = 989) indicated whether they experienced dizziness, and if so whether the symptoms were typical for BPPV. If affirmed, a diagnostic maneuver was performed. Positive patients were treated at once. All suspected patients completed quality of life questionnaires and were followed for 3 and 6 months. Positive BPPV patients were compared with negative (but suspected) patients. Almost one quarter of the patients (226 patients, 23 %) suffered from dizziness, among whom 101 were suspected of BPPV. Less than half (n = 45) underwent the diagnostic maneuver, of whom 13 (29 %) were positive for BPPV. At follow-up, one patient developed BPPV, leading to a total of 14 positive patients (overall prevalence 1.4 %). BPPV positive patients did not differ from BPPV negative patients. Among a large group of older patients, one quarter experiences dizziness, and 1.4 % has definite BPPV.

  15. Regioselective alkane hydroxylation with a mutant AlkB enzyme

    DOEpatents

    Koch, Daniel J.; Arnold, Frances H.

    2012-11-13

    AlkB from Pseudomonas putida was engineered using in-vivo directed evolution to hydroxylate small chain alkanes. Mutant AlkB-BMO1 hydroxylates propane and butane at the terminal carbon at a rate greater than the wild-type to form 1-propanol and 1-butanol, respectively. Mutant AlkB-BMO2 similarly hydroxylates propane and butane at the terminal carbon at a rate greater than the wild-type to form 1-propanol and 1-butanol, respectively. These biocatalysts are highly active for small chain alkane substrates and their regioselectivity is retained in whole-cell biotransformations.

  16. Conformational features and binding affinities to Cripto, ALK7 and ALK4 of Nodal synthetic fragments.

    PubMed

    Calvanese, Luisa; Sandomenico, Annamaria; Caporale, Andrea; Focà, Annalia; Focà, Giuseppina; D'Auria, Gabriella; Falcigno, Lucia; Ruvo, Menotti

    2015-04-01

    Nodal, a member of the TGF-β superfamily, is a potent embryonic morphogen also implicated in tumor progression. As for other TGF-βs, it triggers the signaling functions through the interaction with the extracellular domains of type I and type II serine/threonine kinase receptors and with the co-receptor Cripto. Recently, we reported the molecular models of Nodal in complex with its type I receptors (ALK4 and ALK7) as well as with Cripto, as obtained by homology modeling and docking simulations. From such models, potential binding epitopes have been identified. To validate such hypotheses, a series of mutated Nodal fragments have been synthesized. These peptide analogs encompass residues 44-67 of the Nodal protein, corresponding to the pre-helix loop and the H3 helix, and reproduce the wild-type sequence or bear some modifications to evaluate the hot-spot role of modified residues in the receptor binding. Here, we show the structural characterization in solution by CD and NMR of the Nodal peptides and the measurement of binding affinity toward Cripto by surface plasmon resonance. Data collected by both conformational analyses and binding measurements suggest a role for Y58 of Nodal in the recognition with Cripto and confirm that previously reported for E49 and E50. Surface plasmon resonance binding assays with recombinant proteins show that Nodal interacts in vitro also with ALK7 and ALK4 and preliminary data, generated using the Nodal synthetic fragments, suggest that Y58 of Nodal may also be involved in the recognition with these protein partners.

  17. Combination therapy with brentuximab vedotin and cisplatin/cytarabine in a patient with primarily refractory anaplastic lymphoma kinase positive anaplastic large cell lymphoma.

    PubMed

    Heidegger, Simon; Beer, Ambros J; Geissinger, Eva; Rosenwald, Andreas; Peschel, Christian; Ringshausen, Ingo; Keller, Ulrich

    2014-01-01

    Anaplastic large cell lymphoma (ALCL) is a common subtype of the heterogeneous group of peripheral T-cell lymphomas, which is characterized by large pleomorphic cells with strong expression of CD30. Translocations involving ALK, the anaplastic lymphoma kinase gene, are associated with a favorable clinical outcome. Such ALK-positive ALCLs are usually responsive to a multidrug chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). However, there is no general consensus on the optimal therapy for relapsed or refractory ALCL. We report the case of a 24-year-old male suffering from ALK-positive ALCL with an uncommon manifestation of only extranodal disease in the gastric cardia region that showed primary refractoriness to standard CHOP chemotherapy. A combination therapy consisting of the anti-CD30 drug conjugate, brentuximab vedotin, and classical lymphoma salvage regimen DHAP (cisplatin, high-dose cytarabine and dexamethasone) was administered. Following two treatment cycles in 21-day intervals, the lymphoma showed considerable regression based on imaging diagnostics and no evidence of vital lymphoma in a subsequent biopsy. We did not observe any increase in toxicity; in particular, polyneuropathy and febrile neutropenia were not observed. In summary, we report that the antibody-drug conjugate brentuximab vedotin and a classical regimen used for aggressive lymphoma, DHAP, could be combined as salvage therapy in a case of refractory ALK-positive ALCL. Phase I/II studies will be required for safety and efficacy analysis.

  18. A critique of positive thinking for patients with cancer.

    PubMed

    Tod, A

    This article provides a critical reflection of the debate regarding the adoption of positive thinking in the care and recovery of patients with cancer. Positive thinking is an approach characterised by adopting a fighting spirit, taking control and being strong and brave. The association of positive thinking with a range of favourable outcomes has been challenged.

  19. 21 CFR 892.5780 - Light beam patient position indicator.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Light beam patient position indicator. 892.5780 Section 892.5780 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... patient and to monitor alignment of the radiation beam with the patient's anatomy. (b)...

  20. 21 CFR 892.5780 - Light beam patient position indicator.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Light beam patient position indicator. 892.5780 Section 892.5780 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... patient and to monitor alignment of the radiation beam with the patient's anatomy. (b)...

  1. 21 CFR 892.5780 - Light beam patient position indicator.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Light beam patient position indicator. 892.5780 Section 892.5780 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... patient and to monitor alignment of the radiation beam with the patient's anatomy. (b)...

  2. 21 CFR 892.5780 - Light beam patient position indicator.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Light beam patient position indicator. 892.5780 Section 892.5780 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... patient and to monitor alignment of the radiation beam with the patient's anatomy. (b)...

  3. 21 CFR 892.5780 - Light beam patient position indicator.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Light beam patient position indicator. 892.5780 Section 892.5780 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... patient and to monitor alignment of the radiation beam with the patient's anatomy. (b)...

  4. Genotype-driven therapies for non-small cell lung cancer: focus on EGFR, KRAS and ALK gene abnormalities.

    PubMed

    Gaughan, Elizabeth M; Costa, Daniel B

    2011-05-01

    Non-small cell lung cancers (NSCLCs) are heterogeneous cancers. In 2004, the identification of epidermal growth factor receptor (EGFR) somatic mutations provided the first glimpse of a clinically relevant NSCLC oncogene. Approximately 70% of NSCLCs with EGFR mutations (exon 19 deletions or the exon 21 L858R) attain responses to EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, with improved response rate (RR), progression-free survival (PFS) and in some reports overall survival (OS) when compared with EGFR wildtype (WT) cases. Three randomized trials of gefitinib versus chemotherapy (IPASS, WJTOG3405, NEJ002) in stage IV NSCLC have consistently demonstrated better RR and PFS (hazard ratios of 0.48 [IPASS], 0.49 [WJTOG3405] and 0.30 [NEJ002]) for EGFR-mutated NSCLCs treated with gefitinib. Novel irreversible EGFR TKIs (afatinib, XL647, PF00299804) show similar activity in EGFR-mutated patients. A translocation involving the anaplastic lymphoma kinase (ALK) gene with EML4, identified in 2007, is the most recent oncogene found in NSCLC. Crizotinib (PF02341066), an ALK TKI, has shown impressive activity against ALK translocated NSCLC in an expanded cohort of a phase I trial (NCT00585195). Over 80 patients have been treated and the RR is ∼60% with the 6-month PFS rate exceeding 70%. A registration phase III trial of crizotinib versus second-line chemotherapy (pemetrexed/docetaxel) is underway (PROFILE 1007, NCT00932893). KRAS, EGFR mutations and ALK translocations are mutually exclusive and few EGFR WT NSCLCs respond to EGFR TKIs. The promising results of EGFR and ALK TKIs in molecular subgroups of NSCLCs herald a new age of drug and clinical trial development for patients with NSCLC.

  5. Combating autophagy is a strategy to increase cytotoxic effects of novel ALK inhibitor entrectinib in neuroblastoma cells

    PubMed Central

    Aveic, Sanja; Pantile, Marcella; Seydel, Anke; Esposito, Maria Rosaria; Zanon, Carlo; Li, Gary; Tonini, Gian Paolo

    2016-01-01

    Neuroblastoma (NB) is a threatening childhood malignancy. Its prognosis is affected by several morphological, and biological characteristics, including the constitutive expression of ALK tyrosine kinase. In this study we examined the therapeutic potential of a novel ALK inhibitor, entrectinib, in obliterating NB tumor cells. Entrectinib showed the growth-inhibitory effects on NB cells with a 50% inhibitory concentration range of 0.03–5 μM. In the ALK-dependent cells, entrectinib mediated G1-arrest, which was associated with modified expression of multiple cell-cycle regulators. Down-regulation of Ki-67, and attenuated phosphorylation of ERK1/2, and STAT3, correlated with observed antiproliferative capacity of entrectinib. Initial cytostatic activity of entrectinib was followed by concentration-dependent apoptotic cell death, and Caspase-3 activation. However, we delineated a reduced sensitivity of ALK mutated NB cells to entrectinib, and demonstrated strong activation of autophagy in SH-SY5YF1174L NB cell line. Abrogation of autophagy by chloroquine increased significantly the toxicity of entrectinib, as confirmed by enhanced death rate, and PARP protein cleavage in SH-SY5YF1174L cells. In aggregate, our data show that entrectinib inhibits proliferation, and induces G1-arrest, and apoptosis in NB cells. We propose entrectinib for further consideration in treatment of NB, and recommend pharmacological inhibition of autophagy to be explored for a combined therapeutic approach in NB patients that might develop resistance to entrectinib. PMID:26735175

  6. Accuracy of patient positioning in mantle field irradiation.

    PubMed

    Creutzberg, C L; Visser, A G; De Porre, P M; Meerwaldt, J H; Althof, V G; Levendag, P C

    1992-04-01

    A prospective study of the accuracy of patient positioning in mantle field irradiation was carried out in 13 lymphoma patients treated with curative radiotherapy. Patients were treated in the supine and prone position for anterior and posterior fields, respectively. Individually shaped divergent shielding blocks were placed in a fixed position in a template which was positioned on a tray above the patient. A total number of 94 megavoltage portal films (MV) was analysed and compared to 26 simulation films (SIM). MV-SIM differences were larger for posterior fields than for anterior fields. Regarding the position of the lung shielding blocks, mean MV-SIM differences ranged from 1.3 to 4.4 mm and errors exceeding 1 cm were found in 7.2% of cases. Most discrepancies appeared to be randomly distributed. A 4-5 mm systematic cranial shift of patients in the posterior treatment position was noted. Discrepancies in the position of the laryngeal block, spinal cord shielding block and humerus blocks were small with mean MV-SIM differences ranging from 0.3 to 2.7 mm. Differences between simulation set-up and treatment set-up were modest as compared to error rates reported in the literature. Shielding of tumour-bearing areas did not occur. It was concluded that the present standardised technique of patient positioning and the design of treatment fields results in acceptable error rates. Attention should be directed towards increasing the stability of patients in the prone treatment position in order to further reduce both systematic and random error rates.

  7. Benefit-Risk Summary of Crizotinib for the Treatment of Patients With ROS1 Alteration-Positive, Metastatic Non-Small Cell Lung Cancer

    PubMed Central

    Blumenthal, Gideon M.; Luo, Lola; He, Kun; Fran, Ingrid; Lemery, Steven; Pazdur, Richard

    2016-01-01

    On March 11, 2016, after an expedited 5-month review, the U.S. Food and Drug Administration expanded the crizotinib metastatic non-small cell lung cancer (mNSCLC) indication to include the treatment of patients whose tumors harbor a ROS1 rearrangement. The approval was based on a clinically meaningful, durable objective response rate (ORR) in a multicenter, single-arm clinical trial (ROS1 cohort of Trial PROFILE 1001) in patients with ROS1-positive mNSCLC. The trial enrolled 50 patients (age range: 25–77 years) whose tumors were prospectively determined to have a ROS1 gene rearrangement by break-apart fluorescence in situ hybridization (96%) or reverse transcriptase polymerase chain reaction (4%) clinical trial assays. Crizotinib demonstrated an ORR of 66% (95% confidence interval [CI]: 51%–79%) with a median duration of response of 18.3 months by independent radiology review and 72% (95% CI: 58%–84%) by investigator review. Patients received crizotinib 250 mg twice daily and had a median duration of exposure of 34.4 months. The toxicity profile in ROS1-positive patients was generally consistent with the randomized safety data in the U.S. Product Insert from two ALK-positive mNSCLC trials. The most common (≥25%) adverse reactions and laboratory test abnormalities included vision disorders, elevation of alanine transaminase and aspartate transaminase levels, nausea, hypophosphatemia, diarrhea, edema, vomiting, constipation, neutropenia, and fatigue. There were no treatment-related deaths. A favorable benefit-to-risk evaluation led to the traditional approval of crizotinib for this new supplemental indication. Implications for Practice: Given the results from the ROS1 cohort of the clinical trial PROFILE 1001, crizotinib represents a new treatment option and the first approved therapy for patients with metastatic non-small cell lung cancer whose tumors are ROS1 positive. Crizotinib demonstrated efficacy irrespective of prior treatment status. PMID:27328934

  8. Late Alk4/5/7 signaling is required for anterior skeletal patterning in sea urchin embryos.

    PubMed

    Piacentino, Michael L; Ramachandran, Janani; Bradham, Cynthia A

    2015-03-01

    Skeletal patterning in the sea urchin embryo requires a conversation between the skeletogenic primary mesenchyme cells (PMCs) and the overlying pattern-dictating ectoderm; however, our understanding of the molecular basis for this process remains incomplete. Here, we show that TGF-β-receptor signaling is required during gastrulation to pattern the anterior skeleton. To block TGF-β signaling, we used SB431542 (SB43), a specific inhibitor of the TGF-β type I receptor Alk4/5/7. Treatment with SB43 during gastrulation blocks anterior PMC positioning and the formation of the anterior skeleton, but does not perturb general ectoderm specification or development. This is the first example of a signaling event required for patterning of a specific part of the skeleton. Alk4/5/7 inhibition does not prevent the formation of a mouth, although SB43-treated plutei display reduced feeding ability, presumably due to the loss of the structural support for the mouth conferred by the anterior skeleton. Both Univin and Nodal are potential ligands for Alk4/5/7; however, Nodal is unilaterally expressed on only the right side, whereas Univin is bilaterally expressed in the ectoderm adjacent to the anterior skeleton during the relevant time period. Our results demonstrate that Univin is both necessary and sufficient for secondary skeletal development in a control background, consistent with the hypothesis that Univin is a relevant Alk4/5/7 ligand for anterior skeletal patterning. Taken together, our data demonstrate that Alk4/5/7 signaling during gastrulation is required to direct PMCs to the oral hood, and suggest that Univin is a relevant ligand for this signaling event.

  9. [Comparative studies of patient positioning for lumbar intervertebral disk operation].

    PubMed

    Rudolph, Ch; Schaffranietz, L; Hellmundt, L; Vitzthum, H E; Olthoff, D

    2002-01-01

    For surgery on lumbar disks by the posterior route, patients are placed either on a Wilson frame or in genupectoral position. The aim of the prospective study was to record and describe the haemodynamic changes resulting from the patients' position. After written informed consent had been received, 80 neurosurgical patients undergoing lumbar disk surgery were randomly divided into two groups; group I--Wilson frame, group II--genupectoral position. In each group, 20 patients received total intravenous anaesthesia (Alfentanil or Remifentanil, Propofol) and 20 balanced anaesthesia with Isoflurane and Alfentanil or Remifentanil. Haemodynamic parameters (mean arterial pressure--MAP and heart rate--HR) were recorded automatically at three measuring times (MT): firstly, after induction of anaesthesia; secondly, before re-direction; thirdly, after re-direction on the Wilson frame or in the genupectoral position. Induction of anaesthesia did not lead to a significant decrease in MAP (MT 1: 92.5 +/- 15.2 mmHg, MT 2: 89 +/- 13.4 mmHg, n = 80). In group I (n = 40), no significant changes were observed in MAP and HR at MT 3 (p = 0.882, p = 0.051). In comparison to group I, the genupectoral position was associated with significant drops in MAP and HR. The genupectoral position caused a significant decrease in MAP (p < 0.001) and HR (p = 0.016) at MT 3. Our data suggest that body weight or body mass index do not necessarily lead to a preference for one of the two possible positions of the patient. Complications resulting from haemodynamic changes were not seen in either group. We recommend the Wilson frame for neurosurgical lumbar disk surgery in cases of cardiovascular or cerebrovascular disorders. The adaptive capacities in the genupectoral position as a result of the modifying distribution of blood volume are limited in these patients. Furthermore, the dose-dependent effects of different anaesthetics on haemodynamic parameters in these prone positions should be explored.

  10. Diagnosing ANCA-associated vasculitis in ANCA positive patients

    PubMed Central

    Houben, Eline; Bax, Willem A.; van Dam, Bastiaan; Slieker, Walentina A.T.; Verhave, Gideon; Frerichs, Fenneke C.P.; van Eijk, Izhar C.; Boersma, Wim G.; de Kuyper, Guido T.M.; Penne, Erik L.

    2016-01-01

    Abstract Currently no validated diagnostic system for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is available. Therefore, diagnosing AAV is often challenging. We aimed to identify factors that lead to a clinical diagnosis AAV in ANCA positive patients in a teaching hospital in The Netherlands. In this study, all patients that tested positive for ANCA proteinase 3 (PR3) and/or myeloperoxidase (MPO) between 2005 and 2015 were analysed. Patients with a clinical diagnosis of AAV were compared with patients without a clinical diagnosis of AAV. Clinical symptoms and laboratory variables at presentation, including the ANCA titre, were collected for both patients with and without AAV. Clinical and laboratory variables related with AAV were investigated, using multivariable logistic regression. Two hundred thirty seven consecutive patients with a positive ANCA were included, of whom 119 were clinically diagnosed with AAV. Of the 118 ANCA positive patients without AAV, 87 patients had an alternative diagnosis, including inflammatory bowel disease (n = 24), other rheumatic diseases (n = 23), infection (n = 11), malignancy (n = 4), and other diagnoses (n = 25). In a multivariable regression model, a high ANCA titre (odds ratio [OR] 14.16, 95% confidence interval [CI] 6.93–28.94) and a high number of affected organ systems (OR 7.67, 95% CI 3.69–15.94) were associated with AAV. MPO and PR3 ANCA can be positive in a variety of diseases that mimic AAV. A higher ANCA titre and multiple affected organ systems may help to discriminate between AAV and other systemic illnesses in anti-PR3 and anti-MPO positive patients. A diagnostic scoring system incorporating these factors should be considered. PMID:27749588

  11. Lumican Peptides: Rational Design Targeting ALK5/TGFBRI

    NASA Astrophysics Data System (ADS)

    Gesteira, Tarsis Ferreira; Coulson-Thomas, Vivien J.; Yuan, Yong; Zhang, Jianhua; Nader, Helena B.; Kao, Winston W.-Y.

    2017-02-01

    Lumican, a small leucine rich proteoglycan (SLRP), is a component of extracellular matrix which also functions as a matrikine regulating multiple cell activities. In the cornea, lumican maintains corneal transparency by regulating collagen fibrillogenesis, promoting corneal epithelial wound healing, regulating gene expression and maintaining corneal homeostasis. We have recently shown that a peptide designed from the 13 C-terminal amino acids of lumican (LumC13) binds to ALK5/TGFBR1 (type1 receptor of TGFβ) to promote wound healing. Herein we evaluate the mechanism by which this synthetic C-terminal amphiphilic peptide (LumC13), binds to ALK5. These studies clearly reveal that LumC13-ALK5 form a stable complex. In order to determine the minimal amino acids required for the formation of a stable lumican/ALK5 complex derivatives of LumC13 were designed and their binding to ALK5 investigated in silico. These LumC13 derivatives were tested both in vitro and in vivo to evaluate their ability to promote corneal epithelial cell migration and corneal wound healing, respectively. These validations add to the therapeutic value of LumC13 (Lumikine) and aid its clinical relevance of promoting the healing of corneal epithelium debridement. Moreover, our data validates the efficacy of our computational approach to design active peptides based on interactions of receptor and chemokine/ligand.

  12. Lumican Peptides: Rational Design Targeting ALK5/TGFBRI

    PubMed Central

    Gesteira, Tarsis Ferreira; Coulson-Thomas, Vivien J.; Yuan, Yong; Zhang, Jianhua; Nader, Helena B.; Kao, Winston W.-Y.

    2017-01-01

    Lumican, a small leucine rich proteoglycan (SLRP), is a component of extracellular matrix which also functions as a matrikine regulating multiple cell activities. In the cornea, lumican maintains corneal transparency by regulating collagen fibrillogenesis, promoting corneal epithelial wound healing, regulating gene expression and maintaining corneal homeostasis. We have recently shown that a peptide designed from the 13 C-terminal amino acids of lumican (LumC13) binds to ALK5/TGFBR1 (type1 receptor of TGFβ) to promote wound healing. Herein we evaluate the mechanism by which this synthetic C-terminal amphiphilic peptide (LumC13), binds to ALK5. These studies clearly reveal that LumC13-ALK5 form a stable complex. In order to determine the minimal amino acids required for the formation of a stable lumican/ALK5 complex derivatives of LumC13 were designed and their binding to ALK5 investigated in silico. These LumC13 derivatives were tested both in vitro and in vivo to evaluate their ability to promote corneal epithelial cell migration and corneal wound healing, respectively. These validations add to the therapeutic value of LumC13 (Lumikine) and aid its clinical relevance of promoting the healing of corneal epithelium debridement. Moreover, our data validates the efficacy of our computational approach to design active peptides based on interactions of receptor and chemokine/ligand. PMID:28181591

  13. Transplantation in resource-limited setting: using HIV-positive donors for HIV-positive patients

    PubMed Central

    Muller, Elmi

    2015-01-01

    Abstract. Background: A HIV positive-to-positive program was started in South Africa in 2008. The program was started because dialysis is not freely available to everyone, but severely limited and only available to a selected group of patients. Patients and Methods: Between September 2008 and March 2015, 29 patients were transplanted from HIV-positive brain-dead donors at Groote Schuur Hospital transplant team. Donors were either naïve to anti-retroviral therapy or on first line therapy. The recipients were selected to have undetectable plasma HIV type 1 RNA levels and be on a stable antiretroviral regimen. CD4+ T-cell counts of at least 200/mm3 in last 6 months prior to transplant, with no previous serious opportunistic infections. Results: Survivors in the study were followed for a median of 2.4 years. The rate of patient survival was 84% at 1 year and 74% at 5 years. The corresponding graft survival rate was 93% and 84%. Conclusion: Using HIV-positive donors might resolve some of the problems we are experiencing in getting enough donors for our patients wit ESRD. In the USA the HOPE act was accepted in 2014 and this might now also impact on the use of HIV positive donors elsewhere in the world.

  14. Optimal marker placement in photogrammetry patient positioning system.

    PubMed

    Liu, Haisong; Yu, Yan; Schell, M C; O'Dell, Walter G; Ruo, Russell; Okunieff, Paul

    2003-02-01

    A photogrammetry-based patient positioning system has been used instead of the conventional laser alignment technique for patient set-up in external beam radiotherapy. It tracks skin affixed reflective markers with multiple infrared cameras. The three-dimensional (3D) positions of the markers provide reference information to determine the treatment plan isocenter location and hence provide the ability to position the lesion at the isocenter of the treatment linear accelerator. However, in current clinical practice for lung or liver lesion treatments, fiducial markers are usually randomly affixed onto the patients' chest and abdomen, so that the actual target registration error (TRE) of the internal lesions inside the body may be large, depending on the fiducial registration error (FRE). There exists an optimal marker configuration that can minimize the TRE. In this paper, we developed methods to design the patient-specific optimal configurations of the surface makers to minimize the TRE, given the patient's surface contour, the lesion position and the FRE. Floating genetic algorithm (GA) optimization was used to optimize the positions of the skin markers. The surface curve of the patient body was determined by an automatic segmentation algorithm from the planning CT. The method was evaluated using a body phantom implanted with a metal ball (a simulated target). By registering two CT scans using the surface markers and measuring the displacement of the target, the TRE was measured. The TRE was also measured by taking two orthogonal portal films after positioning the phantom using the photogrammetry based patient positioning system. A 50% reduction in TRE has been achieved by using the optimal configuration compared to the random configuration. This result demonstrates that the optimization of a fiducial configuration can result in improved tumor targeting ability.

  15. Reducing patient posture variability using the predicted couch position.

    PubMed

    de Kruijf, Wilhelmus J M; Martens, Rob J W

    2015-01-01

    A method is presented in which the couch position is predicted before the treatment instead of obtaining a reference position at the first treatment fraction. This prevents systematic differences in patient posture between preparation and treatment. In literature, only limited data are available on couch positioning. We position our patients at the planned couch position, allowing a small difference between skin marks and lasers, followed by online imaging. For a 3-month period, our standard deviations (mm) in couch position in the vertical, longitudinal, and lateral directions were head and neck-1.6, 2.8, and 2.5; thorax-2.9, 5.5, and 4.5; breast-3.0, 4.1, and 4.0; and pelvis-3.5, 4.0, and 4.7, respectively. We have improved the reproducibility of patient posture in our institute by using the predicted couch position. Our data may serve as a reference for other institutes because the couch position variation is less than that published in literature.

  16. Reducing patient posture variability using the predicted couch position

    SciTech Connect

    Kruijf, Wilhelmus J.M. de Martens, Rob J.W.

    2015-10-01

    A method is presented in which the couch position is predicted before the treatment instead of obtaining a reference position at the first treatment fraction. This prevents systematic differences in patient posture between preparation and treatment. In literature, only limited data are available on couch positioning. We position our patients at the planned couch position, allowing a small difference between skin marks and lasers, followed by online imaging. For a 3-month period, our standard deviations (mm) in couch position in the vertical, longitudinal, and lateral directions were head and neck—1.6, 2.8, and 2.5; thorax—2.9, 5.5, and 4.5; breast—3.0, 4.1, and 4.0; and pelvis—3.5, 4.0, and 4.7, respectively. We have improved the reproducibility of patient posture in our institute by using the predicted couch position. Our data may serve as a reference for other institutes because the couch position variation is less than that published in literature.

  17. Excess of NPM-ALK oncogenic signaling promotes cellular apoptosis and drug dependency

    PubMed Central

    Mologni, Luca; Poggio, Teresa; Varesio, Lydia M.; Menotti, Matteo; Bombelli, Silvia; Rigolio, Roberta; Manazza, Andrea D.; Di Giacomo, Filomena; Ambrogio, Chiara; Giudici, Giovanni; Casati, Cesare; Mastini, Cristina; Compagno, Mara; Turner, Suzanne D.; Gambacorti-Passerini, Carlo; Chiarle, Roberto; Voena, Claudia

    2016-01-01

    Most of Anaplastic Large Cell Lymphoma (ALCL) cases carry the t(2;5; p23;q35) that produces the fusion protein NPM-ALK. NPM-ALK deregulated kinase activity drives several pathways that support malignant transformation of lymphoma cells. We found that in ALK-rearranged ALCL cell lines NPM-ALK was distributed in equal amounts between the cytoplasm and the nucleus. Only the cytoplasmic portion was catalytically active in both cell lines and primary ALCL, whereas the nuclear portion was inactive due to heterodimerization with NPM1. Thus, about 50% of the NPM-ALK is not active and sequestered as NPM-ALK/NPM1 heterodimers in the nucleus. Overexpression or re-localization of NPM-ALK to the cytoplasm by NPM genetic knock-out or knock-down caused ERK1/2 increased phosphorylation and cell death through the engagement of an ATM/Chk2 and γH2AX mediated DNA damage response. Remarkably, human NPM-ALK amplified cell lines resistant to ALK tyrosine kinase inhibitors (TKIs) underwent apoptosis upon drug withdrawal as a consequence of ERK1/2 hyperactivation. Altogether, these findings indicate that an excess of NPM-ALK activation and signaling induces apoptosis via oncogenic stress responses. A “drug holiday” where the ALK TKI treatment is suspended could represent a therapeutic option in cells that become resistant by NPM-ALK amplification. PMID:26657151

  18. The patient position for PNL: does it matter?

    PubMed

    Cracco, Cecilia Maria; Scoffone, Cesare Marco; Poggio, Massimiliano; Scarpa, Roberto Mario

    2010-03-01

    Currently, PNL is the treatment of choice for large and/or otherwise complex urolithiasis. PNL was initially performed with the patient in a supine-oblique position, but later on the prone position became the conventional one for habit and handiness. The prone position provides a larger area for percutaneous renal access, a wider space for instrument manipulation, and a claimed lower risk of splanchnic injury. Nonetheless, it implies important anaesthesiological risks, including circulatory, haemodynamic, and ventilatory difficulties; need of several nurses to be present for intraoperative changes of the decubitus in case of simultaneous retrograde instrumentation of the ureter, implying evident risks related to pressure points; an increased radiological hazard to the urologist's hands; patient discomfort. To overcome these drawbacks, various safe and effective changes in patient positioning for PNL have been proposed over the years, including the reverse lithotomy position, the prone split-leg position, the lateral decubitus, the supine position, and the Galdakao-modified supine Valdivia (GMSV) position. Among these, the GMSV position is safe and effective, and seems profitable and ergonomic. It allows optimal cardiopulmonary control during general anaesthesia; an easy puncture of the kidney; a reduced risk of colonic injury; simultaneous antero-retrograde approach to the renal cavities (PNL and retrograde ureteroscopy = ECIRS, Endoscopic Combined IntraRenal Surgery), with no need of intraoperative repositioning of the anaesthetized patient, less need for nurses in the operating room, less occupational risk due to shifting of heavy loads, less risk of pressure injuries related to inaccurate repositioning, and reduced duration of the procedure; facilitated spontaneous evacuation of stone fragments; a comfortable sitting position and a restrained X-ray exposure of the hands for the urologist. But, first of all, GMSV position fully supports a new comprehensive

  19. A Suicide Prevention Program for HIV-Positive Patients.

    ERIC Educational Resources Information Center

    Shaw, Seana; Rothberg, Joseph M.

    Research has shown that suicide risk is elevated in the patient who has tested positive for Human Immunodeficiency Virus (HIV). Studies within the Army have found that the three most turbulent periods for the soldier with HIV infection are: (1) at the time of notification of diagnosis; (2) when the family and peer group learn of the diagnosis; and…

  20. Ethambutol induced toxic optic neuropathy in HIV positive patients

    PubMed Central

    Mustak, Hamzah; Rogers, Graeme; Cook, Colin

    2013-01-01

    AIM To determine whether HIV and the use of antiretroviral therapy is a risk factor for the development of ethambutol toxic optic neuropathy. To describe the clinical course of ethambutol toxic optic neuropathy in patients with HIV and to identify prognostic factors. METHODS The case notes of 14 consecutive patients referred to the neuro-ophthalmology clinic were reviewed. Data regarding HIV status, antiretroviral therapy, visual function, ethambutol therapy dosage, and ethambutol therapy duration were collected and analysed. RESULTS Eleven of the 14 patients were HIV positive. Ten of the HIV positive patients were receiving antiretroviral therapy. The mean dose of ethambutol was 17.25mg/kg/day. No statistically significant difference in mean dose, duration of therapy, age or CD4 count was found between those who showed visual improvement and those who did not. Delay in presentation of more than one month post symptom onset was correlated with poor visual outcome (P=0.001). CONCLUSION HIV and, perhaps more importantly, the potential mitochondrial toxic effects of Nucleoside analogue reverse transcriptase inhibitors (NRTIs) may be a risk factor for the development of toxic optic neuropathy from ethambutol therapy via a multiple hit effect. Delay in presentation results in poor visual outcome. Regular monitoring is recommended for HIV positive patients receiving antiretrovirals and requiring ethambutol therapy in order to avoid permanent visual loss. PMID:23991394

  1. Error compensation algorithm for patient positioning robotics system

    NASA Astrophysics Data System (ADS)

    Murty, Pilaka V.; Talpasanu, Ilie; Roz, Mugur A.

    2009-03-01

    Surgeons in various medical areas (orthopedic surgery, neurosurgery, dentistry etc.) are using motor-driven drilling tools to make perforations in hard tissues (bone, enamel, dentine, cementum etc.) When the penetration requires very precise angles and accurate alignment with respect to different targets, precision cannot be obtained by using visual estimation and hand-held tools. Robots have been designed to allow for very accurate relative positioning of the patient and the surgical tools, and in certain classes of applications the location of bone target and inclination of the surgical tool can be accurately specified with respect to an inertial frame of reference. However, patient positioning errors as well as position changes during surgery can jeopardize the precision of the operation, and drilling parameters have to be dynamically adjusted. In this paper the authors present a quantitative method to evaluate the corrected position and inclination of the drilling tool, to account for translational and rotational errors in displaced target position. The compensation algorithm applies principles of inverse kinematics wherein a faulty axis in space caused by the translational and rotational errors of the target position is identified with an imaginary true axis in space by enforcing identity through a modified trajectory. In the absence of any specific application, this algorithm is verified on Solid Works, a commercial CAD tool and found to be correct. An example problem given at the end vindicates this statement.

  2. The use of cellular thermal shift assay (CETSA) to study Crizotinib resistance in ALK-expressing human cancers

    PubMed Central

    Alshareef, Abdulraheem; Zhang, Hai-Feng; Huang, Yung-Hsing; Wu, Chengsheng; Zhang, Jing Dong; Wang, Peng; El-Sehemy, Ahmed; Fares, Mohamed; Lai, Raymond

    2016-01-01

    Various forms of oncogenic ALK proteins have been identified in various types of human cancers. While Crizotinib, an ALK inhibitor, has been found to be therapeutically useful against a subset of ALK+ tumours, clinical resistance to this drug has been well recognized and the mechanism of this phenomenon is incompletely understood. Using the cellular thermal shift assay (CETSA), we measured the Crizotinib—ALK binding in a panel of ALK+ cell lines, and correlated the findings with the ALK structure and its interactions with specific binding proteins. The Crizotinib IC50 significantly correlated with Crizotinib—ALK binding. The suboptimal Crizotinib—ALK binding in Crizotinib-resistant cells is not due to the cell-specific environment, since transfection of NPM-ALK into these cells revealed substantial Crizotinib—NPM-ALK binding. Interestingly, we found that the resistant cells expressed higher protein level of β-catenin and siRNA knockdown restored Crizotinib—ALK binding (correlated with a significant lowering of IC50). Computational analysis of the crystal structures suggests that β-catenin exerts steric hindrance to the Crizotinib—ALK binding. In conclusion, the Crizotinib—ALK binding measurable by CETSA is useful in predicting Crizotinib sensitivity, and Crizotinib—ALK binding is in turn dictated by the structure of ALK and some of its binding partners. PMID:27641368

  3. Acquired epidermodysplasia verruciformis in an HIV-positive patient.

    PubMed

    Lau, Carmen; Acharya, Sashi; Arumainayagam, Joseph T; Kasparis, Christos; Dhesi, I

    2016-10-01

    Epidermodysplasia verruciformis (EV) is a rare dermatological manifestation of the human papillomavirus (HPV) infection, which causes distinctive skin lesions in sun-exposed areas. Both inherited and acquired forms exist. Immunocompromised individuals, such as HIV patients, are at risk of acquired EV. EV poses challenges in its management and variable responses are seen in different individuals. In addition, EV carries a significant risk of skin malignancy with certain HPV types that require skin surveillance. A case of acquired EV in a HIV-positive patient is presented in this report.

  4. Activin Receptor-Like Kinase Receptors ALK5 and ALK1 Are Both Required for TGFβ-Induced Chondrogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells

    PubMed Central

    de Kroon, Laurie M. G.; Narcisi, Roberto; Blaney Davidson, Esmeralda N.; Cleary, Mairéad A.; van Beuningen, Henk M.; Koevoet, Wendy J. L. M.; van Osch, Gerjo J. V. M.; van der Kraan, Peter M.

    2015-01-01

    Introduction Bone marrow-derived mesenchymal stem cells (BMSCs) are promising for cartilage regeneration because BMSCs can differentiate into cartilage tissue-producing chondrocytes. Transforming Growth Factor β (TGFβ) is crucial for inducing chondrogenic differentiation of BMSCs and is known to signal via Activin receptor-Like Kinase (ALK) receptors ALK5 and ALK1. Since the specific role of these two TGFβ receptors in chondrogenesis is unknown, we investigated whether ALK5 and ALK1 are expressed in BMSCs and whether both receptors are required for chondrogenic differentiation of BMSCs. Materials & Methods ALK5 and ALK1 gene expression in human BMSCs was determined with RT-qPCR. To induce chondrogenesis, human BMSCs were pellet-cultured in serum-free chondrogenic medium containing TGFβ1. Chondrogenesis was evaluated by aggrecan and collagen type IIα1 RT-qPCR analysis, and histological stainings of proteoglycans and collagen type II. To overexpress constitutively active (ca) receptors, BMSCs were transduced either with caALK5 or caALK1. Expression of ALK5 and ALK1 was downregulated by transducing BMSCs with shRNA against ALK5 or ALK1. Results ALK5 and ALK1 were expressed in in vitro-expanded as well as in pellet-cultured BMSCs from five donors, but mRNA levels of both TGFβ receptors did not clearly associate with chondrogenic induction. TGFβ increased ALK5 and decreased ALK1 gene expression in chondrogenically differentiating BMSC pellets. Neither caALK5 nor caALK1 overexpression induced cartilage matrix formation as efficient as that induced by TGFβ. Moreover, short hairpin-mediated downregulation of either ALK5 or ALK1 resulted in a strong inhibition of TGFβ-induced chondrogenesis. Conclusion ALK5 as well as ALK1 are required for TGFβ-induced chondrogenic differentiation of BMSCs, and TGFβ not only directly induces chondrogenesis, but also modulates ALK5 and ALK1 receptor signaling in BMSCs. These results imply that optimizing cartilage formation by

  5. Prone position in patients with acute respiratory distress syndrome

    PubMed Central

    Setten, Mariano; Plotnikow, Gustavo Adrián; Accoce, Matías

    2016-01-01

    Acute respiratory distress syndrome occupies a great deal of attention in intensive care units. Despite ample knowledge of the physiopathology of this syndrome, the focus in intensive care units consists mostly of life-supporting treatment and avoidance of the side effects of invasive treatments. Although great advances in mechanical ventilation have occurred in the past 20 years, with a significant impact on mortality, the incidence continues to be high. Patients with acute respiratory distress syndrome, especially the most severe cases, often present with refractory hypoxemia due to shunt, which can require additional treatments beyond mechanical ventilation, among which is mechanical ventilation in the prone position. This method, first recommended to improve oxygenation in 1974, can be easily implemented in any intensive care unit with trained personnel. Prone position has extremely robust bibliographic support. Various randomized clinical studies have demonstrated the effect of prone decubitus on the oxygenation of patients with acute respiratory distress syndrome measured in terms of the PaO2/FiO2 ratio, including its effects on increasing patient survival. The members of the Respiratory Therapists Committee of the Sociedad Argentina de Terapia Intensiva performed a narrative review with the objective of discovering the available evidence related to the implementation of prone position, changes produced in the respiratory system due to the application of this maneuver, and its impact on mortality. Finally, guidelines are suggested for decision-making. PMID:27925054

  6. Prone position in patients with acute respiratory distress syndrome.

    PubMed

    Setten, Mariano; Plotnikow, Gustavo Adrián; Accoce, Matías

    2016-01-01

    Acute respiratory distress syndrome occupies a great deal of attention in intensive care units. Despite ample knowledge of the physiopathology of this syndrome, the focus in intensive care units consists mostly of life-supporting treatment and avoidance of the side effects of invasive treatments. Although great advances in mechanical ventilation have occurred in the past 20 years, with a significant impact on mortality, the incidence continues to be high. Patients with acute respiratory distress syndrome, especially the most severe cases, often present with refractory hypoxemia due to shunt, which can require additional treatments beyond mechanical ventilation, among which is mechanical ventilation in the prone position. This method, first recommended to improve oxygenation in 1974, can be easily implemented in any intensive care unit with trained personnel. Prone position has extremely robust bibliographic support. Various randomized clinical studies have demonstrated the effect of prone decubitus on the oxygenation of patients with acute respiratory distress syndrome measured in terms of the PaO2/FiO2 ratio, including its effects on increasing patient survival. The members of the Respiratory Therapists Committee of the Sociedad Argentina de Terapia Intensiva performed a narrative review with the objective of discovering the available evidence related to the implementation of prone position, changes produced in the respiratory system due to the application of this maneuver, and its impact on mortality. Finally, guidelines are suggested for decision-making.

  7. Role of liver transplantation in human immunodeficiency virus positive patients

    PubMed Central

    Joshi, Deepak; Agarwal, Kosh

    2015-01-01

    End-stage liver disease (ESLD) is a leading cause of morbidity and mortality amongst human immunodeficiency virus (HIV)-positive individuals. Chronic hepatitis B and hepatitis C virus (HCV) infection, drug-induced hepatotoxicity related to combined anti-retro-viral therapy, alcohol related liver disease and non-alcohol related fatty liver disease appear to be the leading causes. It is therefore, anticipated that more HIV-positive patients with ESLD will present as potential transplant candidates. HIV infection is no longer a contraindication to liver transplantation. Key transplantation outcomes such as rejection and infection rates as well as medium term graft and patient survival match those seen in the non-HIV infected patients in the absence of co-existing HCV infection. HIV disease does not seem to be negatively impacted by transplantation. However, HIV-HCV co-infection transplant outcomes remain suboptimal due to recurrence. In this article, we review the key challenges faced by this patient cohort in the pre- and post-transplant period. PMID:26604639

  8. Extensive Giant Molluscum Contagiosum in a HIV Positive Patient

    PubMed Central

    Pilani, Abhishek P.; Kota, Rahul Krishna

    2015-01-01

    Molluscum contagiosum (MC) is a very common benign self-limiting cutaneous viral infection caused by molluscum contagiosum virus. Disease is self-limiting in immunocompetent individuals, while it is severe and prolonged when associated with Human Immunodeficiency Virus (HIV) infection. The widespread and refractory mollusca of HIV disease occur especially on the face. In advanced stages of immunosuppression, giant or verrucous forms of MC may occur. Molluscum contagiosum tends to take a chronic course and is usually not responsive to various treatments in immunocompromised patients. Here, we present a HIV positive male patient with extensive papulonodular lesions over face, neck, bilateral upper limbs since 2 months, diagnosed as giant molluscum contagiosum, treated with cryotherapy with little improvement for few weeks after which patient did not turn up. PMID:26672647

  9. Enzymological and structural studies of the mechanism of promiscuous substrate recognition by the oxidative DNA repair enzyme AlkB

    PubMed Central

    Yu, Bomina; Hunt, John F.

    2009-01-01

    Promiscuous substrate recognition, the ability to catalyze transformations of chemically diverse compounds, is an evolutionarily advantageous, but poorly understood phenomenon. The promiscuity of DNA repair enzymes is particularly important, because it enables diverse kinds of damage to different nucleotide bases to be repaired in a metabolically parsimonious manner. We present enzymological and crystallographic studies of the mechanisms underlying promiscuous substrate recognition by Escherichia coli AlkB, a DNA repair enzyme that removes methyl adducts and some larger alkylation lesions from endocyclic positions on purine and pyrimidine bases. In vitro Michaelis–Menten analyses on a series of alkylated bases show high activity in repairing N1-methyladenine (m1A) and N3-methylcytosine (m3C), comparatively low activity in repairing 1,N6-ethenoadenine, and no detectable activity in repairing N1-methylguanine or N3-methylthymine. AlkB has a substantially higher kcat and Km for m3C compared with m1A. Therefore, the enzyme maintains similar net activity on the chemically distinct substrates by increasing the turnover rate of the substrate with nominally lower affinity. Cocrystal structures provide insight into the structural basis of this “kcat/Km compensation,” which makes a significant contribution to promiscuous substrate recognition by AlkB. In analyzing a large ensemble of crystal structures solved in the course of these studies, we observed 2 discrete global conformations of AlkB differing in the accessibility of a tunnel hypothesized to control diffusion of the O2 substrate into the active site. Steric interactions between a series of protein loops control this conformational transition and present a plausible mechanism for preventing O2 binding before nucleotide substrate binding. PMID:19706517

  10. Enzymological and Structural Studies of the Mechanism of Promiscuous Substrate Recognition by the Oxidative DNA Repair Enzyme AlkB

    SciTech Connect

    Yu, B.; Hunt, J

    2009-01-01

    Promiscuous substrate recognition, the ability to catalyze transformations of chemically diverse compounds, is an evolutionarily advantageous, but poorly understood phenomenon. The promiscuity of DNA repair enzymes is particularly important, because it enables diverse kinds of damage to different nucleotide bases to be repaired in a metabolically parsimonious manner. We present enzymological and crystallographic studies of the mechanisms underlying promiscuous substrate recognition by Escherichia coli AlkB, a DNA repair enzyme that removes methyl adducts and some larger alkylation lesions from endocyclic positions on purine and pyrimidine bases. In vitro Michaelis-Menten analyses on a series of alkylated bases show high activity in repairing N1-methyladenine (m1A) and N3-methylcytosine (m3C), comparatively low activity in repairing 1,N6-ethenoadenine, and no detectable activity in repairing N1-methylguanine or N3-methylthymine. AlkB has a substantially higher kcat and Km for m3C compared with m1A. Therefore, the enzyme maintains similar net activity on the chemically distinct substrates by increasing the turnover rate of the substrate with nominally lower affinity. Cocrystal structures provide insight into the structural basis of this 'kcat/Km compensation,' which makes a significant contribution to promiscuous substrate recognition by AlkB. In analyzing a large ensemble of crystal structures solved in the course of these studies, we observed 2 discrete global conformations of AlkB differing in the accessibility of a tunnel hypothesized to control diffusion of the O2 substrate into the active site. Steric interactions between a series of protein loops control this conformational transition and present a plausible mechanism for preventing O2 binding before nucleotide substrate binding.

  11. Regulation of alkane degradation pathway by a TetR family repressor via an autoregulation positive feedback mechanism in a Gram-positive Dietzia bacterium.

    PubMed

    Liang, Jie-Liang; Nie, Yong; Wang, Miaoxiao; Xiong, Guangming; Wang, Yi-Ping; Maser, Edmund; Wu, Xiao-Lei

    2016-01-01

    n-Alkanes are ubiquitous in nature and serve as important carbon sources for both Gram-positive and Gram-negative bacteria. Hydroxylation of n-alkanes by alkane monooxygenases is the first and most critical step in n-alkane metabolism. However, regulation of alkane degradation genes in Gram-positive bacteria remains poorly characterized. We therefore explored the transcriptional regulation of an alkB-type alkane hydroxylase-rubredoxin fusion gene, alkW1, from Dietzia sp. DQ12-45-1b. The alkW1 promoter was characterized and so was the putative TetR family regulator, AlkX, located downstream of alkW1 gene. We further identified an unusually long 48 bp inverted repeat upstream of alkW1 and demonstrated the binding of AlkX to this operator. Analytical ultracentrifugation and microcalorimetric results indicated that AlkX formed stable dimers in solution and two dimers bound to one operator in a positive cooperative fashion characterized by a Hill coefficient of 1.64 (± 0.03) [k(D)  = 1.06 (± 0.16) μM, k(D) ' = 0.05 (± 0.01) μM]. However, the DNA-binding affinity was disrupted in the presence of long-chain fatty acids (C10-C24), suggesting that AlkX can sense the concentrations of n-alkane degradation metabolites. A model was therefore proposed where AlkX controls alkW1 expression in a metabolite-dependent manner. Bioinformatic analysis revealed that the alkane hydroxylase gene regulation mechanism may be common among Actinobacteria.

  12. Nigerian dental students' willingness to treat HIV-positive patients.

    PubMed

    Azodo, Clement Chinedu; Ehigiator, Osarobo; Oboro, Helen Oziofu; Ehizele, Adebola Oluyemisi; Umoh, Agnes; Ezeja, Ejike Bartholomew; Omili, Michael; Ehigiator, Laura

    2010-04-01

    Dental care of HIV-positive individuals plays a vital role in improving their nutritional intake, medication tolerance and effectiveness, treatment success rate, and quality of life. It is therefore important to ensure optimal dental care of this group of people, especially since more of them, with or without knowledge of their serologic status, are now utilizing dental services. The objective of this study was to assess Nigerian dental students' willingness to treat HIV-positive individuals. A descriptive cross-sectional survey of all seventy-six final-year dental students of the University of Benin, Nigeria, was conducted in December 2007 using a self-administered questionnaire that elicited information on the students' demography, self-rated knowledge on HIV/AIDS, attitude towards homosexuals, infection control practices, occupational risk perception, and willingness to provide care for HIV-positive individuals. The response rate was 76.3 percent. Over 77 percent of the respondents were in the twenty-five to thirty years age group. The male-female ratio was approximately 1.6:1. HIV-related knowledge was reported as high by only 31 percent of the respondents. Eighty-one percent showed great interest in HIV-related information, while about half (53.4 percent) exhibited significant worry about occupational contagion. Forty-eight (82.7 percent) desired more knowledge about safety precautions during treatment of HIV patients. Fifty respondents (86.2 percent) reported good infection control practices. About three-fourths (74.2 percent) rated the risk of HIV contagion from patients high, while only one-fourth (25.8 percent) reported having an unsympathetic attitude towards homosexuals. Almost all respondents (98.3 percent) agreed that oral care for HIV-positive individuals improves their quality of life, but only 58.8 percent expressed a willingness to treat HIV-positive patients and only 46.5 percent said they will render volunteer dental services in HIV centers. HIV

  13. Targeting brain metastases in ALK-rearranged non-small-cell lung cancer.

    PubMed

    Zhang, Isabella; Zaorsky, Nicholas G; Palmer, Joshua D; Mehra, Ranee; Lu, Bo

    2015-10-01

    The incidence of brain metastases has increased as a result of improved systemic control and advances in imaging. However, development of novel therapeutics with CNS activity has not advanced at the same rate. Research on molecular markers has revealed many potential targets for antineoplastic agents, and a particularly important aberration is translocation in the ALK gene, identified in non-small-cell lung cancer (NSCLC). ALK inhibitors have shown systemic efficacy against ALK-rearranged NSCLC in many clinical trials, but the effectiveness of crizotinib in CNS disease is limited by poor blood-brain barrier penetration and acquired drug resistance. In this Review, we discuss potential pathways to target ALK-rearranged brain metastases, including next generation ALK inhibitors with greater CNS penetration and mechanisms to overcome resistance. Other important mechanisms to control CNS disease include targeting pathways downstream of ALK phosphorylation, increasing the permeability of the blood-brain barrier, modifying the tumour microenvironment, and adding concurrent radiotherapy.

  14. Alk7 Depleted Mice Exhibit Prolonged Cardiac Repolarization and Are Predisposed to Ventricular Arrhythmia

    PubMed Central

    Ying, Shaozhen; Cao, Hong; Hu, He; Wang, Xin; Tang, Yanhong; Huang, Congxin

    2016-01-01

    We aimed to investigate the role of activin receptor-like kinase (ALK7) in regulating cardiac electrophysiology. Here, we showed that Alk7-/- mice exhibited prolonged QT intervals in telemetry ECG recordings. Furthermore, Langendorff-perfused Alk7-/- hearts had significantly longer action potential duration (APD) and greater incidence of ventricular arrhythmia (AV) induced by burst pacing. Using whole-cell patch clamp, we found that the densities of repolarizing K+ currents Ito and IK1 were profoundly reduced in Alk7-/- ventricular cardiomyocytes. Mechanistically, the expression of Kv4.2 (a major subunit of Ito carrying channel) and KCHIP2 (a key accessory subunit of Ito carrying channel), was markedly decreased in Alk7-/- hearts. These findings suggest that endogenous expression of ALK7 is necessary to maintain repolarizing K+ currents in ventricular cardiomyocytes, and finally prevent action potential prolongation and ventricular arrhythmia. PMID:26882027

  15. RecA stimulates AlkB-mediated direct repair of DNA adducts

    PubMed Central

    Shivange, Gururaj; Monisha, Mohan; Nigam, Richa; Kodipelli, Naveena; Anindya, Roy

    2016-01-01

    The Escherichia coli AlkB protein is a 2-oxoglutarate/Fe(II)-dependent demethylase that repairs alkylated single stranded and double stranded DNA. Immunoaffinity chromatography coupled with mass spectrometry identified RecA, a key factor in homologous recombination, as an AlkB-associated protein. The interaction between AlkB and RecA was validated by yeast two-hybrid assay; size-exclusion chromatography and standard pull down experiment and was shown to be direct and mediated by the N-terminal domain of RecA. RecA binding results AlkB–RecA heterodimer formation and RecA–AlkB repairs alkylated DNA with higher efficiency than AlkB alone. PMID:27378775

  16. A Genetically Engineered Mouse Model of Neuroblastoma Driven by Mutated ALK and MYCN

    DTIC Science & Technology

    2014-09-01

    AWARD NUMBER: W81XWH-13-1-0220 TITLE: A Genetically Engineered Mouse Model of Neuroblastoma ...CONTRACT NUMBER A Genetically Engineered Mouse Model of Neuroblastoma Driven by Mutated ALK and MYCN 5b. GRANT NUMBER W81XWH-13-1-0220 5c...common ALK mutations in neuroblastoma , F1174L and R1275Q. We have determined that in tumors cells expressing mutated ALK, different downstream

  17. A Genetically Engineered Mouse Model of Neuroblastoma Driven by Mutated ALK and MYCN

    DTIC Science & Technology

    2015-09-01

    AWARD NUMBER: W81XWH-13-1-0220 TITLE: A Genetically Engineered Mouse Model of Neuroblastoma Driven by Mutated ALK and MYCN PRINCIPAL...4. TITLE AND SUBTITLE A Genetically Engineered Mouse Model of Neuroblastoma Driven by Mutated ALK and MYCN 5a. CONTRACT NUMBER 5b. GRANT NUMBER... genetic and epigenetic changes that occur during tumorigenesis. 15. SUBJECT TERMS Anaplastic lymphoma kinase, neuroblastoma, ALK, ALKF1174L, MYCN, CDK7

  18. Diversity of alkane degrading bacteria associated with plants in a petroleum oil-contaminated environment and expression of alkane monooxygenase (alkB) genes

    NASA Astrophysics Data System (ADS)

    Andria, V.; Yousaf, S.; Reichenauer, T. G.; Smalla, K.; Sessitsch, A.

    2009-04-01

    Among twenty-six different plant species, Italian ryegrass (Lolium multiflorum var. Taurus), Birdsfoot trefoil (Lotus corniculatus var. Leo), and the combination of both plants performed well in a petroleum oil contaminated soil. Hydrocarbon degrading bacteria were isolated from the rhizosphere, root interior and shoot interior and subjected to the analysis of 16S rRNA, the 16S and 23S rRNA intergenic spacer region and alkane hydroxylase genes. Higher numbers of culturable, degrading bacteria were associated with Italian ryegrass, which were also characterized by a higher diversity, particularly in the plant interior. Only half of the isolated bacteria hosted known alkane hydroxylase genes (alkB and cytochrome P153-like). Our results indicated that alkB genes have spread through horizontal gene transfer, particularly in the Italian ryegrass rhizosphere, and suggested mobility of catabolic genes between Gram-negative and Gram-positive bacteria. We furthermore studied the colonization behaviour of selected hydrocarbon-degrading strains (comprising an endopyhte and a rhizosphere strain) as well as the expression of their alkane monooxygenase genes in association with Italian ryegrass. Results showed that the endophyte strain better colonized the plant, particularly the plant interior, and also showed higher expression of alkB genes suggesting a more efficient degradation of the pollutant. Furthermore, plants inoculated with the endophyte were better able to grow in the presence of diesel. The rhizosphere strain colonized primarily the rhizosphere and showed low alkB gene expression in the plant interior.

  19. Porokeratosis of Mibelli in an HIV-positive patient*

    PubMed Central

    Ottoni, Luiza de Queiroz; Kakizaki, Priscila; Pinheiro, Rafael Ribeiro; Sittart, José Alexandre de Souza; Valente, Neusa Yuriko Sakai

    2016-01-01

    Porokeratosis represents a group of disorders of epidermal keratinization that are characterized by one or more annular plaques surrounded by a histologically distinctive hyperkeratotic ridge-like border called the cornoid lamella. Many studies showed that organ transplantation and immunosuppression were associated in a significant number of cases. Furthermore, an association with squamous cell carcinoma and basal cell carcinoma has been noted in all variants of porokeratosis. The rarity of this disorder and its atypical clinical presentation – a single lesion on the thumb of an HIV-positive male patient – motivated this report. PMID:28300920

  20. The Escherichia coli AlkB protein protects human cells against alkylation-induced toxicity.

    PubMed Central

    Chen, B J; Carroll, P; Samson, L

    1994-01-01

    Escherichia coli can ameliorate the toxic effects of alkylating agents either by preventing DNA alkylation or by repairing DNA alkylation damage. The alkylation-sensitive phenotype of E. coli alkB mutants marks the alkB pathway as an extremely effective defense mechanism against the cytotoxic effects of the SN2, but not the SN1, alkylating agents. Although it is clear that AlkB helps cells to better handle alkylated DNA, no DNA alkylation repair function could be assigned to the purified AlkB protein, suggesting that AlkB either acts as part of a complex or acts to regulate the expression of other genes whose products are directly responsible for alkylation resistance. However, here we present evidence that the provision of alkylation resistance is an intrinsic function of the AlkB protein per se. We expressed the E. coli AlkB protein in two human cell lines and found that it confers the same characteristic alkylation-resistant phenotype in this foreign environment as it does in E. coli. AlkB expression rendered human cells extremely resistant to cell killing by the SN2 but not the SN1 alkylating agents but did not affect the ability of dimethyl sulfate (an SN2 agent) to alkylate the genome. We infer that SN2 agents produce a class of DNA damage that is not efficiently produced by SN1 agents and that AlkB somehow prevents this damage from killing the cell. Images PMID:7928996

  1. Identification of ALK germline mutation (3605delG) in pediatric anaplastic medulloblastoma.

    PubMed

    Coco, Simona; De Mariano, Marilena; Valdora, Francesca; Servidei, Tiziana; Ridola, Vita; Andolfo, Immacolata; Oberthuer, André; Tonini, Gian Paolo; Longo, Luca

    2012-10-01

    The anaplastic lymphoma kinase (ALK) gene has been found either rearranged or mutated in several neoplasms such as anaplastic large-cell lymphoma, non-small-cell lung cancer, neuroblastoma and anaplastic thyroid cancer. Medulloblastoma (MB) is an embryonic pediatric cancer arising from nervous system, a tissue in which ALK is expressed during embryonic development. We performed an ALK mutation screening in 52 MBs and we found a novel heterozygous germline deletion of a single base in exon 23 (3605delG) in a case with marked anaplasia. This G deletion results in a frameshift mutation producing a premature stop codon in exon 25 of ALK tyrosine kinase domain. We also screened three human MB cell lines without finding any mutation of ALK gene. Quantitative expression analysis of 16 out of 52 samples showed overexpression of ALK mRNA in three MBs. In the present study, we report the first mutation of ALK found in MB. Moreover, a deletion of ALK gene producing a stop codon has not been detected in human tumors up to now. Further investigations are now required to elucidate whether the truncated form of ALK may have a role in signal transduction.

  2. The Use of a Combination of alkB Primers to Better Characterize the Distribution of Alkane-Degrading Bacteria.

    PubMed

    Jurelevicius, Diogo; Alvarez, Vanessa Marques; Peixoto, Raquel; Rosado, Alexandre S; Seldin, Lucy

    2013-01-01

    The alkane monooxygenase AlkB, which is encoded by the alkB gene, is a key enzyme involved in bacterial alkane degradation. To study the alkB gene within bacterial communities, researchers need to be aware of the variations in alkB nucleotide sequences; a failure to consider the sequence variations results in the low representation of the diversity and richness of alkane-degrading bacteria. To minimize this shortcoming, the use of a combination of three alkB-targeting primers to enhance the detection of the alkB gene in previously isolated alkane-degrading bacteria was proposed. Using this approach, alkB-related PCR products were detected in 79% of the strains tested. Furthermore, the chosen set of primers was used to study alkB richness and diversity in different soils sampled in Carmópolis, Brazil and King George Island, Antarctica. The DNA extracted from the different soils was PCR amplified with each set of alkB-targeting primers, and clone libraries were constructed, sequenced and analyzed. A total of 255 alkB phylotypes were detected. Venn diagram analyses revealed that only low numbers of alkB phylotypes were shared among the different libraries derived from each primer pair. Therefore, the combination of three alkB-targeting primers enhanced the richness of alkB phylotypes detected in the different soils by 45% to 139%, when compared to the use of a single alkB-targeting primer. In addition, a dendrogram analysis and beta diversity comparison of the alkB composition showed that each of the sampling sites studied had a particular set of alkane-degrading bacteria. The use of a combination of alkB primers was an efficient strategy for enhancing the detection of the alkB gene in cultivable bacteria and for better characterizing the distribution of alkane-degrading bacteria in different soil environments.

  3. The Use of a Combination of alkB Primers to Better Characterize the Distribution of Alkane-Degrading Bacteria

    PubMed Central

    Jurelevicius, Diogo; Alvarez, Vanessa Marques; Peixoto, Raquel; Rosado, Alexandre S.; Seldin, Lucy

    2013-01-01

    The alkane monooxygenase AlkB, which is encoded by the alkB gene, is a key enzyme involved in bacterial alkane degradation. To study the alkB gene within bacterial communities, researchers need to be aware of the variations in alkB nucleotide sequences; a failure to consider the sequence variations results in the low representation of the diversity and richness of alkane-degrading bacteria. To minimize this shortcoming, the use of a combination of three alkB-targeting primers to enhance the detection of the alkB gene in previously isolated alkane-degrading bacteria was proposed. Using this approach, alkB-related PCR products were detected in 79% of the strains tested. Furthermore, the chosen set of primers was used to study alkB richness and diversity in different soils sampled in Carmópolis, Brazil and King George Island, Antarctica. The DNA extracted from the different soils was PCR amplified with each set of alkB-targeting primers, and clone libraries were constructed, sequenced and analyzed. A total of 255 alkB phylotypes were detected. Venn diagram analyses revealed that only low numbers of alkB phylotypes were shared among the different libraries derived from each primer pair. Therefore, the combination of three alkB-targeting primers enhanced the richness of alkB phylotypes detected in the different soils by 45% to 139%, when compared to the use of a single alkB-targeting primer. In addition, a dendrogram analysis and beta diversity comparison of the alkB composition showed that each of the sampling sites studied had a particular set of alkane-degrading bacteria. The use of a combination of alkB primers was an efficient strategy for enhancing the detection of the alkB gene in cultivable bacteria and for better characterizing the distribution of alkane-degrading bacteria in different soil environments. PMID:23825163

  4. Anaplastic lymphoma kinase (ALK 1) staining and molecular analysis in inflammatory myofibroblastic tumours of the bladder: a preliminary clinicopathological study of nine cases and review of the literature.

    PubMed

    Freeman, Alex; Geddes, Nicola; Munson, Philippa; Joseph, Jean; Ramani, Pramila; Sandison, Ann; Fisher, Cyril; Parkinson, M Connie

    2004-07-01

    Inflammatory myofibroblastic tumours (IMFT) may arise at any anatomical site, including lung, soft tissues, retroperitoneum and bladder. Although morphologically similar, these lesions encompass a spectrum of entities with differing aetiology, ranging from reactive/regenerative proliferations to low-grade neoplasms with a risk of local recurrence, but no significant metastatic potential. Vesical IMFT usually presents as a polypoid mass with a pale firm cut surface and can be of considerable size, mimicking a malignant tumour clinically and radiologically. Its good outcome, however, warrants conservative surgical excision, emphasising the importance of identification and distinction from malignant tumours of the bladder that may require more radical surgery and/or adjuvant therapy. We conducted a preliminary retrospective, comparative immunocytochemical study of 20 bladder tumours, including nine IMFTs, five spindle cell (sarcomatoid) carcinomas, two rhabdomyosarcomas, two leiomyosarcomas and two neurofibromas. The results confirmed IMFT positivity for smooth muscle actin, desmin and cytokeratin in 78-89% cases, resulting in potential confusion with sarcomatoid carcinoma or leiomyosarcoma. In contrast, cytoplasmic anaplastic lymphoma kinase (ALK 1) staining was present in eight IMFT (89%), but was not seen in any other lesion examined. The ALK 1 staining was confirmed by fluorescence in situ hybridisation, with translocation of the ALK gene present in 15-60% tumour cells in four of six IMFT examined, but not in four cases of sarcomatoid carcinoma or three of leiomyosarcoma. In conclusion, ALK 1 staining may be of value in the distinction of vesical IMFT from morphologically similar entities, and often reflects ALK gene translocations in these lesions.

  5. Amphiregulin triggered epidermal growth factor receptor activation confers in vivo crizotinib-resistance of EML4-ALK lung cancer and circumvention by epidermal growth factor receptor inhibitors.

    PubMed

    Taniguchi, Hirokazu; Takeuchi, Shinji; Fukuda, Koji; Nakagawa, Takayuki; Arai, Sachiko; Nanjo, Shigeki; Yamada, Tadaaki; Yamaguchi, Hiroyuki; Mukae, Hiroshi; Yano, Seiji

    2017-01-01

    Crizotinib, a first-generation anaplastic lymphoma kinase (ALK) tyrosine-kinase inhibitor, is known to be effective against echinoderm microtubule-associated protein-like 4 (EML4)-ALK-positive non-small cell lung cancers. Nonetheless, the tumors subsequently become resistant to crizotinib and recur in almost every case. The mechanism of the acquired resistance needs to be deciphered. In this study, we established crizotinib-resistant cells (A925LPE3-CR) via long-term administration of crizotinib to a mouse model of pleural carcinomatous effusions; this model involved implantation of the A925LPE3 cell line, which harbors the EML4-ALK gene rearrangement. The resistant cells did not have the secondary ALK mutations frequently occurring in crizotinib-resistant cells, and these cells were cross-resistant to alectinib and ceritinib as well. In cell clone #2, which is one of the clones of A925LPE3-CR, crizotinib sensitivity was restored via the inhibition of epidermal growth factor receptor (EGFR) by means of an EGFR tyrosine-kinase inhibitor (erlotinib) or an anti-EGFR antibody (cetuximab) in vitro and in the murine xenograft model. Cell clone #2 did not have an EGFR mutation, but the expression of amphiregulin (AREG), one of EGFR ligands, was significantly increased. A knockdown of AREG with small interfering RNAs restored the sensitivity to crizotinib. These data suggest that overexpression of EGFR ligands such as AREG can cause resistance to crizotinib, and that inhibition of EGFR signaling may be a promising strategy to overcome crizotinib resistance in EML4-ALK lung cancer.

  6. HIV positive patient with HSV-2 encephalitis: case report.

    PubMed

    Pagliano, Pasquale; Ascione, Tiziana; Carleo, Maria Aurora; Boccia, Giovanni; De Caro, Francesco; Tortora, Fabio

    2016-09-01

    Incidence of brain infections in Human Immunodeficiency Virus (HIV) positive patients is reduced after the availability of current high active antiretroviral therapy (HAART). Herpes Simplex Virus type 2 (HSV-2) is an infrequent cause of encephalitis in HIV patients despite it is frequently involved in sexual transmitted infections. Here, we report a case of HSV-2 encephalitis occurring in a patient without full suppression of HIV replication within the brain. A 38 year-old HIV infected man was admitted to our department because of recurrent generalized seizure and fever during the previous 24 hours. Eight months before our observation the patient was switched from a protease inhibitor based regimen to a rilpivirine-based regimen without any evidence of HIV-RNA replication in the plasma. When the patient was admitted in our hospital, he was febrile and moderately confused, no deficit of cranial nerves was reported, motility was conserved, but he was unable to walk. Laboratory examinations performed at admission demonstrated an increase of cerebrospinal fluid (CSF) protein and cells with lymphocyte prevalence, and normal CSF glucose. HSV-2-DNA and HIV-RNA were present within CSF at admission. Nuclear Magnetic Resonance imaging of the brain revealed lesions of the medial part of both temporal lobes including hippocampus without any sign of bleeding. A 21-day course of acyclovir therapy was administered with consistent improvement of clinical findings and disappearance of HSV-2-DNA within CSF. After the episode, HAART was switched to a regimen with high CSF penetrability containing abacavir, lamivudine, darunavir and ritonavir. Twelve months after HSV-2 encephalitis neurologic evaluation was normal, but symptoms of depression were reported, HIV-RNA remained undetectable both in the plasma and CSF, and CD4+ lymphocytes were above 500/μL. No opportunistic infection was reported. Patients switched to regimen well tolerated such those containing rilpivirine, that have

  7. Patient Positioning and Port Placement for Robot-Assisted Surgery

    PubMed Central

    Chang, Charles; Steinberg, Zoe; Shah, Anup

    2014-01-01

    Abstract The introduction of robotic surgical systems and their integration into minimally invasive procedures have changed the landscape of laparoscopic surgery dramatically. Intuitive Surgical's da Vinci Surgical System was first approved by the Food and Drug Administration for cardiothoracic procedures in the late 1990s. This trend quickly spread through other surgical specialties, with urologists as one of the frontrunners in adoption. Subsequently, pediatric urologists have adopted robot-assisted procedures in selected centers, performing procedures such as pyeloplasty for ureteropelvic junction obstruction, partial and complete nephrectomy, and both intravesical and extravesical ureteral reimplantation. In this article, we will discuss technical considerations related to patient positioning and port placement in pediatric robot-assisted surgery. PMID:24548088

  8. Treatment of leishmaniasis in HIV-positive patients.

    PubMed

    Laguna, F

    2003-10-01

    Although, in southern Europe, there has been considerable experience in the treatment of visceral leishmaniasis (VL) in HIV-positive patients, the optimal therapy has yet to be established. Pentavalent antimony salts, free amphotericin B deoxycholate (ABD) and lipidic formulations of amphotericin B are the drugs most commonly used. Treatment with pentavalent antimonials requires daily injections for 28 days, is not well tolerated and leads to initial clinical cure in only 66% of the co-infected cases. Free ABD has to be given, intravenously, for just as long, has significant toxicity and leads to initial clinical cure in even fewer cases (62%). In a prospective, comparative trial, treatment of co-infected cases with a pentavalent antimonial was found to have similar efficacy and toxicity to treatment with free ABD. The duration of treatment and the associated toxicity may both be reduced by the use of lipidic formulations of amphotericin B. Anecdotal evidence and the results of non-randomized trials indicate that treatment with liposomal amphotericin B is highly effective. In a comparative trial, amphotericin B lipid complex was found to be not only as effective as a pentavalent antimonial but also better tolerated. At the moment, however, such lipidic formulations have only been tested against VL/HIV cases in Europe, not elsewhere in the world, and they remain very expensive. However successful the treatment in terms of initial clinical cure, almost all VL/HIV cases develop VL relapses. Although the data available on secondary prophylaxis are limited and often inconclusive, it appears that regular treatment with a pentavalent antimonial drug, liposomal amphothericin B or amphotericin B lipid complex can reduce the incidence of leishmanial relapses in HIV-positive patients with VL. The development of new regimens, use of new oral drugs (such as miltefosine) and the development of new antileishmanial drugs could all improve the treatment of HIV-related VL in the

  9. Positioning.

    ERIC Educational Resources Information Center

    Conone, Ruth M.

    The key to positioning is the creation of a clear benefit image in the consumer's mind. One positioning strategy is creating in the prospect's mind a position that takes into consideration the company's or agency's strengths and weaknesses as well as those of its competitors. Another strategy is to gain entry into a position ladder owned by…

  10. Shear induced collateral artery growth modulated by endoglin but not by ALK1

    PubMed Central

    Seghers, Leonard; de Vries, Margreet R; Pardali, Evangelia; Hoefer, Imo E; Hierck, Beerend P; ten Dijke, Peter ten; Goumans, Marie Jose; Quax, Paul HA

    2012-01-01

    Transforming growth factor-beta (TGF-β) stimulates both ischaemia induced angiogenesis and shear stress induced arteriogenesis by signalling through different receptors. How these receptors are involved in both these processes of blood flow recovery is not entirely clear. In this study the role of TGF-β receptors 1 and endoglin is assessed in neovascularization in mice. Unilateral femoral artery ligation was performed in mice heterozygous for either endoglin or ALK1 and in littermate controls. Compared with littermate controls, blood flow recovery, monitored by laser Doppler perfusion imaging, was significantly hampered by maximal 40% in endoglin heterozygous mice and by maximal 49% in ALK1 heterozygous mice. Collateral artery size was significantly reduced in endoglin heterozygous mice compared with controls but not in ALK1 heterozygous mice. Capillary density in ischaemic calf muscles was unaffected, but capillaries from endoglin and ALK1 heterozygous mice were significantly larger when compared with controls. To provide mechanistic evidence for the differential role of endoglin and ALK1 in shear induced or ischaemia induced neovascularization, murine endothelial cells were exposed to shear stress in vitro. This induced increased levels of endoglin mRNA but not ALK1. In this study it is demonstrated that both endoglin and ALK1 facilitate blood flow recovery. Importantly, endoglin contributes to both shear induced collateral artery growth and to ischaemia induced angiogenesis, whereas ALK1 is only involved in ischaemia induced angiogenesis. PMID:22436015

  11. Precision medicine in NSCLC and pathology: how does ALK fit in the pathway?

    PubMed

    Kerr, K M; López-Ríos, F

    2016-09-01

    The evolution of personalised medicine in lung cancer has dramatically impacted diagnostic pathology. Current challenges centre on the growing demands placed on small tissue samples by molecular diagnostic techniques. In this review, expert recommendations are provided regarding successful identification of anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC). Steps to correctly process and conserve tumour tissue during diagnostic testing are essential to ensure tissue availability. For example, storing extra tissue sections ready for molecular diagnostic steps allows faster testing and preserves tissue. Fluorescence in situ hybridisation (FISH) is commonly used to detect ALK rearrangements, with most laboratories favouring screening by immunohistochemistry followed by a confirmatory FISH assay. Reverse transcription-polymerase chain reaction can also identify ALK fusion gene mRNA transcripts but can be limited by the quality of RNA and the risk that rare fusion variants may not be captured. Next-generation sequencing (NGS) technology has recently provided an alternative method for detecting ALK rearrangements. While current experience is limited, NGS is set to become the most efficient approach as an increasing number of genetic abnormalities is required to be tested. Upfront, reflex testing for ALK gene rearrangement should become routine as ALK tyrosine kinase inhibitor therapy moves into the first-line setting. Guidelines recommend that EGFR and ALK tests are carried out in parallel on all confirmed and potential adenocarcinomas, and this is more efficient in terms of tissue usage and testing turnaround time for both of these actionable gene alterations. The practice of sequential testing is not recommended. Identification of ALK rearrangements is now essential for the diagnosis of NSCLC, underpinned by the benefits of ALK inhibitors. As scientific understanding and diagnostic technology develops, ALK testing will continue to be an

  12. HTLV infection in HCV-antibody positive patients in Spain.

    PubMed

    Treviño, Ana; Aguilera, Antonio; Rodríguez-Iglesias, Manuel A; Hernandez, Araceli; Benito, Rafael; Roc, Lourdes; Ramos, José Manuel; Ortíz de Lejarazu, Raúl; Poveda, Eva; Rodríguez, Carmen; Del Romero, Jorge; Calderon, Enrique; García, Juan; Requena, Silvia; Soriano, Vincent; de Mendoza, Carmen

    2017-03-07

    Since hepatitis C virus (HCV) and human T-lymphotropic virus (HTLV) share transmission routes, dual infection could be frequent. In Spain, HTLV underdiagnosis is highlighted by the high proportion of patients presenting either with tropical spastic paraparesis (TSP) or adult T-cell leukemia (ATL) at first diagnosis. We examined whether the renewed efforts for expanding HCV testing may provide a sentinel population that might selectively be targeted to unveil asymptomatic HTLV carriers. The presence of anti-HTLV antibodies was examined in 3,838 consecutive individuals with reactive HCV serology attended during the last three years at 13 hospitals distributed across the Spanish geography. Overall 71% were male and the median age was 41-years old. Foreigners represented 9% of the study population. A total of 50 individuals (1.3%) were seroreactive for HTLV, being 30 confirmed as HTLV-2 and two as HTLV-1 (0.12%). The remaining 18 had indeterminate Western blot patterns. Most individuals with HTLV-2 and HTLV indeterminate serology were HIV-positive, former injection drug users and native Spaniards. In contrast, the two HTLV-1 infections were found in men coming from Brazil and the Dominican Republic, respectively. In summary, the overall prevalence of HTLV infection in individuals living in Spain seropositive for HCV is 1.3%, more than 10-fold greater than in general outclinics in Spain. However, immigrants from HTLV-1 endemic regions and former injection drug users with HTLV-2 infection are by far the major contributory groups in HCV patients. Therefore, testing for HTLV in newly diagnosed HCV individuals would not contribute much to improve late HTLV diagnosis in Spain.

  13. Oncogenic TPM3-ALK activation requires dimerization through the coiled-coil structure of TPM3

    SciTech Connect

    Amano, Yosuke; Ishikawa, Rie; Sakatani, Toshio; Ichinose, Junji; Sunohara, Mitsuhiro; Watanabe, Kousuke; Kage, Hidenori; Nakajima, Jun; Nagase, Takahide; Ohishi, Nobuya; Takai, Daiya

    2015-02-13

    Inflammatory myofibroblastic tumor (IMT) is a mesenchymal tumor that can arise from anywhere in the body. Anaplastic lymphoma kinase (ALK) gene rearrangements, most often resulting in the tropomyosin 3 (TPM3)-ALK fusion gene, are the main causes of IMT. However, the mechanism of malignant transformation in IMT has yet to be elucidated. The purpose of this study was to clarify the role of the TPM3 region in the transformation of IMT via TPM3-ALK. Lentivirus vectors containing a TPM3-ALK fusion gene lacking various lengths of TPM3 were constructed and expressed in HEK293T and NIH3T3 cell lines. Focus formation assay revealed loss of contact inhibition in NIH3T3 cells transfected with full-length TPM3-ALK, but not with ALK alone. Blue-native polyacrylamide gel electrophoresis (BN-PAGE) revealed that TPM3-ALK dimerization increased in proportion to the length of TPM3. Western blot showed phosphorylation of ALK, ERK1/2, and STAT3 in HEK293T cells transfected with TPM3-ALK. Thus, the coiled-coil structure of TPM3 contributes to the transforming ability of the TPM3-ALK fusion protein, and longer TPM3 region leads to higher dimer formation. - Highlights: • TPM3-ALK fusion protein dimerizes through the coiled-coil structure of TPM3. • Longer coiled-coil structure of TPM3 leads to higher TPM3-ALK dimer formation. • Presence of TPM3-ALK dimer leads to ALK, STAT3, and ERK1/2 phosphorylation. • Presence of TPM3-ALK leads to loss of contact inhibition. • BN-PAGE is a simple technique for visualizing oncogenic dimerization.

  14. Spinal factors influencing change in pelvic sagittal inclination from supine position to standing position in patients before total hip arthroplasty.

    PubMed

    Tamura, Satoru; Takao, Masaki; Sakai, Takashi; Nishii, Takashi; Sugano, Nobuhiko

    2014-12-01

    In some atypical patients, pelvic sagittal inclination (PSI) changes posteriorly by >10° from supine to standing position before total hip arthroplasty (THA). Several studies have suggested PSI in standing position is related to lumbar degeneration. The purpose of this study was to investigate spinal factors influencing changes in PSI from supine to standing position before THA. Participants comprised 163 consecutive patients who had undergone THA. Presence of compression fractures, presence of lumbar spondylolisthesis, thoracic kyphosis angle, lumbar lordosis angle, S1 anterior tilt angle and T4 plumb line position were investigated as spinal factors. Presence of compression fractures, age, presence of lumbar spondylolisthesis and small S1 anterior tilt angle were independently associated with posterior change in PSI from supine to standing position in patients before THA.

  15. Positive Effects of Massage Therapy on a Patient with Narcolepsy

    PubMed Central

    Hill, Robyn; Baskwill, Amanda

    2013-01-01

    Purpose The purpose of this case report was to investigate the effects of massage therapy on the sleep patterns of a woman with narcolepsy. Participant The 23-year-old woman’s primary symptoms included excessive daytime sleepiness and periodic leg movements (PLM), which were associated with her diagnoses of both narcolepsy and cataplexy. Intervention Five 45-minute massage therapy treatments were administered over a five-week period. The patient’s sleep patterns were recorded each week before the treatment. A final measurement was recorded in the sixth week. The sleep patterns were monitored using the Leeds Sleep Evaluation Questionnaire, which included ten visual analogue scales. Results The results of this case report included an improvement in getting to sleep by 148%, an improvement in quality of sleep by 1100%, an improvement in awake following sleep by 121%, and an improvement in behaviour following wakening by 28% using the Leeds Sleep Evaluation Questionnaire. Conclusion This case report suggests that massage therapy had a positive effect on this patient with narcolepsy. Further research is needed to investigate the effects of massage therapy on narcolepsy and sleep patterns. PMID:23730398

  16. Thoracoabdominal Aortic Aneurysm in a HIV-positive Patient

    PubMed Central

    Lucas, Márcio Luís; Binotto, Ívia; Behar, Paulo; Erling Jr., Nilon; Lichtenfels, Eduardo; Aerts, Newton

    2017-01-01

    Advent of antiretroviral therapy has increased survival of patients with human immunodeficiency virus (HIV) infections, with the result that some of these patients now develop degenerative diseases, such as atherosclerotic aneurysms. Degenerative thoracoabdominal aortic aneurysm is rare in HIV patients. In this report, a 63-year-old male patient with HIV submitted to open repair of thoracoabdominal aortic aneurysm. The patient did not suffer any type of complication in the perioperative period and remained well in a 28-month follow-up period. In summary, open repair still remains a good alternative for aortic complex aneurysms even in HIV patients.

  17. Rhein Inhibits AlkB Repair Enzymes and Sensitizes Cells to Methylated DNA Damage.

    PubMed

    Li, Qi; Huang, Yue; Liu, Xichun; Gan, Jianhua; Chen, Hao; Yang, Cai-Guang

    2016-05-20

    The AlkB repair enzymes, including Escherichia coli AlkB and two human homologues, ALKBH2 and ALKBH3, are iron(II)- and 2-oxoglutarate-dependent dioxygenases that efficiently repair N(1)-methyladenine and N(3)-methylcytosine methylated DNA damages. The development of small molecule inhibitors of these enzymes has seen less success. Here we have characterized a previously discovered natural product rhein and tested its ability to inhibit AlkB repair enzymes in vitro and to sensitize cells to methyl methane sulfonate that mainly produces N(1)-methyladenine and N(3)-methylcytosine lesions. Our investigation of the mechanism of rhein inhibition reveals that rhein binds to AlkB repair enzymes in vitro and promotes thermal stability in vivo In addition, we have determined a new structural complex of rhein bound to AlkB, which shows that rhein binds to a different part of the active site in AlkB than it binds to in fat mass and obesity-associated protein (FTO). With the support of these observations, we put forth the hypothesis that AlkB repair enzymes would be effective pharmacological targets for cancer treatment.

  18. NeuroD1 promotes neuroblastoma cell growth by inducing the expression of ALK.

    PubMed

    Lu, Fangjin; Kishida, Satoshi; Mu, Ping; Huang, Peng; Cao, Dongliang; Tsubota, Shoma; Kadomatsu, Kenji

    2015-04-01

    Neuroblastoma is derived from the sympathetic neuronal lineage of neural crest cells, and is the most frequently observed of the extracranial pediatric solid tumors. The neuronal differentiation factor, NeuroD1, has previously been shown to promote cell motility in neuroblastoma by suppressing the expression of Slit2. Here we report that NeuroD1 is also involved in the proliferation of neuroblastoma cells, including human cell lines and primary tumorspheres cultured from the tumor tissues of model mice. Interestingly, the growth inhibition of neuroblastoma cells induced by knockdown of NeuroD1 was accompanied by a reduction of ALK expression. ALK is known to be one of the important predisposition genes for neuroblastoma. The phenotype resulting from knockdown of NeuroD1 was suppressed by forced expression of ALK and, therefore, NeuroD1 appears to act mainly through ALK to promote the proliferation of neuroblastoma cells. Furthermore, we showed that NeuroD1 directly bound to the promoter region of ALK gene. In addition, the particular E-box in the promoter was responsible for NeuroD1-mediated ALK expression. These results indicate that ALK should be a direct target gene of NeuroD1. Finally, the expressions of NeuroD1 and ALK in the early tumor lesions of neuroblastoma model mice coincided in vivo. We conclude that the novel mechanism would regulate the expression of ALK in neuroblastoma and that NeuroD1 should be significantly involved in neuroblastoma tumorigenesis.

  19. DNA bending and a flip-out mechanism for base excision by the helix–hairpin–helix DNA glycosylase, Escherichia coli AlkA

    PubMed Central

    Hollis, Thomas; Ichikawa, Yoshitaka; Ellenberger, Tom

    2000-01-01

    The Escherichia coli AlkA protein is a base excision repair glycosylase that removes a variety of alkylated bases from DNA. The 2.5 Å crystal structure of AlkA complexed to DNA shows a large distortion in the bound DNA. The enzyme flips a 1–azaribose abasic nucleotide out of DNA and induces a 66° bend in the DNA with a marked widening of the minor groove. The position of the 1–azaribose in the enzyme active site suggests an SN1-type mechanism for the glycosylase reaction, in which the essential catalytic Asp238 provides direct assistance for base removal. Catalytic selectivity might result from the enhanced stacking of positively charged, alkylated bases against the aromatic side chain of Trp272 in conjunction with the relative ease of cleaving the weakened glycosylic bond of these modified nucleotides. The structure of the AlkA–DNA complex offers the first glimpse of a helix–hairpin–helix (HhH) glycosylase complexed to DNA. Modeling studies suggest that other HhH glycosylases can bind to DNA in a similar manner. PMID:10675345

  20. Clinical effect of a positive surgical margin after hepatectomy on survival of patients with intrahepatic cholangiocarcinoma

    PubMed Central

    Yeh, Chun-Nan; Hsieh, Feng-Jen; Chiang, Kun-Chun; Chen, Jen-Shi; Yeh, Ta-Sen; Jan, Yi-Yin; Chen, Miin-Fu

    2015-01-01

    Background Several unfavorable prognostic factors have been proposed for peripheral cholangiocarcinoma (PCC) in patients undergoing hepatectomy, including gross type of tumor, vascular invasion, lymph node metastasis, a high carbohydrate antigen 19-9 level, and a positive resection margin. However, the clinical effect of a positive surgical margin on the survival of patients with PCC after hepatectomy still needs to be clarified due to conflicting results. Methods A total of 224 PCC patients who underwent hepatic resection with curative intent between 1977 and 2007 were retrospectively reviewed. Eighty-nine patients had a positive resection margin, with 62 having a microscopically positive margin and 27 a grossly positive margin (R2). The clinicopathological features, outcomes, and recurrence pattern were compared with patients with curative hepatectomy. Results PCC patients with hepatolithiasis, periductal infiltrative or periductal infiltrative mixed with mass-forming growth, higher T stage, and more advanced stage tended to have higher positive resection margin rates after hepatectomy. PCC patients who underwent curative hepatectomy had a significantly higher survival rate than did those with a positive surgical margin. When PCC patients underwent hepatectomy with a positive resection margin, the histological grade of the tumor, nodal positivity, and chemotherapy significantly affected overall survival. Locoregional recurrence was the most common pattern of recurrence. Conclusion A positive resection margin had an unfavorable effect on overall survival in PCC patients undergoing hepatectomy. In these patients, the prognosis was determined by the biology of the tumor, including differentiation and nodal positivity, and chemotherapy increased overall survival. PMID:25552905

  1. The expression of SALL4 is significantly associated with EGFR, but not KRAS or EML4-ALK mutations in lung cancer

    PubMed Central

    Jia, Xiangbo; Qian, Rulin; Zhang, Binbin

    2016-01-01

    Background Lung cancer is the leading cause of cancer-related deaths worldwide; unfortunately, its prognosis is still very poor. Therefore, developing the target molecular is very important for lung cancer diagnosis and treatment, especially in the early stage. With this in view, spalt-like transcription factor 4 (SALL4) is considered a potential biomarker for diagnosis and prognosis in cancers, including lung cancer. Methods In order to better investigate the association between the expression of SALL4 and driver genes mutation, 450 histopathologically diagnosed patients with lung cancer and 11 non-cancer patients were enrolled to test the expression of SALL4 and the status of driver genes mutation. This investigation included epidermal growth factor receptor (EGFR), kirsten rat sarcoma viral oncogene homolog (KRAS), and a fusion gene of the echinoderm microtubule-associated protein-like 4 (EML4) and the anaplastic lymphoma kinase (ALK). Results The results of the study showed that females harbored more EGFR mutation in adenocarcinoma (ADC). The mutation rate of KRAS and EML4-ALK was about 5%, and the double mutations of EGFR/EML4-ALK were higher than EGFR/KRAS. In the expression analysis, the expression of SALL4 was much higher in cancer tissues than normally expected, especially in tissues that carried EGFR mutation (P<0.05), however, there were no significant differences between different mutation types. Likewise, there were no significant differences between expression of SALL4 and KRAS and EML4-ALK mutations. Conclusions SALL4 is up regulated in lung cancer specimens and harbors EGFR mutation; this finding indicates that SALL4 expression may be relevant with EGFR, which could provide a new insight to lung cancer therapy. The mechanism needs further investigation and analysis. PMID:27867542

  2. For staining of ALK protein, the novel D5F3 antibody demonstrates superior overall performance in terms of intensity and extent of staining in comparison to the currently used ALK1 antibody.

    PubMed

    Taheri, Diana; Zahavi, David J; Del Carmen Rodriguez, Maria; Meliti, Abdelrazak; Rezaee, Neda; Yonescu, Raluca; Ricardo, Bernardo F P; Dolatkhah, Shahaboddin; Ning, Yi; Bishop, Justin A; Netto, George J; Sharma, Rajni

    2016-09-01

    Inflammatory myofibroblastic tumor (IMT) is a rare neoplasm. Approximately 50 % of IMTs show an anaplastic lymphoma kinase (ALK) gene fusion resulting in ALK overexpression on immunohistochemistry (IHC). A novel anti-ALK monoclonal antibody (D5F3) has been suggested to be of superior sensitivity to the ALK1 antibody which is currently used. We compared the performance of D5F3 in detecting ALK protein expression in IMTs from various anatomic sites compared to the currently utilized ALK1. We selected 25 IMTs from our surgical pathology files (2005-2015). The novel rabbit monoclonal anti-human CD246 (clone D5F3) and the currently used mouse monoclonal anti-human CD246 (clone ALK1) were used for immunohistochemical staining (IHC) in an automated slide stainer. The percentage of immunoreactive tumor cells (0, <5 %, 5-50 %, >50 %) and cytoplasmic staining intensity (graded 0-3) were assessed and compared between the two antibodies. Fluorescence in situ hybridization (FISH) studies for ALK gene rearrangement were performed on 11 tumors. D5F3 antibody stained 76 % and ALK1 antibody stained 72 % of IMTs (p = 0.747). Compared to staining with ALK1, D5F3 stained a higher proportion of cases extensively (>50 % cells) (76 vs. 28 %, p < 0.001) and with high intensity (grade 3 76 % vs 0; p < 0.001). FISH and IHC findings (for both antibodies) were concordant in 9/10 (90 %) IMTs, in which results were informative. The novel anti-ALK rabbit monoclonal antibody (D5F3 clone) demonstrates superior overall performance in term of intensity and extent of staining of ALK protein in IMT. We found IHC staining with both antibody clones to correlate equally well with FISH results for detection of ALK rearrangement.

  3. Patient positioning and prevention of injuries in patients undergoing laparoscopic and robot-assisted urologic procedures.

    PubMed

    Sukhu, Troy; Krupski, Tracey L

    2014-04-01

    Positioning injuries in the perioperative period are one of the inherent risks of surgery, but particularly in robot-assisted urologic surgery, and can result in often unrecognized morbidity. Injuries such as upper or lower extremity peripheral neuropathies occur via neural mechanisms and injuries such as compartment syndrome, rhabdomyolysis, ischemic optic neuropathy, and acute arterial occlusion occur via vascular mechanisms. The risk of injury may be exacerbated by operative and patient-related risk factors. Patient-related risk factors include ASA class and BMI, while surgery-related risk factors include physical orientation of the patient and operative length. These injuries can be prevented or reduced by joint effort of the surgeon, anesthesiologist, and operating room staff.

  4. Detection of t(2;5)(p23;q35) translocation by reverse transcriptase polymerase chain reaction and in situ hybridization in CD30-positive primary cutaneous lymphoma and lymphomatoid papulosis.

    PubMed Central

    Beylot-Barry, M.; Lamant, L.; Vergier, B.; de Muret, A.; Fraitag, S.; Delord, B.; Dubus, P.; Vaillant, L.; Delaunay, M.; MacGrogan, G.; Beylot, C.; de Mascarel, A.; Delsol, G.; Merlio, J. P.

    1996-01-01

    The t(2;5) generates a chimeric NPM-ALK transcript encoded by the nucleophosmin NPM gene fused to the anaplastic lymphoma kinase gene ALK. Using a reverse transcriptase nested polymerase chain reaction assay we have detected NPM-ALK transcripts within CD30+ primary cutaneous lymphoma and lymphomatoid papulosis (LP). The t(2;5) was identified in 4 out of 9 CD30+ anaplastic lymphomas and in 1 out of 4 CD30+ pleomorphic lymphomas. Moreover, the t(2;5) was detected in 3 out of 10 LPs. All NPM-ALK-positive lymphomas and 1 NPM-ALK-positive LP exhibited a clonal rearrangement of the T cell receptor gamma-chain gene. The t(2;5) was detected in 2 cases of LP without other evidence for a clonal lymphoid population. To identify cells carrying the t(2;5) translocation, we used immunohistochemistry to detect the ALK-encoded p80 protein and in situ hybridization for the specific detection of NPM-ALK transcripts. Both p80 protein and NPM-ALK transcripts were expressed by anaplastic or large CD30+ lymphoma cells with positive NPM-ALK amplification. The presence of t(2;5) in a subset of CD30+ cutaneous lymphoma and LP may indicate a common pathogenesis with a subset of anaplastic nodal lymphoma. Images Figure 2 Figure 3 PMID:8701987

  5. Synergistic Effects of Crizotinib and Temozolomide in Experimental FIG-ROS1 Fusion-Positive Glioblastoma

    PubMed Central

    Das, Arabinda; Cheng, Ron Ron; Hilbert, Megan L.T.; Dixon-Moh, Yaenette N.; Decandio, Michele; Vandergrift, William Alex; Banik, Naren L.; Lindhorst, Scott M.; Cachia, David; Varma, Abhay K.; Patel, Sunil J.; Giglio, Pierre

    2015-01-01

    Glioblastoma (GB) is the most common malignant brain tumor. Drug resistance frequently develops in these tumors during chemotherapy. Therefore, predicting drug response in these patients remains a major challenge in the clinic. Thus, to improve the clinical outcome, more effective and tolerable combination treatment strategies are needed. Robust experimental evidence has shown that the main reason for failure of treatments is signal redundancy due to coactivation of several functionally linked receptor tyrosine kinases (RTKs), including anaplastic lymphoma kinase (ALK), c-Met (hepatocyte growth factor receptor), and oncogenic c-ros oncogene1 (ROS1: RTK class orphan) fusion kinase FIG (fused in GB)-ROS1. As such, these could be attractive targets for GB therapy. The study subjects consisted of 19 patients who underwent neurosurgical resection of GB tissues. Our in vitro and ex vivo models promisingly demonstrated that treatments with crizotinib (PF-02341066: dual ALK/c-Met inhibitor) and temozolomide in combination induced synergistic antitumor activity on FIG-ROS1-positive GB cells. Our results also showed that ex vivo FIG-ROS1+ slices (obtained from GB patients) when cultured were able to preserve tissue architecture, cell viability, and global gene-expression profiles for up to 14 days. Both in vitro and ex vivo studies indicated that combination blockade of FIG, p-ROS1, p-ALK, and p-Met augmented apoptosis, which mechanistically involves activation of Bim and inhibition of survivin, p-Akt, and Mcl-1 expression. However, it is important to note that we did not see any significant synergistic effect of crizotinib and temozolomide on FIG-ROS1-negative GB cells. Thus, these ex vivo culture results will have a significant impact on patient selection for clinical trials and in predicting response to crizotinib and temozolomide therapy. Further studies in different animal models of FIG-ROS1-positive GB cells are warranted to determine useful therapies for the

  6. Synergistic Effects of Crizotinib and Temozolomide in Experimental FIG-ROS1 Fusion-Positive Glioblastoma.

    PubMed

    Das, Arabinda; Cheng, Ron Ron; Hilbert, Megan L T; Dixon-Moh, Yaenette N; Decandio, Michele; Vandergrift, William Alex; Banik, Naren L; Lindhorst, Scott M; Cachia, David; Varma, Abhay K; Patel, Sunil J; Giglio, Pierre

    2015-01-01

    Glioblastoma (GB) is the most common malignant brain tumor. Drug resistance frequently develops in these tumors during chemotherapy. Therefore, predicting drug response in these patients remains a major challenge in the clinic. Thus, to improve the clinical outcome, more effective and tolerable combination treatment strategies are needed. Robust experimental evidence has shown that the main reason for failure of treatments is signal redundancy due to coactivation of several functionally linked receptor tyrosine kinases (RTKs), including anaplastic lymphoma kinase (ALK), c-Met (hepatocyte growth factor receptor), and oncogenic c-ros oncogene1 (ROS1: RTK class orphan) fusion kinase FIG (fused in GB)-ROS1. As such, these could be attractive targets for GB therapy. The study subjects consisted of 19 patients who underwent neurosurgical resection of GB tissues. Our in vitro and ex vivo models promisingly demonstrated that treatments with crizotinib (PF-02341066: dual ALK/c-Met inhibitor) and temozolomide in combination induced synergistic antitumor activity on FIG-ROS1-positive GB cells. Our results also showed that ex vivo FIG-ROS1+ slices (obtained from GB patients) when cultured were able to preserve tissue architecture, cell viability, and global gene-expression profiles for up to 14 days. Both in vitro and ex vivo studies indicated that combination blockade of FIG, p-ROS1, p-ALK, and p-Met augmented apoptosis, which mechanistically involves activation of Bim and inhibition of survivin, p-Akt, and Mcl-1 expression. However, it is important to note that we did not see any significant synergistic effect of crizotinib and temozolomide on FIG-ROS1-negative GB cells. Thus, these ex vivo culture results will have a significant impact on patient selection for clinical trials and in predicting response to crizotinib and temozolomide therapy. Further studies in different animal models of FIG-ROS1-positive GB cells are warranted to determine useful therapies for the

  7. The bHLH transcription factor Hand is regulated by Alk in the Drosophila embryonic gut

    SciTech Connect

    Varshney, Gaurav K.; Palmer, Ruth H. . E-mail: Ruth.Palmer@ucmp.umu.se

    2006-12-29

    During embryonic development the midgut visceral muscle is formed by fusion of cells within the visceral mesoderm, a process initiated by the specification of a specialised cell type, the founder cell, within this tissue. Activation of the receptor tyrosine kinase Anaplastic lymphoma kinase (Alk) in the developing visceral muscle of Drosophila melanogaster initiates a signal transduction pathway required for muscle fusion. In this paper, we have investigated downstream components which are regulated by this novel signalling pathway. Here we show that Alk-mediated signal transduction drives the expression of the bHLH transcription factor Hand in vivo. Loss of Alk function results in a complete lack of Hand expression in this tissue, whereas Alk gain of function results in an expansion of Hand expression. Finally, we have investigated the process of muscle fusion in the gut of Hand mutant animals and can find no obvious defects in this process, suggesting that Hand is not critical for visceral muscle fusion per se.

  8. [Primary gastric lymphoma in an HIV positive patient].

    PubMed

    Sebastián, J J; Fuentes, J; García, S; Uribarrena, R; Yus, C; Boldova, I

    1995-10-01

    We report the case of a young male patient, VIH (+), who was admitted in our hospital with severe epigastric pain. Endoscopical and histological diagnosis was primary gastric non-Hodgkin lymphoma without Helicobacter pylori. The patient was treated with chemotherapy by CHOP scheme (6 cycles), with high clinical improvement and endoscopical and histological regression of the lesion. We comment some features of this peculiar association.

  9. Effects of Pharmacologic and Genetic Inhibition of Alk on Cognitive Impairments in NF1 Mutant Mice

    DTIC Science & Technology

    2014-06-01

    neuroblastoma 12-15. Orally active small molecule inhibitors have shown notable effectiveness in the treatment of lung cancer and are actively being...tested for the treatment of neuroblastoma 16-18. The normal function of Alk in humans is less clear though its expression in both the developing and...Y. P. et al. Identification of ALK as a major familial neuroblastoma predisposition gene. Nature 455, 930-935 (2008). 13 Janoueix-Lerosey, I. et

  10. ALK1 heterozygosity increases extracellular matrix protein expression, proliferation and migration in fibroblasts.

    PubMed

    Muñoz-Félix, José M; Perretta-Tejedor, Nuria; Eleno, Nélida; López-Novoa, José M; Martínez-Salgado, Carlos

    2014-06-01

    Fibrosis is a pathological situation in which excessive amounts of extracellular matrix (ECM) are deposited in the tissue. Myofibroblasts play a crucial role in the development and progress of fibrosis as they actively synthesize ECM components such as collagen I, fibronectin and connective tissue growth factor (CTGF) and cause organ fibrosis. Transforming growth factor beta 1 (TGF-β1) plays a major role in tissue fibrosis. Activin receptor-like kinase 1 (ALK1) is a type I receptor of TGF-β1 with an important role in angiogenesis whose function in cellular biology and TGF-β signaling is well known in endothelial cells, but its role in fibroblast biology and its contribution to fibrosis is poorly studied. We have recently demonstrated that ALK1 regulates ECM protein expression in a mouse model of obstructive nephropathy. Our aim was to evaluate the role of ALK1 in several processes involved in fibrosis such as ECM protein expression, proliferation and migration in ALK1(+/+) and ALK1(+/-) mouse embryonic fibroblasts (MEFs) after TGF-β1 stimulations and inhibitors. ALK1 heterozygous MEFs show increased expression of ECM proteins (collagen I, fibronectin and CTGF/CCN2), cell proliferation and migration due to an alteration of TGF-β/Smad signaling. ALK1 heterozygous disruption shows an increase of Smad2 and Smad3 phosphorylation that explains the increases in CTGF/CCN2, fibronectin and collagen I, proliferation and cell motility observed in these cells. Therefore, we suggest that ALK1 plays an important role in the regulation of ECM protein expression, proliferation and migration.

  11. Cavitary Lung Disease in an HIV-Positive Patient

    DTIC Science & Technology

    2009-04-01

    effusion or pneumothorax visualized. Diagnosis Aspergillus niducans Report Documentation Page Form ApprovedOMB No. 0704-0188 Public...positive for Aspergillus niducans. Other assays performed ruled out Pneumocystis jiroveci (carinii), Legionella, coccidiomycosis, histoplasmosis... Aspergillus niducans. Pulmonary aspergilloma are cavitary lesions with a pathognomonic “halo sign” on computed tomography scan, or, more commonly

  12. American Health Information Management Association. Position statement. Issue: patient cards.

    PubMed

    1993-11-01

    In its simplest form, a patient card is a credit card sized record made of paper or plastic that contains identification information. A card may contain additional information, such as insurance or limited health information. Of the many technologies available, chip cards and optical cards are best suited for use in healthcare. If their expense can be justified and nation-wide standards established, cards could help improve timely access to basic health information such as demographic, insurance, and basic medical information needed for emergency treatment. Technology may permit a patient's entire longitudinal (lifetime) health history to be maintained on a card, but this should not be the only source of the longitudinal record. To assure its accessibility to legitimate users throughout the healthcare system, the longitudinal health record must be a computer-based patient record maintained on a controlled access network.

  13. Disseminated Kaposi's Sarcoma in an HIV-Positive Patient: A Rare Entity in an Indian Patient.

    PubMed

    Behera, Biswanath; Chandrashekar, Laxmisha; Thappa, Devinder Mohan; Toi, Pampa Ch; Vinod, Kolar Vishwanath

    2016-01-01

    AIDS-associated disseminated Kaposi sarcoma (KS) is a rare entity, especially in India due to the low prevalence of human herpes virus-8 infections in Indian population. Due to its rapid and progressive nature, early diagnosis and institution of highly active antiretroviral therapy is crucial in AIDS-associated KS, with a view to achieving favorable prognosis. We report a case of disseminated KS in an HIV-1 positive patient, who presented with two months history of multiple violaceous patches and plaques over the trunk, bilateral upper limbs, lower limbs, and hard palate. The patient died of recurrent massive pleural effusion before starting antiretroviral therapy. This case is being reported due to the paucity of KS in the Indian literature, especially the disseminated type and to highlight its rapidly progressive course which can be fatal.

  14. Disseminated Kaposi's Sarcoma in an HIV-Positive Patient: A Rare Entity in an Indian Patient

    PubMed Central

    Behera, Biswanath; Chandrashekar, Laxmisha; Thappa, Devinder Mohan; Toi, Pampa Ch; Vinod, Kolar Vishwanath

    2016-01-01

    AIDS-associated disseminated Kaposi sarcoma (KS) is a rare entity, especially in India due to the low prevalence of human herpes virus-8 infections in Indian population. Due to its rapid and progressive nature, early diagnosis and institution of highly active antiretroviral therapy is crucial in AIDS-associated KS, with a view to achieving favorable prognosis. We report a case of disseminated KS in an HIV-1 positive patient, who presented with two months history of multiple violaceous patches and plaques over the trunk, bilateral upper limbs, lower limbs, and hard palate. The patient died of recurrent massive pleural effusion before starting antiretroviral therapy. This case is being reported due to the paucity of KS in the Indian literature, especially the disseminated type and to highlight its rapidly progressive course which can be fatal. PMID:27293276

  15. Arteriovenous malformations in hereditary haemorrhagic telangiectasia: looking beyond ALK1-NOTCH interactions.

    PubMed

    Peacock, Hanna M; Caolo, Vincenza; Jones, Elizabeth A V

    2016-02-01

    Hereditary haemorrhagic telangiectasia (HHT) is characterized by the development of arteriovenous malformations--enlarged shunts allowing arterial flow to bypass capillaries and enter directly into veins. HHT is caused by mutations in ALK1 or Endoglin; however, the majority of arteriovenous malformations are idiopathic and arise spontaneously. Idiopathic arteriovenous malformations differ from those due to loss of ALK1 in terms of both location and disease progression. Furthermore, while arteriovenous malformations in HHT and Alk1 knockout models have decreased NOTCH signalling, some idiopathic arteriovenous malformations have increased NOTCH signalling. The pathogenesis of these lesions also differs, with loss of ALK1 causing expansion of the shunt through proliferation, and NOTCH gain of function inducing initial shunt enlargement by cellular hypertrophy. Hence, we propose that idiopathic arteriovenous malformations are distinct from those of HHT. In this review, we explore the role of ALK1-NOTCH interactions in the development of arteriovenous malformations and examine a possible role of two signalling pathways downstream of ALK1, TMEM100 and IDs, in the development of arteriovenous malformations in HHT. A nuanced understanding of the precise molecular mechanisms underlying idiopathic and HHT-associated arteriovenous malformations will allow for development of targeted treatments for these lesions.

  16. Distribution of alkB genes within n-alkane-degrading bacteria.

    PubMed

    Vomberg, A; Klinner, U

    2000-08-01

    Fifty-four bacterial strains belonging to 37 species were tested for their ability to assimilate short chain and/or medium chain liquid n-alkanes. A gene probe derived from the alkB gene of Pseudomonas oleovorans ATCC 29347 was utilized in hybridization experiments. Results of Southern hybridization of PCR-amplificates were compared with those of colony hybridization and dot blot hybridization. Strongest signals were received only from Gram-negative bacteria growing solely with short n-alkanes (C10). Hybridization results with soil isolates growing with n-alkanes of different chain lengths suggested as well that alkB genes seem to be widespread only in solely short-chain n-alkane-degrading pseudomonads. PCR products of Rhodococcus sp., Nocardioides sp., Gordona sp. and Sphingomonas sp. growing additionally or solely with medium-chain n-alkane as hexadecane had only few sequence identity with alkB though hybridizing with the gene probe. The derived amino acid sequence of the alkB-amplificate of Pseudomonas aureofaciens showed high homology (95%) with AlkB from Ps. oleovorans. alkB gene disruptants were not able to grow with decane.

  17. Where Are Patients Positioned in Your Seamless Care Strategies?

    PubMed Central

    Fox, Brent I.; Felkey, Bill G.

    2015-01-01

    In our earliest thoughts of how to engage patients in self-care management, we found online banking and finance to be the best model for health care to follow. This model is still right for today. Although no digital approach will apply to 100% of any population, there is evidence that older patient populations see the benefit of being able to access their health care providers online and on mobile devices. It’s all about the data, the systems, and the people. PMID:26405316

  18. Patient position alters attenuation effects in multipinhole cardiac SPECT

    SciTech Connect

    Timmins, Rachel; Ruddy, Terrence D.; Wells, R. Glenn

    2015-03-15

    Purpose: Dedicated cardiac cameras offer improved sensitivity over conventional SPECT cameras. Sensitivity gains are obtained by large numbers of detectors and novel collimator arrangements such as an array of multiple pinholes that focus on the heart. Pinholes lead to variable amounts of attenuation as a source is moved within the camera field of view. This study evaluated the effects of this variable attenuation on myocardial SPECT images. Methods: Computer simulations were performed for a set of nine point sources distributed in the left ventricular wall (LV). Sources were placed at the location of the heart in both an anthropomorphic and a water-cylinder computer phantom. Sources were translated in x, y, and z by up to 5 cm from the center. Projections were simulated with and without attenuation and the changes in attenuation were compared. A LV with an inferior wall defect was also simulated in both phantoms over the same range of positions. Real camera data were acquired on a Discovery NM530c camera (GE Healthcare, Haifa, Israel) for five min in list-mode using an anthropomorphic phantom (DataSpectrum, Durham, NC) with 100 MBq of Tc-99m in the LV. Images were taken over the same range of positions as the simulations and were compared based on the summed perfusion score (SPS), defect width, and apparent defect uptake for each position. Results: Point sources in the water phantom showed absolute changes in attenuation of ≤8% over the range of positions and relative changes of ≤5% compared to the apex. In the anthropomorphic computer simulations, absolute change increased to 20%. The changes in relative attenuation caused a change in SPS of <1.5 for the water phantom but up to 4.2 in the anthropomorphic phantom. Changes were larger for axial than for transverse translations. These results were supported by SPS changes of up to six seen in the physical anthropomorphic phantom for axial translations. Defect width was also seen to significantly increase. The

  19. Automated Verification of IGRT-based Patient Positioning.

    PubMed

    Jiang, Xiaojun; Fox, Tim; Cordova, James S; Schreibmann, Eduard

    2015-11-08

    A system for automated quality assurance in radiotherapy of a therapist's registration was designed and tested in clinical practice. The approach compliments the clinical software's automated registration in terms of algorithm configuration and performance, and constitutes a practical approach for ensuring safe patient setups. Per our convergence analysis, evolutionary algorithms perform better in finding the global optima of the cost function with discrepancies from a deterministic optimizer seen sporadically.

  20. Automated Verification of IGRT-based Patient Positioning

    PubMed Central

    Jiang, Xiaojun; Fox, Tim; Cordova, Scott S; Schreibmann, Eduard

    2016-01-01

    A system for automated quality assurance in radiotherapy of a therapist’s registration was designed and tested in clinical practice. The approach compliments the clinical software’s automated registration in terms of algorithm configuration and performance, and constitutes a practical approach for ensuring safe patient setups. Per our convergence analysis, evolutionary algorithms perform better in finding the global optima of the cost function with discrepancies from a deterministic optimizer seen sporadically. PMID:26699548

  1. Oncogenic ALK regulates EMT in non-small cell lung carcinoma through repression of the epithelial splicing regulatory protein 1

    PubMed Central

    Menotti, Matteo; Poggio, Teresa; Panizza, Elena; Wang, Qi; Minero, Valerio G.; Fagoonee, Sharmila; Compagno, Mara; Altruda, Fiorella; Monti, Stefano; Chiarle, Roberto

    2016-01-01

    A subset of Non-Small Cell Lung Carcinoma (NSCLC) carries chromosomal rearrangements involving the Anaplastic Lymphoma Kinase (ALK) gene. ALK-rearranged NSCLC are typically adenocarcinoma characterized by a solid signet-ring cell pattern that is frequently associated with a metastatic phenotype. Recent reports linked the presence of ALK rearrangement to an epithelial-mesenchymal transition (EMT) phenotype in NSCLC, but the extent and the mechanisms of an ALK-mediated EMT in ALK-rearranged NSCLC are largely unknown. We found that the ALK-rearranged H2228 and DFCI032, but not the H3122, cell lines displayed a mesenchymal phenotype. In these cell lines, oncogenic ALK activity dictated an EMT phenotype by directly suppressing E-cadherin and up-regulating vimentin expression, as well as expression of other genes involved in EMT. We found that the epithelial splicing regulatory protein 1 (ESRP1), a key regulator of the splicing switch during EMT, was repressed by EML4-ALK activity. The treatment of NSCLC cells with ALK tyrosine kinase inhibitors (TKIs) led to up-regulation of ESRP1 and E-cadherin, thus reverting the phenotype from mesenchymal to epithelial (MET). Consistently, ESRP1 knock-down impaired E-cadherin up-regulation upon ALK inhibition, whereas enforced expression of ESRP1 was sufficient to increase E-cadherin expression. These findings demonstrate an ALK oncogenic activity in the regulation of an EMT phenotype in a subset of NSCLC with potential implications for the biology of ALK-rearranged NSCLC in terms of metastatic propensity and resistance to therapy. PMID:27119231

  2. Clinicopathological characteristics and prognosis of alpha-fetoprotein positive gastric cancer in Chinese patients

    PubMed Central

    Wang, Daguang; Li, Chunping; Xu, Yuechao; Xing, Yanpeng; Qu, Limei; Guo, Yuchen; Zhang, Yang; Sun, Xuan; Suo, Jian

    2015-01-01

    Purpose: This study aimed to review the clinicopathological, histochemical, and prognostic features of Alpha-Fetoprotein (AFP) positive gastric cancer. Patients and methods: Six hundred and fifty one patients with gastric cancer who underwent gastrectomy between January 2009 and December 2012 at The First Hospital of Jilin University were enrolled in the study. Among them, 45 patients were identified as AFP positive gastric cancer. The clinicopathologic characteristics and prognosis of the AFP positive gastric cancer patients were analyzed. Results: Among the 45 AFP positive patients, serum levels of AFP were < 100 µg/L in nine patients. The histological classification of 45 patients was as follows: hepatoid type, 25 (55.6%) cases; fetal gastrointestinal type, 12 (26.7%) cases; yolk sac tumor type, 2 (4.4%) cases; and mixed type, 6 (13.3%) cases. Twenty nine (64.4%) cases were AFP positive by immunohistochemical analysis; we found no significant difference in AFP positivity and histologic type. However, the differences in the number of metastasis lymph nodes, the maximum tumor diameter, pathological stage, vascular invasion and liver metastasis between the AFP positive group and the negative group were significant. At the same T stage, the liver metastasis status of the AFP positive group was higher than that of the negative group. The AFP positive group had a much poorer prognosis than the negative group. Conclusion: AFP positive gastric cancer is associated with aggressive behavior and poorer prognosis compared to that of AFP negative gastric cancer. PMID:26261510

  3. Microalbumin excretion in patients with positive exercise electrocardiogram tests.

    PubMed

    Horton, R C; Gosling, P; Reeves, C N; Payne, M; Nagle, R E

    1994-10-01

    Thirty-three subjects underwent exercise electrocardiogram testing, 20 had a history of myocardial infarction and 13 were age-matched volunteers. Exercise electrocardiograms were positive in 15 subjects, negative in 12 and anomalous in six. Urinary microalbumin excretion was measured at rest, 30 and 60 min after exercise. Urinary microalbumin excretion was expressed as the albumin-creatinine ratio in mg.mmol-1. In the positive exercise electrocardiogram group median albumin-creatinine ratio increased from 1.0 mg.mmol-1 (95% CI 0.94-1.49) at rest to 2.0 mg.mmol-1 (95% CI 1.51-3.94) 30 min after exercise, whilst in the negative electrocardiogram group median resting and 30 min post exercise albumin-creatinine ratio values of 0.85 (95% CI 0.53-1.32) and 1.80 (95% CI 0.63-2.32) mg.mmol-1 respectively were not significantly different. These results suggest that exercise-induced myocardial ischaemia is associated with increased urinary microalbumin excretion.

  4. Automated Verification of IGRT-based Patient Positioning.

    PubMed

    Jiang, Xiaojun; Fox, Tim; Cordova, James S; Schreibmann, Eduard

    2015-11-01

    A system for automated quality assurance in radiotherapy of a therapist's registration was designed and tested in clinical practice. The approach compliments the clinical software's automated registration in terms of algorithm configuration and performance, and constitutes a practical approach for ensuring safe patient setups. Per our convergence analysis, evolutionary algorithms perform better in finding the global optima of the cost function with discrepancies from a deterministic optimizer seen sporadically. PACS number(s): 87.55.Qr, 87.55.T, 87.55.N.

  5. Porphyria cutanea tarda in a HIV- positive patient*

    PubMed Central

    Franzon, Valéria Aparecida Zanela; Mikilita, Emanuella Stella; Camelo, Fernanda Henriques; Camargo, Rosana

    2016-01-01

    This is a case report about Porphyria cutanea tarda (PCT) and its relationship with the infection caused by the human immunodeficiency virus (HIV). Cutaneous porphyria is an illness caused by enzymatic modification that results in partial deficiency of uroporphyrinogen decarboxylase (Urod), which may be hereditary or acquired. Several studies suggest that HIV infection associated with cofactors might trigger the development of porphyria cutanea tarda. In this case report, we present a patient infected with HIV, who after the introduction of antiretroviral therapy (ART) enjoyed clinical improvement of porphyria cutanea tarda symptoms. PMID:27579753

  6. Design, synthesis and pharmacological evaluation of 2-(thiazol-2-amino)-4-arylaminopyrimidines as potent anaplastic lymphoma kinase (ALK) inhibitors.

    PubMed

    Liu, Zhiqing; Yue, Xihua; Song, Zilan; Peng, Xia; Guo, Junfeng; Ji, Yinchun; Cheng, Zhen; Ding, Jian; Ai, Jing; Geng, Meiyu; Zhang, Ao

    2014-10-30

    A series of new 2,4-diarylaminopyrimidine analogues (DAAPalogues) was developed by incorporation of a substituted 2-aminothiazole component as the C-2 substituent of the center pyrimidine core. Compound 5i showed highest potency of 12.4 nM against ALK and 24.1 nM against ALK gatekeeper mutation L1196M. Although only having moderate cellular potency in the SUP-M2 cells harboring NPM-ALK, compound 5i showed good kinase selectivity and dose-dependently inhibited phosphorylation of ALK and its down-stream signaling pathways.

  7. Nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) oncoprotein induces the T regulatory cell phenotype by activating STAT3

    PubMed Central

    Kasprzycka, Monika; Marzec, Michal; Liu, Xiaobin; Zhang, Qian; Wasik, Mariusz A.

    2006-01-01

    The mechanisms of malignant cell transformation mediated by the oncogenic, chimeric nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) tyrosine kinase remain only partially understood. Here we report that the NPM/ALK-carrying T cell lymphoma (ALK+TCL) cells secrete IL-10 and TGF-β and express FoxP3, indicating their T regulatory (Treg) cell phenotype. The secreted IL-10 suppresses proliferation of normal immune, CD3/CD28-stimulated peripheral blood mononuclear cells and enhances viability of the ALK+TCL cells. The Treg phenotype of the affected cells is strictly dependent on NPM/ALK expression and function as demonstrated by transfection of the kinase into BaF3 cells and inhibition of its enzymatic activity and expression in ALK+TCL cells. NPM/ALK, in turn, induces the phenotype through activation of its key signal transmitter, signal transducer and activator of transcription 3 (STAT3). These findings identify a mechanism of NPM/ALK-mediated oncogenesis based on induction of the Treg phenotype of the transformed CD4+ T cells. These results also provide an additional rationale to therapeutically target the chimeric kinase and/or STAT3 in ALK+TCL. PMID:16766651

  8. The type I BMP receptor Alk3 is required for the induction of hepatic hepcidin gene expression by interleukin-6.

    PubMed

    Mayeur, Claire; Lohmeyer, Lisa K; Leyton, Patricio; Kao, Sonya M; Pappas, Alexandra E; Kolodziej, Starsha A; Spagnolli, Ester; Yu, Binglan; Galdos, Rita L; Yu, Paul B; Peterson, Randall T; Bloch, Donald B; Bloch, Kenneth D; Steinbicker, Andrea U

    2014-04-03

    Increased IL-6 production induces, via STAT3 phosphorylation, hepatic transcription of the gene encoding the iron-regulatory hormone, hepcidin, leading to development of anemia of chronic disease (ACD). Inhibition of bone morphogenetic protein (BMP) signaling prevents the induction of hepcidin gene expression by IL-6 and ameliorates ACD. Using mice with hepatocyte-specific deficiency of Alk2 or Alk3, we sought to identify the BMP type I receptor that participates in IL-6-mediated induction of hepcidin gene expression. Mice were injected with adenovirus specifying IL-6 (Ad.IL-6) or control adenovirus. Seventy-two hours later, serum iron concentrations and hepatic levels of STAT3 phosphorylation and hepcidin messenger RNA were measured. Additional mice were injected with recombinant murine IL-6 (mIL-6) or vehicle, and hepatic hepcidin gene expression was measured 4 hours later. Deficiency of Alk2 or Alk3 did not alter the ability of Ad.IL-6 injection to induce hepatic STAT3 phosphorylation. Ad.IL-6 increased hepatic hepcidin messenger RNA levels and decreased serum iron concentrations in Alk2- but not Alk3-deficient mice. Similarly, administration of mIL-6 induced hepatic hepcidin gene expression in Alk2- but not Alk3-deficient mice. These results demonstrate that the ability of IL-6 to induce hepatic hepcidin gene expression and reduce serum iron concentrations is dependent on the BMP type I receptor Alk3.

  9. Osteoporosis management in patients with breast cancer: EMAS position statement.

    PubMed

    Trémollieres, Florence A; Ceausu, Iuliana; Depypere, Herman; Lambrinoudaki, Irene; Mueck, Alfred; Pérez-López, Faustino R; van der Schouw, Yvonne T; Senturk, Levent M; Simoncini, Tommaso; Stevenson, John C; Stute, Petra; Rees, Margaret

    2017-01-01

    Aromatase inhibitors (AIs) are the first-line recommended standard of care for postmenopausal estrogen receptor-positive breast cancer. Because they cause a profound suppression of estrogen levels, concerns regarding their potential to increase the risk of fracture were rapidly raised. There is currently a general consensus that a careful baseline evaluation is needed of the risk of fracture in postmenopausal women about to start treatment with AIs but also in all premenopausal women with early disease. Bisphosphonates have been shown in several phase III trials to prevent the bone loss induced by cancer treatment, although no fracture data are available. Even though they do not have regulatory approval for this indication, their use must be discussed with women at high risk of fracture. Accordingly, several guidelines recommend considering treatment in women with a T-score ≤-2 or those with two or more clinical risk factors. Moreover, recent data suggest that bisphosphonates, especially intravenous zoledronic acid, may have an anticancer effect, in that they reduce bone recurrence as well as extra-skeletal metastasis and breast cancer mortality in postmenopausal women. The anti-RANK ligand antibody denosumab is also emerging as a new adjuvant therapeutic option to prevent AI-induced bone loss. It has been shown to extend the time to first fracture in postmenopausal women treated with AIs. Several issues still need to be addressed regarding the use of these different agents in an adjuvant setting. The purpose of this position statement is to review the literature on antifracture therapy and to discuss the current guidelines for the management of osteoporosis in women with early breast cancer.

  10. Evaluation of a new simple treatment for positional sleep apnoea patients.

    PubMed

    van Maanen, J Peter; Richard, Wietske; Van Kesteren, Ellen R; Ravesloot, Madeline J L; Laman, D Martin; Hilgevoord, Antonius A J; de Vries, Nico

    2012-06-01

    Obstructive sleep apnoea syndrome is a common clinical problem. Positional sleep apnoea syndrome, defined as having a supine apnoea-hypopnoea index of twice or more compared to the apnoea-hypopnoea index in the other positions, occurs in 56% of obstructive sleep apnoea patients. A limited number of studies focus on decreasing the severity of sleep apnoea by influencing sleep position. In these studies an object was strapped to the back (tennis balls, squash balls, special vests), preventing patients from sleeping in the supine position. Frequently, this was not successful due to arousals while turning from one lateral position to the other, thereby disturbing sleep architecture and sleep quality. We developed a new neck-worn device which influences sleep position by offering a vibration when in supine position, without significantly reducing total sleep time. Thirty patients with positional sleep apnoea were included in this study. No side effects were reported. The mean apnoea-hypopnoea index dropped from 27.7 ± 2.4 to 12.8 ± 2.2. Seven patients developed an overall apnoea-hypopnoea index below 5 when using the device in ON modus. We expect that positional therapy with such a device can be applied as a single treatment in many patients with mild to moderate position-dependent obstructive sleep apnoea, while in patients with a more severe obstructive sleep apnoea such a device could be used in combination with other treatment modalities.

  11. [Prone position: effect on gas exchange and functional capacity for exercise in patients with pulmonary hypertension].

    PubMed

    Bastidas-L, Andrea Carolina; Colina-Chourio, José A; Guevara, Jesnel M; Nunez, Alexis

    2015-03-01

    The objective of this investigation was to evaluate gas exchange and cardiopulmonary functional behavior in patients with pulmonary hypertension (PH) before, during and after the change to a prone position. Thirty patients with PH and alterations in gas exchange were included in the study. Gas exchange measurements were performed in four stages: at the baseline supine position and after 30, 120 and 240 minutes in prone position. Also, the patients were evaluated by the six minutes walking test (6MWT) after 30 days in prone position during night's sleep. After four hours in prone position, all patients showed an increase of PaO2 and arterial saturation of oxygen (SaO2), with a decrease of intrapulmonary shunts, improving the gas exchange and therefore the physiological demand imposed by exercise in patients with PH.

  12. Patients' preferences for positioning during phaco-emulsification under topical-intracameral anaesthesia.

    PubMed

    Tsatsos, Michael; Chong, Loy; Eke, Tom

    2009-09-01

    In many eye departments it is routine to ask patients to lie completely flat for cataract surgery. However, many patients prefer not to lie completely flat, if given the choice. It is our practice to ensure patients are in a comfortable position before commencing surgery. We conducted a prospective observational study of our routine practice comprising 125 consecutive cataract operations conducted by a single surgeon with local anaesthesia (occasional phaco under general anaesthetic was not included). All patients were initially positioned lying flat on the reclining chair and were given the option of staying in that position throughout the operation or having the chair-back raised until they were comfortable. Only 27% (34 patients of 125 total) were happy to lie flat (angle between 0 degrees and 5 degrees ). The majority of our patients (62%--78 patients) preferred to sit up slightly, with the chair-back 10 degrees to 25 degrees above the horizontal; 8% (10 patients) of the patients were sited at an angle of 30 degrees to 35 degrees and 2% (three patients) needed to be sited at 35 degrees or more. Patients who sat up above 30 degrees generally had a medical reason such as orthopnoea (3%--four patients), back pain (5%--six patients), anxiety (2%--two patients), Meniere's disease (1%--one patient). Patients who sat up below 25 degrees chose this position for comfort or preference. Our results show that patient preferences for positioning during cataract phaco-emulsification under topical-intracameral anaesthesia should increase overall patient satisfaction without the need to compromise safety.

  13. Care of HIV-positive obstetric patients. Meeting a multigenerational challenge.

    PubMed Central

    Peckan, C. M.

    1994-01-01

    Caring for pregnant women who are HIV-positive challenges family physicians to manage a disease that can be multigenerational, directly affecting parents and their offspring and indirectly affecting many others. I review current literature on prenatal, intrapartum, and postpartum care of HIV-positive patients. Management of HIV-positive women must be comprehensive, supportive, and sensitive to new information. PMID:8081123

  14. Identification of peptides applicable as vaccines for HLA-A26-positive cancer patients.

    PubMed

    Niu, Yamei; Terasaki, Yasunobu; Komatsu, Nobukazu; Noguchi, Masanori; Shichijo, Shigeki; Itoh, Kyogo

    2009-11-01

    One-fifth of the Japanese population is positive for HLA-A26, but few peptides are available as potential cancer vaccines for HLA-A26-positive cancer patients. The objective of this study was to identify peptide vaccine candidates for HLA-A26-positive cancer patients. The HLA-A*2601-crossbinding activity of 24 peptides currently under clinical trial as vaccines for HLA-A2, -A24, or HLA-A3 supertype-positive cancer patients was evaluated by stabilization assay. Three peptides with HLA-A2-binding activity could bind the HLA-A*2601 molecule. These three peptides induced HLA-A26-restricted cytotoxic T lymphocytes from HLA-A*2601-, -A*2602-, or -A*2603-positive prostate cancer patients against HLA-A*2601- and HLA-A*2603-positive cancer cells in CD8-dependent and peptide-specific manners. In addition, one peptide with HLA-A24-binding activity could bind to HLA-A*2601 and induced HLA-A26-restricted cytotoxic T lymphocytes from HLA-A*2601-, -A*2602-, or -A*2603-positive prostate cancer patients against HLA-A*2603-positive cancer cells. These results may provide novel information for the development of a peptide-based cancer vaccine for HLA-A26-positive patients.

  15. Evaluation of EML4-ALK Fusion Proteins in Non-Small Cell Lung Cancer Using Small Molecule Inhibitors12

    PubMed Central

    Li, Yongjun; Ye, Xiaofen; Liu, Jinfeng; Zha, Jiping; Pei, Lin

    2011-01-01

    The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene resulting from an inversion within chromosome 2p occurs in approximately 5% of non-small cell lung cancer and is mutually exclusive with Ras and EGFR mutations. In this study, we have used a potent and selective ALK small molecule inhibitor, NPV-TAE684, to assess the oncogenic role of EML4-ALK in non-small cell lung cancer (NSCLC). We show here that TAE684 inhibits proliferation and induces cell cycle arrest, apoptosis, and tumor regression in two NSCLC models that harbor EML4-ALK fusions. TAE684 inhibits EML4-ALK activation and its downstream signaling including ERK, AKT, and STAT3. We used microarray analysis to carry out targeted pathway studies of gene expression changes in H2228 NSCLC xenograft model after TAE684 treatment and identified a gene signature of EML4-ALK inhibition. The gene signature represents 1210 known human genes, and the top biologic processes represented by these genes are cell cycle, DNA synthesis, cell proliferation, and cell death. We also compared the effect of TAE684 with PF2341066, a c-Met and ALK small molecule inhibitor currently in clinical trial in cancers harboring ALK fusions, and demonstrated that TAE684 is a much more potent inhibitor of EML4-ALK. Our data demonstrate that EML4-ALK plays an important role in the pathogenesis of a subset of NSCLC and provides insight into the mechanism of EML4-ALK inhibition by a small molecule inhibitor. PMID:21245935

  16. Specificity and Structure of a High Affinity Activin Receptor-like Kinase 1 (ALK1) Signaling Complex

    PubMed Central

    Townson, Sharon A.; Martinez-Hackert, Erik; Greppi, Chloe; Lowden, Patricia; Sako, Dianne; Liu, June; Ucran, Jeffrey A.; Liharska, Katia; Underwood, Kathryn W.; Seehra, Jasbir; Kumar, Ravindra; Grinberg, Asya V.

    2012-01-01

    Activin receptor-like kinase 1 (ALK1), an endothelial cell-specific type I receptor of the TGF-β superfamily, is an important regulator of normal blood vessel development as well as pathological tumor angiogenesis. As such, ALK1 is an important therapeutic target. Thus, several ALK1-directed agents are currently in clinical trials as anti-angiogenic cancer therapeutics. Given the biological and clinical importance of the ALK1 signaling pathway, we sought to elucidate the biophysical and structural basis underlying ALK1 signaling. The TGF-β family ligands BMP9 and BMP10 as well as the three type II TGF-β family receptors ActRIIA, ActRIIB, and BMPRII have been implicated in ALK1 signaling. Here, we provide a kinetic and thermodynamic analysis of BMP9 and BMP10 interactions with ALK1 and type II receptors. Our data show that BMP9 displays a significant discrimination in type II receptor binding, whereas BMP10 does not. We also report the crystal structure of a fully assembled ternary complex of BMP9 with the extracellular domains of ALK1 and ActRIIB. The structure reveals that the high specificity of ALK1 for BMP9/10 is determined by a novel orientation of ALK1 with respect to BMP9, which leads to a unique set of receptor-ligand interactions. In addition, the structure explains how BMP9 discriminates between low and high affinity type II receptors. Taken together, our findings provide structural and mechanistic insights into ALK1 signaling that could serve as a basis for novel anti-angiogenic therapies. PMID:22718755

  17. No clinical predictors of intraepithelial neoplasia in HIV-positive patients with external condilomata acuminata

    PubMed Central

    Giacaman, Paula; Martínez, María José; Chnaiderman, Jonas; Ampuero, Sandra; Santander, Ester; Ramis, Claudia; Sazunic, Ivo; Garmendia, María Luisa; Gómez, Orietta

    2011-01-01

    To identify clinical parameters in association with human papilloma virus (HPV) genotypes and histopathology diagnosis in HIV-positive patients with external condylomata acuminata (ECA), 400 Chilean HIV-positive patients were included in the study. Forty-seven patients presented ECA. Clinical parameters and socio demographic data were recorded. Histopathology study and HPV linear array genotyping assay were performed. Intraepithelial neoplasia (IEN) grade 2 or 3 was found in 8.5% of patients, associated to HPV-16. Patients were mainly single, MSM, with history of sexually transmitted disease (STD), multiple sexual partners, receiving antiretroviral therapy and with recurrent lesions. All ECA were mainly perianal, grey or pink colored, exophytic with less than two years evolution. No clinical parameter could predict the development of high grade IEN in HIV patients with ECA. It seems necessary to perform biopsy and genotype all HIV positive patients with ECA. PMID:21799573

  18. Abundance and diversity of n-alkane-degrading bacteria in a forest soil co-contaminated with hydrocarbons and metals: a molecular study on alkB homologous genes.

    PubMed

    Pérez-de-Mora, Alfredo; Engel, Marion; Schloter, Michael

    2011-11-01

    Unraveling functional genes related to biodegradation of organic compounds has profoundly improved our understanding of biological remediation processes, yet the ecology of such genes is only poorly understood. We used a culture-independent approach to assess the abundance and diversity of bacteria catalyzing the degradation of n-alkanes with a chain length between C(5) and C(16) at a forest site co-contaminated with mineral oil hydrocarbons and metals for nearly 60 years. The alkB gene coding for a rubredoxin-dependent alkane monooxygenase enzyme involved in the initial activation step of aerobic aliphatic hydrocarbon metabolism was used as biomarker. Within the area of study, four different zones were evaluated: one highly contaminated, two intermediately contaminated, and a noncontaminated zone. Contaminant concentrations, hydrocarbon profiles, and soil microbial respiration and biomass were studied. Abundance of n-alkane-degrading bacteria was quantified via real-time PCR of alkB, whereas genetic diversity was examined using molecular fingerprints (T-RFLP) and clone libraries. Along the contamination plume, hydrocarbon profiles and increased respiration rates suggested on-going natural attenuation at the site. Gene copy numbers of alkB were similar in contaminated and control areas. However, T-RFLP-based fingerprints suggested lower diversity and evenness of the n-alkane-degrading bacterial community in the highly contaminated zone compared to the other areas; both diversity and evenness were negatively correlated with metal and hydrocarbon concentrations. Phylogenetic analysis of alkB denoted a shift of the hydrocarbon-degrading bacterial community from Gram-positive bacteria in the control zone (most similar to Mycobacterium and Nocardia types) to Gram-negative genotypes in the contaminated zones (Acinetobacter and alkB sequences with little similarity to those of known bacteria). Our results underscore a qualitative rather than a quantitative response of

  19. The influence of patient positioning uncertainties in proton radiotherapy on proton range and dose distributions

    SciTech Connect

    Liebl, Jakob; Paganetti, Harald; Zhu, Mingyao; Winey, Brian A.

    2014-09-15

    Purpose: Proton radiotherapy allows radiation treatment delivery with high dose gradients. The nature of such dose distributions increases the influence of patient positioning uncertainties on their fidelity when compared to photon radiotherapy. The present work quantitatively analyzes the influence of setup uncertainties on proton range and dose distributions. Methods: Thirty-eight clinical passive scattering treatment fields for small lesions in the head were studied. Dose distributions for shifted and rotated patient positions were Monte Carlo-simulated. Proton range uncertainties at the 50%- and 90%-dose falloff position were calculated considering 18 arbitrary combinations of maximal patient position shifts and rotations for two patient positioning methods. Normal tissue complication probabilities (NTCPs), equivalent uniform doses (EUDs), and tumor control probabilities (TCPs) were studied for organs at risk (OARs) and target volumes of eight patients. Results: The authors identified a median 1σ proton range uncertainty at the 50%-dose falloff of 2.8 mm for anatomy-based patient positioning and 1.6 mm for fiducial-based patient positioning as well as 7.2 and 5.8 mm for the 90%-dose falloff position, respectively. These range uncertainties were correlated to heterogeneity indices (HIs) calculated for each treatment field (38% < R{sup 2} < 50%). A NTCP increase of more than 10% (absolute) was observed for less than 2.9% (anatomy-based positioning) and 1.2% (fiducial-based positioning) of the studied OARs and patient shifts. For target volumes TCP decreases by more than 10% (absolute) occurred in less than 2.2% of the considered treatment scenarios for anatomy-based patient positioning and were nonexistent for fiducial-based patient positioning. EUD changes for target volumes were up to 35% (anatomy-based positioning) and 16% (fiducial-based positioning). Conclusions: The influence of patient positioning uncertainties on proton range in therapy of small lesions

  20. Pilot testing the augmentech body position sensor on the morbidly obese patient.

    PubMed

    Hand, Mark C; Rose, Mary Ann; Pokorny, Marie Elizabeth; Castles, Ricky T; Watkins, Frank; Kirkpatrick, Mary K; Swanson, Melvin; Engelke, Martha; Moore, Rachel; Wu, Qiang; Chen, Kaun

    2013-05-01

    The Augmentech Body Position Sensor (ABPS), a device for monitoring patient repositioning, was tested for use in morbidly obese patients. Specific aims were to: determine whether there was correspondence between data on patient turning and repositioning from the ABPS and data gathered through human observation; determine whether the ABPS is an acceptable instrument for measuring body movements in morbidly obese patients in terms of ease of use, comfort and ability to stay in place. A descriptive study was conducted. Data from the ABPS recording patients' body positions were compared with data from videotapes taken of the same patients during the same time period. The sleep center of a tertiary care facility in the southeastern United States was used. Ten participants with BMI ≥30 were selected from patients referred to the sleep center for polysomnography. Positioning the device on the patient's thigh, data were collected from midnight until discharge. Videotapes taken of the same patient during the same time period were examined for changes in body position over time. There was a strong correspondence between the videotaped data and the ABPS data. The device was comfortable and not irritating to the patient. The APBS can be a useful measure for determining changes in body position but further study should be undertaken to test other sites for placement.

  1. BMP9/ALK1 inhibits neovascularization in mouse models of age-related macular degeneration

    PubMed Central

    Ntumba, Kalonji; Akla, Naoufal; Oh, S. Paul; Eichmann, Anne; Larrivée, Bruno

    2016-01-01

    Age-related macular degeneration (AMD) is the leading cause of blindness in aging populations of industrialized countries. The drawbacks of inhibitors of vascular endothelial growth factor (VEGFs) currently used for the treatment of AMD, which include resistance and potential serious side-effects, require the identification of new therapeutic targets to modulate angiogenesis. BMP9 signaling through the endothelial Alk1 serine-threonine kinase receptor modulates the response of endothelial cells to VEGF and promotes vessel quiescence and maturation during development. Here, we show that BMP9/Alk1 signaling inhibits neovessel formation in mouse models of pathological ocular angiogenesis relevant to AMD. Activating Alk1 signaling in laser-induced choroidal neovascularization (CNV) and oxygen-induced retinopathy (OIR) inhibited neovascularization and reduced the volume of vascular lesions. Alk1 signaling was also found to interfere with VEGF signaling in endothelial cells whereas BMP9 potentiated the inhibitory effects of VEGFR2 signaling blockade, both in OIR and laser-induced CNV. Together, our data show that targeting BMP9/Alk1 efficiently prevents the growth of neovessels in AMD models and introduce a new approach to improve conventional anti-VEGF therapies. PMID:27517154

  2. A molecular dynamics investigation on the crizotinib resistance mechanism of C1156Y mutation in ALK

    SciTech Connect

    Sun, Hui-Yong; Ji, Feng-Qin

    2012-06-29

    Highlights: Black-Right-Pointing-Pointer The study revealed the detailed resistance mechanism of the non-active mutation C1156Y in ALK. Black-Right-Pointing-Pointer C1156Y leads to crizotinib displacement and conformational changes in the binding cavity. Black-Right-Pointing-Pointer The conformations cause a decline in the vdW and electrostatic energy between crizotinib and ALK. -- Abstract: Crizotinib is an anaplastic lymphoma kinase (ALK) inhibitor that has recently been approved in the US for the treatment of non-small cell lung carcinoma (NSCLC). Despite its outstanding safety and efficacy, several resistant mutations against crizotinib have been detected in the treatment of NSCLC. However, in contrast to the widely accepted mechanism of steric hindrance by mutations at the active site, the mechanism by which the C1156Y non-active site mutation confers resistance against crizotinib remains unclear. In the present study, the resistance mechanism of C1156Y in ALK was investigated using molecular dynamics simulations. The results suggest that despite the non-active site mutation, C1156Y causes the dislocation of crizotinib as well as the indirect conformational changes in the binding cavity, which results in a marked decrease in the van der Waals and electrostatic interactions between crizotinib and ALK. The obtained results provide a detailed explanation of the resistance caused by C1156Y and may give a vital clue for the design of drugs to combat crizotinib resistance.

  3. Change of patient position using a transportation board during lumboperitoneal shunting. Technical note.

    PubMed

    Shimizu, Satoru; Hagiwara, Hiroyuki; Hattori, Satoshi; Nakayama, Kenji; Fujii, Kiyotaka

    2009-04-01

    Lumboperitoneal shunt placement requires access to the lumbar theca in the lateral position, followed by subsequent laparotomy in the supine position. This position change and repeat draping are bothersome, especially in heavy patients, so we developed a method that facilitates changing the patient position while keeping the surgical drapes in place. An oblong plastic board covered with Teflon-coated glassfiber cloth and surrounded by a nylon-cloth sleeve is used. The sleeve can be easily moved over the board, so patients can be moved in the transverse direction with minimal pushing force. The patient is placed in the lateral position on the board on the operating table and draped from the back to the abdomen. After catheter insertion into the lumbar theca and introduction of a subcutaneous tunnel to the flank, the patient is pushed in the ventral direction, moved to the opposite edge of the operating table, and the position is changed from lateral to supine, leaving the original drape intact. Finally, a catheter is placed by laparotomy. We were able to change position easily in 20 patients weighing 47-85 kg (mean 69.6 kg). This technique reduces the labor required for position change and preserves sterility.

  4. Variant translocation partners of the anaplastic lymphoma kinase (ALK) gene in two cases of anaplastic large cell lymphoma, identified by inverse cDNA polymerase chain reaction.

    PubMed

    Takeoka, Kayo; Okumura, Atsuko; Honjo, Gen; Ohno, Hitoshi

    2014-01-01

    In anaplastic large cell lymphoma (ALCL), the anaplastic lymphoma kinase (ALK) gene is rearranged with diverse partners due to variant translocations/inversions. Case 1 was a 39-year-old man who developed multiple tumors in the mediastinum, psoas muscle, lung, and lymph nodes. A biopsy specimen of the inguinal node was effaced by large tumor cells expressing CD30, epithelial membrane antigen, and cytoplasmic ALK, which led to a diagnosis of ALK(+) ALCL. Case 2 was a 51-year-old man who was initially diagnosed with undifferentiated carcinoma. He developed multiple skin tumors eight years after his initial presentation, and was finally diagnosed with ALK(+) ALCL. He died of therapy-related acute myeloid leukemia. G-banding and fluorescence in situ hybridization using an ALK break-apart probe revealed the rearrangement of ALK and suggested variant translocation in both cases. We applied an inverse cDNA polymerase chain reaction (PCR) strategy to identify the partner of ALK. Nucleotide sequencing of the PCR products and a database search revealed that the sequences of ATIC in case 1 and TRAF1 in case 2 appeared to follow those of ALK. We subsequently confirmed ATIC-ALK and TRAF1-ALK fusions by reverse transcriptase PCR and nucleotide sequencing. We successfully determined the partner gene of ALK in two cases of ALK(+) ALCL. ATIC is the second most common partner of variant ALK rearrangements, while the TRAF1-ALK fusion gene was first reported in 2013, and this is the second reported case of ALK(+) ALCL carrying TRAF1-ALK.

  5. Horizontal canal benign paroxysmal positional vertigo: diagnosis and treatment of 37 patients.

    PubMed

    Maranhão, Eliana Teixeira; Maranhão Filho, Péricles

    2015-06-01

    Benign paroxysmal positional vertigo (BPPV), the most frequent cause of vertigo is associated with high morbidity in the elderly population. The most common form is linked to debris in the posterior semicircular canal. However, there has been an increasing number of reported BPPV cases involving the horizontal canals. The purpose of this article is to highlight the clinical features, diagnosis, and treatment in 37 patients with horizontal canal BPPV; twenty-six with geotropic nystagmus, and eleven with the apogeotropic form. Treatment consisted of the Gufoni manoeuver in eighteen patients (48.6%), the barbecue 360° maneuver in twelve patients (32.4%), both manoeuvers in four patients (10.8%), both manoeuvers plus head shaking in one patient (2.7%), and the Gufoni maneuver plus head shaking in two patients. Cupulolithiasis patients were asked to sleep in a forced prolonged position. We obtained a complete resolution of vertigo and nystagmus in 30 patients (81.0%) on the initial visit.

  6. Identification of different ALK mutations in a pair of neuroblastoma cell lines established at diagnosis and relapse

    PubMed Central

    Chen, Lindi; Humphreys, Angharad; Turnbull, Lisa; Bellini, Angela; Schleiermacher, Gudrun; Salwen, Helen; Cohn, Susan L.; Bown, Nick; Tweddle, Deborah A.

    2016-01-01

    Anaplastic Lymphoma Kinase (ALK) is a transmembrane receptor kinase that belongs to the insulin receptor superfamily and has previously been shown to play a role in cell proliferation, migration and invasion in neuroblastoma. Activating ALK mutations are reported in both hereditary and sporadic neuroblastoma tumours, and several ALK inhibitors are currently under clinical evaluation as novel treatments for neuroblastoma. Overall, mutations at codons F1174, R1275 and F1245 together account for ∼85% of reported ALK mutations in neuroblastoma. NBLW and NBLW-R are paired cell lines originally derived from an infant with metastatic MYCN amplified Stage IVS (Evans Criteria) neuroblastoma, at diagnosis and relapse, respectively. Using both Sanger and targeted deep sequencing, this study describes the identification of distinct ALK mutations in these paired cell lines, including the rare R1275L mutation, which has not previously been reported in a neuroblastoma cell line. Analysis of the sensitivity of NBLW and NBLW-R cells to a panel of ALK inhibitors (TAE-684, Crizotinib, Alectinib and Lorlatinib) revealed differences between the paired cell lines, and overall NBLW-R cells with the F1174L mutation were more resistant to ALK inhibitor induced apoptosis compared with NBLW cells. This pair of cell lines represents a valuable pre-clinical model of clonal evolution of ALK mutations associated with neuroblastoma progression. PMID:27888620

  7. External beam boost irradiation for clinically positive pelvic nodes in patients with uterine cervical cancer

    PubMed Central

    Ariga, Takuro; Toita, Takafumi; Kasuya, Goro; Nagai, Yutaka; Inamine, Morihiko; Kudaka, Wataru; Kakinohana, Yasumasa; Aoki, Youichi; Murayama, Sadayuki

    2013-01-01

    The purpose of this study was to retrospectively analyze the treatment results of boost external beam radiotherapy (EBRT) to clinically positive pelvic nodes in patients with uterine cervical cancer. The study population comprised 174 patients with FIGO stages 1B1–4A cervical cancer who were treated with definitive radiotherapy (RT) or concurrent chemoradiotherapy (CCRT) and high-dose-rate intracavitary brachytherapy (HDR-ICBT). Patients with positive para-aortic or common iliac nodes (≥10 mm in the shortest diameter, as evaluated by CT/MRI) were ineligible for the study. Fifty-seven patients (33%) had clinically positive pelvic nodes. The median maximum diameter of the nodes was 15 mm (range, 10–60 mm) and the median number of positive lymph nodes was two (range, one to four). Fifty-two of 57 patients (91%) with positive nodes were treated with boost EBRT (6–10 Gy in three to five fractions). The median prescribed dose of EBRT for nodes was 56 Gy. The median follow-up time for all patients was 66 months (range, 3–142 months). The 5-year overall survival rate, disease-free survival rate and pelvic control rate for patients with positive and negative nodes were 73% and 92% (P = 0.001), 58% and 84% (P < 0.001), and 83% and 92% (P = 0.082), respectively. Five of 57 node-positive patients (9%) developed pelvic node recurrences. All five patients with nodal failure had concomitant cervical failure and/or distant metastases. No significant difference was observed with respect to the incidence or severity of late complications by application of boost EBRT. The current retrospective study demonstrated that boost EBRT to positive pelvic nodes achieves favorable nodal control without increasing late complications. PMID:23365264

  8. Development of a positive psychology intervention for patients with acute cardiovascular disease.

    PubMed

    Huffman, Jeff C; Mastromauro, Carol A; Boehm, Julia K; Seabrook, Rita; Fricchione, Gregory L; Denninger, John W; Lyubomirsky, Sonja

    2011-09-29

    The management of depression and other negative psychological states in cardiac patients has been a focus of multiple treatment trials, though such trials have not led to substantial improvements in cardiac outcomes. In contrast, there has been minimal focus on interventions to increase positive psychological states in cardiac patients, despite the fact that optimism and other positive states have been associated with superior cardiovascular outcomes. Our objective was to develop an 8-week, phone-based positive psychology intervention for patients hospitalized with acute cardiac disease (acute coronary syndrome or decompensated heart failure). Such an intervention would consist of positive psychology exercises adapted for this specific population, and it would need to be feasible for practitioners and patients in real-world settings. By adapting exercises that were previously validated in healthy individuals, we were able to generate a positive psychology telemedicine intervention for cardiac patients that focused on optimism, kindness, and gratitude. In addition, we successfully created a companion treatment manual for subjects to enhance the educational aspects of the intervention and facilitate completion of exercises. Finally, we successfully performed a small pilot trial of this intervention, and found that the positive psychology intervention appeared to be feasible and well-accepted in a cohort of patients with acute cardiac illness. Future studies should further develop this promising intervention and examine its impact on psychological and medical outcomes in this vulnerable population of cardiac patients.

  9. Alk5 inhibition increases delivery of macromolecular and protein-bound contrast agents to tumors

    PubMed Central

    Daldrup-Link, Heike E.; Mohanty, Suchismita; Ansari, Celina; Ito, Ken; Hong, Su Hyun; Hoffmann, Matthias; Pisani, Laura; Boudreau, Nancy; Gambhir, Sanjiv Sam; Coussens, Lisa M.

    2016-01-01

    Limited transendothelial permeability across tumor microvessels represents a significant bottleneck in the development of tumor-specific diagnostic agents and theranostic drugs. Here, we show an approach to increase transendothelial permeability of macromolecular and nanoparticle-based contrast agents via inhibition of the type I TGF-β receptor, activin-like kinase 5 (Alk5), in tumors. Alk5 inhibition significantly increased tumor contrast agent delivery and enhancement on imaging studies, while healthy organs remained relatively unaffected. Imaging data correlated with significantly decreased tumor interstitial fluid pressure, while tumor vascular density remained unchanged. This immediately clinically translatable concept involving Alk5 inhibitor pretreatment prior to an imaging study could be leveraged for improved tumor delivery of macromolecular and nanoparticle-based imaging probes and, thereby, facilitate development of more sensitive imaging tests for cancer diagnosis, enhanced tumor characterization, and personalized, image-guided therapies. PMID:27182558

  10. Occurrence of diverse alkane hydroxylase alkB genes in indigenous oil-degrading bacteria of Baltic Sea surface water.

    PubMed

    Viggor, Signe; Jõesaar, Merike; Vedler, Eve; Kiiker, Riinu; Pärnpuu, Liis; Heinaru, Ain

    2015-12-30

    Formation of specific oil degrading bacterial communities in diesel fuel, crude oil, heptane and hexadecane supplemented microcosms of the Baltic Sea surface water samples was revealed. The 475 sequences from constructed alkane hydroxylase alkB gene clone libraries were grouped into 30 OPFs. The two largest groups were most similar to Pedobacter sp. (245 from 475) and Limnobacter sp. (112 from 475) alkB gene sequences. From 56 alkane-degrading bacterial strains 41 belonged to the Pseudomonas spp. and 8 to the Rhodococcus spp. having redundant alkB genes. Together 68 alkB gene sequences were identified. These genes grouped into 20 OPFs, half of them being specific only to the isolated strains. Altogether 543 diverse alkB genes were characterized in the brackish Baltic Sea water; some of them representing novel lineages having very low sequence identities with corresponding genes of the reference strains.

  11. The AlkB Family of Fe(II)/α-Ketoglutarate-dependent Dioxygenases: Repairing Nucleic Acid Alkylation Damage and Beyond.

    PubMed

    Fedeles, Bogdan I; Singh, Vipender; Delaney, James C; Li, Deyu; Essigmann, John M

    2015-08-21

    The AlkB family of Fe(II)- and α-ketoglutarate-dependent dioxygenases is a class of ubiquitous direct reversal DNA repair enzymes that remove alkyl adducts from nucleobases by oxidative dealkylation. The prototypical and homonymous family member is an Escherichia coli "adaptive response" protein that protects the bacterial genome against alkylation damage. AlkB has a wide variety of substrates, including monoalkyl and exocyclic bridged adducts. Nine mammalian AlkB homologs exist (ALKBH1-8, FTO), but only a subset functions as DNA/RNA repair enzymes. This minireview presents an overview of the AlkB proteins including recent data on homologs, structural features, substrate specificities, and experimental strategies for studying DNA repair by AlkB family proteins.

  12. The AlkB Family of Fe(II)/α-Ketoglutarate-dependent Dioxygenases: Repairing Nucleic Acid Alkylation Damage and Beyond*

    PubMed Central

    Fedeles, Bogdan I.; Singh, Vipender; Delaney, James C.; Li, Deyu; Essigmann, John M.

    2015-01-01

    The AlkB family of Fe(II)- and α-ketoglutarate-dependent dioxygenases is a class of ubiquitous direct reversal DNA repair enzymes that remove alkyl adducts from nucleobases by oxidative dealkylation. The prototypical and homonymous family member is an Escherichia coli “adaptive response” protein that protects the bacterial genome against alkylation damage. AlkB has a wide variety of substrates, including monoalkyl and exocyclic bridged adducts. Nine mammalian AlkB homologs exist (ALKBH1–8, FTO), but only a subset functions as DNA/RNA repair enzymes. This minireview presents an overview of the AlkB proteins including recent data on homologs, structural features, substrate specificities, and experimental strategies for studying DNA repair by AlkB family proteins. PMID:26152727

  13. In silico studies on the interaction between bioactive ligands and ALK5, a biological target related to the cancer treatment.

    PubMed

    Almeida, Michell O; Trossini, Gustavo H G; Maltarollo, Vinícius G; Silva, Danielle da C; Honorio, Kathia M

    2016-09-01

    Studies have showed that there are many biological targets related to the cancer treatment, for example, TGF type I receptor (TGF-βRI or ALK5). The ALK5 inhibition is a strategy to treat some types of cancer, such as breast, lung, and pancreas. Here, we performed CoMFA and CoMSIA studies for 70 ligands with ALK5 inhibition. The internal validation for both models (q(2)LOO = 0.887 and 0.822, respectively) showed their robustness, while the external validations showed their predictive power (CoMFA: r(2)test = 0.998; CoMSIA: r(2)test = 0.975). After all validations, CoMFA and CoMSIA maps indicated physicochemical evidences on the main factors involved in the interaction between bioactive ligands and ALK5. Therefore, these results suggest molecular modifications to design new ALK5 inhibitors.

  14. Patient Positioning Based on a Radioactive Tracer Implanted in Patients With Localized Prostate Cancer: A Performance and Safety Evaluation

    SciTech Connect

    Kruijf, Willy J.M. de; Verstraete, Jan; Neustadter, David; Corn, Benjamin W.; Hol, Sandra; Venselaar, Jack L.M.; Davits, Rob J.; Wijsman, Bart P.; Van den Bergh, Laura; Budiharto, Tom; Oyen, Raymond; Haustermans, Karin; Poortmans, Philip M.P.

    2013-02-01

    Purpose: To evaluate the performance and safety of a radiation therapy positioning system (RealEye) based on tracking a radioactive marker (Tracer) implanted in patients with localized prostate cancer. Methods and Materials: We performed a single-arm multi-institutional trial in 20 patients. The iridium-192 ({sup 192}Ir)-containing Tracer was implanted in the patient together with 4 standard gold seed fiducials. Patient prostate-related symptoms were evaluated with the International Prostate Symptom Score (IPSS) questionnaire. Computed tomography (CT) was performed for treatment planning, during treatment, and after treatment to evaluate the migration stability of the Tracer. At 5 treatment sessions, cone beam CT was performed to test the positioning accuracy of the RealEye. Results: The Tracer was successfully implanted in all patients. No device or procedure-related adverse events occurred. Changes in IPSS scores were limited. The difference between the mean change in Tracer-fiducial distance and the mean change in fiducial-fiducial distance was -0.39 mm (95% confidence interval [CI] upper boundary, -0.22 mm). The adjusted mean difference between Tracer position according to RealEye and the Tracer position on the CBCT for all patients was 1.34 mm (95% CI upper boundary, 1.41 mm). Conclusions: Implantation of the Tracer is feasible and safe. Migration stability of the Tracer is good. Prostate patients can be positioned and monitored accurately by using RealEye.

  15. False positive stress-test in a patient with pericardial effusion.

    PubMed

    Mateja, Candice; Mishkin, Joseph; George, Malika; Chheda, Hemant; Guglin, Maya

    2009-10-02

    We report a case of false positive stress test in a patient with cardiac tamponade. After the drainage of pericardial effusion, reversible defect on a stress test resolved. Cardiac catheterization revealed normal coronary arteries.

  16. Pembrolizumab for HIV-Positive Patients with Recurrent or Refractory Cancer

    Cancer.gov

    In this phase I clinical trial, HIV-positive patients receiving combination antiretroviral therapy who have cancer that has recurred after or has not responded to previous treatment will receive the immune checkpoint inhibitor pembrolizumab.

  17. Alterations in genes other than EGFR/ALK/ROS1 in non-small cell lung cancer: trials and treatment options

    PubMed Central

    Desai, Arpita; Menon, Smitha P.; Dy, Grace K.

    2016-01-01

    During the last decade, we have seen tremendous progress in the therapy of lung cancer. Discovery of actionable mutations in EGFR and translocations in ALK and ROS1 have identified subsets of patients with excellent tumor response to oral targeted agents with manageable side effects. In this review, we highlight treatment options including corresponding clinical trials for oncogenic alterations affecting the receptor tyrosine kinases MET, FGFR, NTRK, RET, HER2, HER3, and HER4 as well as components of the RAS-RAF-MEK signaling pathway. PMID:27144064

  18. An appraisal of thoracic procedures performed in patients with HIV-positive serology.

    PubMed

    Canver, C C

    1995-08-01

    Patients who have contracted the human immunodeficiency virus (HIV) often require a diagnostic or therapeutic thoracic procedure. To determine the clinical benefits of a noncardiac pulmonary intervention in the treatment of HIV-positive individuals, 82 patients with HIV-positive serology who underwent a thoracic procedure for illnesses related to acquired immunodeficiency syndrome (AIDS) between 1987 and 1990 were reviewed. Pneumocystis carinii pneumonia was the most common opportunistic infection and was the initial manifestation for establishing the HIV-positive serology in 54 patients (66%). Fiberoptic bronchoscopy was performed in 74 patients (90%), closed tube thoracostomy in 9 (11%), thoracentesis in 3 (4%), thoracostomy and lung resection in 2 (2.4%), pericardial window in 1 (1.2%), and tracheostomy in 1 (1.2%). The operation was useful in 46 patients (56%) and improved the clinical short-term outcome of 53 patients (64%). Nonfatal complications occurred in only two patients (2.4%). There were no deaths directly caused by the thoracic procedure within the first 30 days. However, overall 8 patients (10%ZZ) succumbed to infectious complications of AIDS. We conclude that thoracic procedures directed toward pulmonary opportunistic infections and their complications in HIV-positive patients are beneficial and may offer an improved short-term outcome.

  19. Increased responsiveness of human pulmonary arteries in patients with positive bronchodilator response.

    PubMed Central

    Cases, E.; Vila, J. M.; Medina, P.; Aldasoro, M.; Segarra, G.; Lluch, S.

    1996-01-01

    1. The effects of noradrenaline, endothelin-1, acetylcholine and sodium nitroprusside were studied in isolated pulmonary arteries obtained from 14 patients undergoing lobectomy for lung carcinoma. Seven patients had shown increased response to a bronchodilator test prior to operation. In the remaining patients (control) the bronchodilator test was negative. 2. Artery rings from patients with a positive bronchodilator response showed greater contraction to noradrenaline (pD2 = 6.44 +/- 0.1; Emax = 93 +/- 9% of response to 100 mM KCl) and endothelin-1 (pD2 = 8.92 +/- 0.1; Emax = 130 +/- 16%) than the rings from control patients (pD2 = 6.04 +/- 0.08; Emax = 56 +/- 8% for noradrenaline; pD2 = 8.29 +/- 0.1; Emax = 78 +/- 10% for endothelin-1). There was no significant difference in the contractile responses to 100 mM KCl between arteries from either group of patients. 3. Arterial rings from patients with a positive bronchodilator test achieved 96 +/- 3% of maximal relaxation in response to acetylcholine, whereas rings from control patients achieved a maximal relaxation of 72 +/- 5%. Rings from both the controls and the patients with a positive bronchodilator test achieved complete relaxation in response to sodium nitroprusside but pD2 values were significantly higher in patients with a positive bronchodilator test. 4. Removal of endothelium or treatment with NG-nitro-L-arginine methyl ester of artery rings from both the control and the patients with a positive bronchodilator test reduced the relaxation to acetylcholine (P < 0.05) but did not modify relaxation to sodium nitroprusside. 5. It is concluded that responsiveness of pulmonary arterial smooth muscle to dilator and constrictor agents is increased in patients showing reversibility of airway constriction. Thus hyperresponsiveness of airway smooth muscle may be associated with a similar phenomenon in the surrounding vascular smooth muscle. PMID:8968540

  20. The pleiotrophin-ALK axis is required for tumorigenicity of glioblastoma stem cells.

    PubMed

    Koyama-Nasu, R; Haruta, R; Nasu-Nishimura, Y; Taniue, K; Katou, Y; Shirahige, K; Todo, T; Ino, Y; Mukasa, A; Saito, N; Matsui, M; Takahashi, R; Hoshino-Okubo, A; Sugano, H; Manabe, E; Funato, K; Akiyama, T

    2014-04-24

    Increasing evidence suggests that brain tumors arise from the transformation of neural stem/precursor/progenitor cells. Much current research on human brain tumors is focused on the stem-like properties of glioblastoma. Here we show that anaplastic lymphoma kinase (ALK) and its ligand pleiotrophin are required for the self-renewal and tumorigenicity of glioblastoma stem cells (GSCs). Furthermore, we demonstrate that pleiotrophin is transactivated directly by SOX2, a transcription factor essential for the maintenance of both neural stem cells and GSCs. We speculate that the pleiotrophin-ALK axis may be a promising target for the therapy of glioblastoma.

  1. Differential repair of etheno-DNA adducts by bacterial and human AlkB proteins

    PubMed Central

    Zdżalik, Daria; Domańska, Anna; Prorok, Paulina; Kosicki, Konrad; van den Born, Erwin; Falnes, Pål Ø.; Rizzo, Carmelo J.; Guengerich, F. Peter; Tudek, Barbara

    2015-01-01

    AlkB proteins are evolutionary conserved Fe(II)/2-oxoglutarate-dependent dioxygenases, which remove alkyl and highly promutagenic etheno (ε)-DNA adducts, but their substrate specificity has not been fully determined. We developed a novel assay for the repair of ε-adducts by AlkB enzymes using oligodeoxynucleotides with a single lesion and specific DNA glycosylases and AP-endonuclease for identification of the repair products. We compared the repair of three ε-adducts, 1,N6-ethenoadenine (εA), 3,N4-ethenocytosine (εC) and 1,N2-ethenoguanine (1,N2-εG) by nine bacterial and two human AlkBs, representing four different structural groups defined on the basis of conserved amino acids in the nucleotide recognition lid, engaged in the enzyme binding to the substrate. Two bacterial AlkB proteins, MT-2B (from Mycobacterium tuberculosis) and SC-2B (Streptomyces coelicolor) did not repair these lesions in either double-stranded (ds) or single-stranded (ss) DNA. Three proteins, RE-2A (Rhizobium etli), SA-2B (Streptomyces avermitilis), and XC-2B (Xanthomonas campestris) efficiently removed all three lesions from the DNA substrates. Interestingly, XC-2B and RE-2A are the first AlkB proteins shown to be specialized for ε-adducts, since they do not repair methylated bases. Three other proteins, EcAlkB (Escherichia coli), SA-1A, and XC-1B removed εA and εC from ds and ssDNA but were inactive toward 1,N2-εG. SC-1A repaired only εA with the preference for dsDNA. The human enzyme ALKBH2 repaired all three ε-adducts in dsDNA, while only εA and εC in ssDNA and repair was less efficient in ssDNA. ALKBH3 repaired only εC in ssDNA Altogether, we have shown for the first time that some AlkB proteins, namely ALKBH2, RE-2A, SA-2B and XC-2B can repair 1,N2-εG and that ALKBH3 removes only εC from ssDNA. Our results also suggest that the nucleotide recognition lid is not the sole determinant of the substrate specificity of AlkB proteins. PMID:25797601

  2. Cherenkoscopy based patient positioning validation and movement tracking during post-lumpectomy whole breast radiation therapy

    NASA Astrophysics Data System (ADS)

    Zhang, Rongxiao; Andreozzi, Jacqueline M.; Gladstone, David J.; Hitchcock, Whitney L.; Glaser, Adam K.; Jiang, Shudong; Pogue, Brian W.; Jarvis, Lesley A.

    2015-01-01

    To investigate Cherenkov imaging (Cherenkoscopy) based patient positioning and movement tracking during external beam radiation therapy (EBRT). In a phase 1 clinical trial, including 12 patients undergoing post-lumpectomy whole breast irradiation, Cherenkov emission was imaged with a time-gated ICCD camera synchronized to the LINAC pulse output, during different fractions of the treatment. Patients were positioned with the aid of the AlignRT system in the beginning of each treatment session. Inter-fraction setup variation was studied by rigid image registrations between images acquired at individual treatments to the average image from all imaged treatment fractions. The amplitude of respiratory motion was calculated from the registration of each frame of Cherenkov images to the reference. A Canny edge detection algorithm was utilized to highlight the beam field edges and biological features provided by major blood vessels apparent in the images. Real-time Cherenkoscopy can monitor the treatment delivery, patient motion and alignment of the beam edge to the treatment region simultaneously. For all the imaged fractions, the patient positioning discrepancies were within our clinical tolerances (3 mm in shifts and 3 degree in pitch angle rotation), with 4.6% exceeding 3 mm but still within 4 mm in shifts. The average discrepancy of repetitive patient positioning was 1.22 mm in linear shift and 0.34 degrees in rotational pitch, consistent with the accuracy reported by the AlignRT system. The edge detection algorithm enhanced features such as field edges and blood vessels. Patient positioning discrepancies and respiratory motion retrieved from rigid image registration were consistent with the edge enhanced images. Besides positioning discrepancies caused by globally inaccurate setups, edge enhanced blood vessels indicate the existence of deformations within the treatment region, especially for large patients. Real-time Cherenkoscopy imaging during EBRT is a

  3. Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1)

    PubMed Central

    Marzec, Michal; Zhang, Qian; Goradia, Ami; Raghunath, Puthiyaveettil N.; Liu, Xiaobin; Paessler, Michele; Wang, Hong Yi; Wysocka, Maria; Cheng, Mangeng; Ruggeri, Bruce A.; Wasik, Mariusz A.

    2008-01-01

    The mechanisms of malignant cell transformation caused by the oncogenic, chimeric nucleophosmin (NPM)/anaplastic lymphoma kinase (ALK) remain only partially understood, with most of the previous studies focusing mainly on the impact of NPM/ALK on cell survival and proliferation. Here we report that the NPM/ALK-carrying T cell lymphoma (ALK+TCL) cells strongly express the immunosuppressive cell-surface protein CD274 (PD-L1, B7-H1), as determined on the mRNA and protein level. The CD274 expression is strictly dependent on the expression and enzymatic activity of NPM/ALK, as demonstrated by inhibition of the NPM/ALK function in ALK+TCL cells by the small molecule ALK inhibitor CEP-14083 and by documenting CD274 expression in IL-3-depleted BaF3 cells transfected with the wild-type NPM/ALK, but not the kinase-inactive NPM/ALK K210R mutant or empty vector alone. NPM/ALK induces CD274 expression by activating its key signal transmitter, transcription factor STAT3. STAT3 binds to the CD274 gene promoter in vitro and in vivo, as shown in the gel electromobility shift and chromatin immunoprecipitation assays, and is required for the PD-L1 gene expression, as demonstrated by siRNA-mediated STAT3 depletion. These findings identify an additional cell-transforming property of NPM/ALK and describe a direct link between an oncoprotein and an immunosuppressive cell-surface protein. These results also provide an additional rationale to therapeutically target NPM/ALK and STAT3 in ALK+TCL. Finally, they suggest that future immunotherapeutic protocols for this type of lymphoma may need to include the inhibition of NPM/ALK and STAT3 to achieve optimal clinical efficacy. PMID:19088198

  4. Chromosomal radiosensitivity of human immunodeficiency virus positive/negative cervical cancer patients in South Africa

    PubMed Central

    HERD, OLIVIA; FRANCIES, FLAVIA; KOTZEN, JEFFREY; SMITH, TRUDY; NXUMALO, ZWIDE; MULLER, XANTHENE; SLABBERT, JACOBUS; VRAL, ANNE; BAEYENS, ANS

    2016-01-01

    Cervical cancer is the second most common cancer amongst South African women and is the leading cause of cancer-associated mortality in this region. Several international studies on radiation-induced DNA damage in lymphocytes of cervical cancer patients have remained inconclusive. Despite the high incidence of cervical cancer in South Africa, and the extensive use of radiotherapy to treat it, the chromosomal radiosensitivity of South African cervical cancer patients has not been studied to date. Since a high number of these patients are human immunodeficiency virus (HIV)-positive, the effect of HIV infection on chromosomal radiosensitivity was also investigated. Blood samples from 35 cervical cancer patients (20 HIV-negative and 15 HIV-positive) and 20 healthy controls were exposed to X-rays at doses of 6 MV of 2 and 4 Gy in vitro. Chromosomal radiosensitivity was assessed using the micronucleus (MN) assay. MN scores were obtained using the Metafer 4 platform, an automated microscopic system. Three scoring methods of the MNScore module of Metafer were applied and compared. Cervical cancer patients had higher MN values than healthy controls, with HIV-positive patients having the highest MN values. Differences between groups were significant when using a scoring method that corrects for false positive and false negative MN. The present study suggested increased chromosomal radiosensitivity in HIV-positive South African cervical cancer patients. PMID:26549042

  5. Viral Outcome in Patients with Occult HBV Infection or HCV-Ab Positivity Treated for Lymphoma.

    PubMed

    Guarino, Maria; Picardi, Marco; Vitello, Anna; Pugliese, Novella; Rea, Matilde; Cossiga, Valentina; Pane, Fabrizio; Caporaso, Nicola; Morisco, Filomena

    2017-01-01

    HBV and HCV reactivation has been widely reported in patients undergoing immunosuppressive therapy for oncohaematological diseases. We aimed to evaluate the HBV and HCV reactivation events in patients with non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma (HL) underwent cytotoxic chemotherapy containing or not rituximab. This is a retrospective observational study, including all patients with NHL and HL attending an Italian tertiary referral hospital, the University of Naples "Federico II". A total of 322 patients were enrolled. We evaluated serum HBV and HCV markers. A total of 47 (38%) patients with occult HBV infection were enrolled. Seven/47 were treated with therapeutic cytotoxic schedule containing rituximab. Of them, 6/7 received prophylaxis with lamivudine. HBV reactivation was observed in two patients treated with rituximab. A reactivation was observed in the only patient (HBcAb+/HBsAb+) not receiving lamivudine prophylaxis, and the other one was observed in 1 patient with isolated HBcAb positivity during lamivudine prophylaxis. Moreover, 8 patients with HCV-Ab positivity were enrolled. No viral reactivation was observed in these patients. In conclusion, patients with occult HBV infection receiving chemotherapy containing rituximab for lymphoma without antiviral prophylaxis are at risk of viral reactivation. On the contrary, there is no risk of reactivation in patients undergoing rituximab-free schedule. Our findings suggest that there is also very low risk of HCV reactivation. This preliminary report underlines the concept that HBV reactivationis strongly related to the type of immunosuppressive therapy administered and that antiviral prophylaxis needs to be tailored.

  6. The Relationship between Bone Mineral Density and Estrogen Receptor Positivity in Patients with Breast Cancer

    PubMed Central

    İyigün, Zeynep Erdoğan; Pilancı, Kezban Nur; Çabuk, Fatmagül Kuşku; İlgün, Serkan; Ordu, Çetin; Duymaz, Tomris; Alço, Gül; Çelebi, Filiz; Sarsenov, Dauren; İzci, Filiz; Öztürk, Alper; Ağaçayak, Filiz; Köksal, Ülkühan İner; Aktepe, Fatma; Eralp, Yeşim; Özmen, Vahit

    2016-01-01

    Objective The effect of estrogen on bone mineral density (BMD) and breast cancer has been known for a long time. The aim of this study was to compare of the BMD of patients with breast cancer and healthy individuals, and to investigate the degree of correlation of estrogen receptor (ER) with BMD. Materials and Methods Seventy-one patients with postmenopausal breast cancer and 79 healthy dividuals were included in the study. The patient demographics (age, menopause age, body mass index, number of children, BMD, Z scores, and estrogen status for breast cancer patients) were taken from hospital records. Results No significant difference was detected between the case and control groups in lumbar region Z scores (p=0.074). At the femur neck, the control group Z scores was higher than patient group (p=0.002). BMI was higher in the patients with breast cancer (p=0.001). There was no statistically significant correlation between ER positivity, BMD, and BMI in ER-positive patients (p=0.495, p=0.8, p=0.846, respectively). There was no difference between the Z scores when the patients were divided into two groups as ER positive and negative (p=0.156, p=0.335, respectively). Conclusion This study revealed that there is no difference in lumbar region Z scores between patients with breast cancer and heathy controls; however, the Z scores were higher in the femur neck in the control group, and the BMI was lower in the patient group. Tumor ER positivity does not positively affect BMD.

  7. SU-E-J-15: Automatically Detect Patient Treatment Position and Orientation in KV Portal Images

    SciTech Connect

    Qiu, J; Yang, D

    2015-06-15

    Purpose: In the course of radiation therapy, the complex information processing workflow will Result in potential errors, such as incorrect or inaccurate patient setups. With automatic image check and patient identification, such errors could be effectively reduced. For this purpose, we developed a simple and rapid image processing method, to automatically detect the patient position and orientation in 2D portal images, so to allow automatic check of positions and orientations for patient daily RT treatments. Methods: Based on the principle of portal image formation, a set of whole body DRR images were reconstructed from multiple whole body CT volume datasets, and fused together to be used as the matching template. To identify the patient setup position and orientation shown in a 2D portal image, the 2D portal image was preprocessed (contrast enhancement, down-sampling and couch table detection), then matched to the template image so to identify the laterality (left or right), position, orientation and treatment site. Results: Five day’s clinical qualified portal images were gathered randomly, then were processed by the automatic detection and matching method without any additional information. The detection results were visually checked by physicists. 182 images were correct detection in a total of 200kV portal images. The correct rate was 91%. Conclusion: The proposed method can detect patient setup and orientation quickly and automatically. It only requires the image intensity information in KV portal images. This method can be useful in the framework of Electronic Chart Check (ECCK) to reduce the potential errors in workflow of radiation therapy and so to improve patient safety. In addition, the auto-detection results, as the patient treatment site position and patient orientation, could be useful to guide the sequential image processing procedures, e.g. verification of patient daily setup accuracy. This work was partially supported by research grant from

  8. Effects of upper extremity training in a standing position on trunk alignment in stroke patients

    PubMed Central

    Kim, Eun Ja; Lee, Kyoung Bo; Hwang, Byong Yong

    2016-01-01

    [Purpose] This study aimed to examine the effect of upper extremity training in the standing position on trunk alignment of patients with stroke. [Subjects and Methods] Twelve stroke patients were enrolled in the study and divided into two groups: a group of six patients in a sitting position and a group of six patients in a standing position. Upper extremity training for 30 min per day, five times a week for six weeks was given to subjects in both groups. In order to assess trunk alignment, lumbar lordosis and thoracic kyphosis were examined before and after upper extremity training using Formetric 4D. [Results] After training the standing position group had no significant change in lumbar lordosis but a significant change in thoracic kyphosis. The sitting position group showed no significant changes in either lumbar lordosis or thoracic kyphosis. The comparison between groups showed there was no significant difference in the change in lumbar lordosis but there was a significant difference in the change in thoracic kyphosis. [Conclusion] Examination of trunk alignment showed that upper extremity training conducted in a standing position reduced thoracic kyphosis more than in a sitting position. PMID:27799662

  9. Results of surgical treatment on benign anal diseases in Korean HIV-positive patients.

    PubMed

    Oh, Heung-Kwon; Moon, Sang-Hui; Ryoo, Seungbum; Choe, Eun Kyung; Park, Kyu Joo

    2014-09-01

    Perianal diseases are the most common reasons for surgery in HIV-positive patients. This study aimed to evaluate the outcomes of these surgical procedures in Korean patients, focusing on wound healing and postoperative complications. Retrospective analysis was performed on 72 HIV-positive patients who underwent surgery by a single surgeon for benign anal disease between 1998 and 2011. Of these, 68.1% (49/72) of patients received surgery for condyloma acuminata, 19.4% (14/72) for anal fistulas, 6.9% (5/72) for hemorrhoids, and 5.6% (4/72) for perianal abscesses. Patients with condyloma acuminata received surgical excision with electrical coagulation, and all wounds healed completely within 3 months, though 16.3% (8/49) of these patients experienced recurrence. Twelve of the 49 patients (24.5%) who were treated for condyloma acuminata underwent simultaneous operations for concomitant anal fistulas (n = 6), hemorrhoids (n = 4), and perianal abscesses (n = 2). Overall, 3 postoperative complications developed following a total of 94 procedures, and there was no significant increase in complication rate for patients with a low CD4+ T-cell count ( < 200/µL) compared to those with a higher count. The results demonstrate favorable results following perianal surgery in HIV-positive Korean patients.

  10. Augmentor α and β (FAM150) are ligands of the receptor tyrosine kinases ALK and LTK: Hierarchy and specificity of ligand–receptor interactions

    PubMed Central

    Reshetnyak, Andrey V.; Murray, Phillip B.; Shi, Xiarong; Mo, Elizabeth S.; Mohanty, Jyotidarsini; Tome, Francisco; Bai, Hanwen; Gunel, Murat; Lax, Irit; Schlessinger, Joseph

    2015-01-01

    Receptor tyrosine kinases (RTKs) are a class of cell surface receptors that, upon ligand binding, stimulate a variety of critical cellular functions. The orphan receptor anaplastic lymphoma kinase (ALK) is one of very few RTKs that remain without a firmly established protein ligand. Here we present a novel cytokine, FAM150B, which we propose naming augmentor-α (AUG-α), as a ligand for ALK. AUG-α binds ALK with high affinity and activates ALK in cells with subnanomolar potency. Detailed binding experiments using cells expressing ALK or the related receptor leukocyte tyrosine kinase (LTK) demonstrate that AUG-α binds and robustly activates both ALK and LTK. We show that the previously established LTK ligand FAM150A (AUG-β) is specific for LTK and only weakly binds to ALK. Furthermore, expression of AUG-α stimulates transformation of NIH/3T3 cells expressing ALK, induces IL-3 independent growth of Ba/F3 cells expressing ALK, and is expressed in neuroblastoma, a cancer partly driven by ALK. These experiments reveal the hierarchy and specificity of two cytokines as ligands for ALK and LTK and set the stage for elucidating their roles in development and disease states. PMID:26630010

  11. Effectiveness of canalith repositioning manoeuvers (CRM) in patients with benign paroxysmal positional vertigo (BPPV).

    PubMed

    Tevzadze, N; Shakarishvili, R

    2007-01-01

    BPPV is the most common disorder of the vestibular system affected up to 21% of vertigo patients, characterised by short-lasting episodes of vertigo in association with rapid changes in head position. We have detected, treated and followed up 204 patients with BPPV during two years. 204 patients (163 women 41men) were enrolled in this study, at the time of evolution the duration of symptoms varied from several days to several months. We evaluated idiophatic forms of BPPV in 126 cases and secondary types BPPV in 78 cases. All patients with typical history of BPPV underwent neurological examination, including Dix-Hallpike (to detect posterior and anterior canal BPPV) and Roll Test (to detect horizontal canal BPPV). We treat patients with CRM and followed up them in 48 hours and 7 days, one month, 6 month and one year after initial management. Posterior semicircular canal was involved in 170 patients, remain 34 patients suffered from canalolithiasis of horisontal (31 patients) and anterior (3 patients) semicircular canal. After a single treatment session the symptoms disappeared completely in 139 patients, in 40 patients after twice, 16 patients after 3 times and 9 patients after 4 times maneuver sessions. No effectiveness was found in 5 patients; during follow-up 7 successfully treated patients experienced a recurrence between 1 and 6 months, in two cases after one year; they were retreated and all achieved a positive result. It is concluded that diagnosis of BPPV is simple and save, do not need expensive neuroradiological tests; CRM provides effective and long term control of symptoms in patients with BPPV.

  12. Bcl-2 associated with positive symptoms of schizophrenic patients in an acute phase.

    PubMed

    Tsai, Meng-Chang; Liou, Chia-Wei; Lin, Tsu-Kung; Lin, I-Mei; Huang, Tiao-Lai

    2013-12-30

    B cell lymphoma protein-2 (Bcl-2) may contribute to the pathophysiology of schizophrenia in the brain. The aim of this study was to investigate the serum levels of Bcl-2 in schizophrenic patients in an acute phase, and evaluate Bcl-2 level changes after antipsychotic treatment. We consecutively enrolled 41 schizophrenia patients in an acute phase; 28 were followed up with a 4-week antipsychotic treatment. Serum Bcl-2 levels were measured with assay kits. All patients were evaluated by examining the correlation between Bcl-2 levels and Positive and Negative Syndrome Scale (PANSS) scores, using Pearson correlation coefficients. In schizophrenic patients in an acute phase, positive PANSS subscores were significantly negatively correlated with Bcl-2 levels. In addition, we found Bcl-2 levels had a significantly negative correlation with PANSS total scores and positive subscores in male patients in an acute phase. Using the paired t-test, we found no significant changes in Bcl-2 levels in schizophrenia patients who had received the 4-week treatment with antipsychotic drugs (n=28). In conclusion, our results suggest that Bcl-2 might be an indicator of schizophrenia severity in the acute phase. In addition, Bcl-2 levels might be associated with positive symptoms in male patients with schizophrenia.

  13. A dynamic compensation strategy to correct patient-positioning errors in conformal prostate radiotherapy.

    PubMed

    Lauve, A D; Siebers, J V; Crimaldi, A J; Hagan, M P; Kealla, P J

    2006-06-01

    Traditionally, pretreatment detected patient-positioning errors have been corrected by repositioning the couch to align the patient to the treatment beam. We investigated an alternative strategy: aligning the beam to the patient by repositioning the dynamic multileaf collimator and adjusting the beam weights, termed dynamic compensation. The purpose of this study was to determine the geometric range of positioning errors for which the dynamic compensation method is valid in prostate cancer patients treated with three-dimensional conformal radiotherapy. Twenty-five previously treated prostate cancer patients were replanned using a four-field technique to deliver 72 Gy to 95% of the planning target volume (PTV). Patient-positioning errors were introduced by shifting the patient reference frame with respect to the treatment isocenter. Thirty-six randomly selected isotropic displacements with magnitudes of 1.0, 2.0, 4.0, 6.0, 8.0, and 10.0 cm were sampled for each patient, for a total of 5400 errors. Dynamic compensation was used to correct each of these errors by conforming the beam apertures to the new target position and adjusting the monitor units using inverse-square and off-axis factor corrections. The dynamic compensation plans were then compared with the original treatment plans via dose-volume histogram (DVH) analysis. Changes of more than 5% of the prescription dose, 3.6 Gy, were deemed significant. Compared with the original treatment plans, dynamic compensation produced small discrepancies in isodose distributions and DVH analyses. These differences increased with the magnitudes of the initial patient-positioning errors. Coverage of the PTV was excellent: D95 and Dmean were not increased or decreased by more than 5% of the prescription dose, and D5 was not decreased by more than 5% of the prescription dose for any of the 5400 simulated positioning errors. D5 was increased by more than 5% of the prescription dose in only three of the 5400 positioning errors

  14. A dynamic compensation strategy to correct patient-positioning errors in conformal prostate radiotherapy

    SciTech Connect

    Lauve, A. D.; Siebers, J. V.; Crimaldi, A. J.; Hagan, M. P.; Keall, P. J.

    2006-06-15

    Traditionally, pretreatment detected patient-positioning errors have been corrected by repositioning the couch to align the patient to the treatment beam. We investigated an alternative strategy: aligning the beam to the patient by repositioning the dynamic multileaf collimator and adjusting the beam weights, termed dynamic compensation. The purpose of this study was to determine the geometric range of positioning errors for which the dynamic compensation method is valid in prostate cancer patients treated with three-dimensional conformal radiotherapy. Twenty-five previously treated prostate cancer patients were replanned using a four-field technique to deliver 72 Gy to 95% of the planning target volume (PTV). Patient-positioning errors were introduced by shifting the patient reference frame with respect to the treatment isocenter. Thirty-six randomly selected isotropic displacements with magnitudes of 1.0, 2.0, 4.0, 6.0, 8.0, and 10.0 cm were sampled for each patient, for a total of 5400 errors. Dynamic compensation was used to correct each of these errors by conforming the beam apertures to the new target position and adjusting the monitor units using inverse-square and off-axis factor corrections. The dynamic compensation plans were then compared with the original treatment plans via dose-volume histogram (DVH) analysis. Changes of more than 5% of the prescription dose, 3.6 Gy, were deemed significant. Compared with the original treatment plans, dynamic compensation produced small discrepancies in isodose distributions and DVH analyses. These differences increased with the magnitudes of the initial patient-positioning errors. Coverage of the PTV was excellent: D{sub 95} and D{sub mean} were not increased or decreased by more than 5% of the prescription dose, and D{sub 5} was not decreased by more than 5% of the prescription dose for any of the 5400 simulated positioning errors. D{sub 5} was increased by more than 5% of the prescription dose in only three of the

  15. Comparison of Serum Lipid Profile in HIV Positive Patients on ART with ART Naïve Patients

    PubMed Central

    V, Vijay; Shekhanawar, M.S.; Rajeshwari; M, Amareshwaras; D, Shantala

    2014-01-01

    Introduction: The widespread use of effective highly active antiretroviral therapy (HAART) in HIV patients has coincided with increasing reports of complications like HIV-associated lipodystrophy syndrome and the metabolic alterations, affecting the lipid and glucose metabolism. Evidences in support of lipodystrophy and dyslipidaemia associated with First- line HAART in our area is scarce. The aim of the present study was 1) to study and compare Lipid profile in HIV positive patients on ART with that of freshly diagnosed HIV positive patients who were yet to be started on ART. 2) To assess lipodystrophy syndrome in patients on ART. Materials and Methods: Hundred newly diagnosed HIV positive patients who were yet to be started on ART were taken as controls (ART-Naïve).Hundred randomly selected HIV+ patients who were already on First-line ART regimen (Stavudine/Zudovudine + Lamivudine + Nevirapine) for more than 12 months were taken as cases (ART). This study was conducted for a period of 12 months at the VIMS ART centre, Bellary, Karnataka, India. Results: There was a significant increase (p<0.001) in serum Total Cholesterol, LDL-C, TG, VLDL, Non-HDL -C & TC/HDL-C ratio in ART patients compared to ART-naïve patients. Of the 100 ART patients 23 had lipodystrophy syndrome (buffalo hump, abnormal fat deposition around neck & back, buccal fat resorption, increase in abdominal fat). Conclusion: To conclude, it is evident from our study that there is increase in lipid profile (except HDL) in ART patients compared to ART Naïve group and 23 ART patients showed lipodystrophy syndrome. Hence it appears reasonable to measure fasting lipid levels before and 3-6 months after antiretroviral therapy is initiated or when ART regimen is changed. PMID:25478335

  16. Prognosis and treatment of patients with positive peritoneal cytology in advanced gastric cancer

    PubMed Central

    Frattini, Francesco; Rausei, Stefano; Chiappa, Corrado; Rovera, Francesca; Boni, Luigi; Dionigi, Gianlorenzo

    2013-01-01

    Positive peritoneal cytology in gastric cancer is classified as M1 disease by the 7th Edition of American Joint Committee on Cancer staging system. With the introduction of laparoscopy and peritoneal washing cytology in the staging of gastric cancer a new category of patients has been identified. These are patients with no macroscopic peritoneal metastases but with peritoneal cytology positive (P0C1). Prognosis and treatment of such patients represent a controversial issue. We evaluate the state of the art of staging system in gastric cancer and discuss standardisation in staging and treatment procedures. There is still a lack of uniformity in the use of laparoscopy with peritoneal cytology in clinical decision making and in the surgical treatment for gastric cancer. Survival of this patient subset remains poor. Multimodal therapies and new therapeutic strategies are required to improve the survival of these patients. PMID:23710290

  17. Prognosis and treatment of patients with positive peritoneal cytology in advanced gastric cancer.

    PubMed

    Frattini, Francesco; Rausei, Stefano; Chiappa, Corrado; Rovera, Francesca; Boni, Luigi; Dionigi, Gianlorenzo

    2013-05-27

    Positive peritoneal cytology in gastric cancer is classified as M1 disease by the 7(th) Edition of American Joint Committee on Cancer staging system. With the introduction of laparoscopy and peritoneal washing cytology in the staging of gastric cancer a new category of patients has been identified. These are patients with no macroscopic peritoneal metastases but with peritoneal cytology positive (P0C1). Prognosis and treatment of such patients represent a controversial issue. We evaluate the state of the art of staging system in gastric cancer and discuss standardisation in staging and treatment procedures. There is still a lack of uniformity in the use of laparoscopy with peritoneal cytology in clinical decision making and in the surgical treatment for gastric cancer. Survival of this patient subset remains poor. Multimodal therapies and new therapeutic strategies are required to improve the survival of these patients.

  18. Management of the node-positive neck in the patient with HPV-associated oropharyngeal cancer

    PubMed Central

    Garden, Adam S.; Gunn, Gary B.; Hessel, Amy; Beadle, Beth M.; Ahmed, Salmaan; El-naggar, Adel; Fuller, Clifton D.; Byers, Lauren A.; Phan, Jack; Frank, Steven J.; Morrison, William H.; Kies, Merill S.; Rosenthal, David I.; Sturgis, Erich M.

    2014-01-01

    Background The goal of this study was to assess the rates of recurrence in the neck for node-positive patients with HPV-associated oropharynx cancer treated with definitive radiation (with or without chemotherapy). Methods This is a single institutional retrospective study. Methodology included database search, and statistical testing including frequency analysis, Kaplan-Meier tests, and comparative tests including chi-square, logistic regression and log-rank. Results The cohort consisted of 401 node-positive patients irradiated between 2006 – June 2012. Three hundred eighty eight patients had CT restaging, and 251 had PET and/or US as a component of their post radiation staging. Eighty patients (20%) underwent neck dissection, and 21 (26%) had a positive specimen. The rate of neck dissection increased with increasing nodal stage, and was lower in patients who had PET scans or ultrasound in addition to CT restaging. The median follow-up was 30 months. The 2-year actuarial neck recurrence rate was 7% and 5% in all patients and those with local control, respectively. Nodal recurrence rates were greater in current smokers (p=.008). There was no difference in nodal recurrences rates in patients who did or did not have a neck dissection (p = .4) Conclusions A treatment strategy of (chemo)radiation with neck dissection performed based on response resulted in high rates of regional disease control in patients with HPV-associated oropharyngeal cancer. PMID:24898672

  19. ClogP(alk): a method for predicting alkane/water partition coefficient.

    PubMed

    Kenny, Peter W; Montanari, Carlos A; Prokopczyk, Igor M

    2013-05-01

    Alkane/water partition coefficients (P(alk)) are less familiar to the molecular design community than their 1-octanol/water equivalents and access to both data and prediction tools is much more limited. A method for predicting alkane/water partition coefficient from molecular structure is introduced. The basis for the ClogP(alk) model is the strong (R² = 0.987) relationship between alkane/water partition coefficient and molecular surface area (MSA) that was observed for saturated hydrocarbons. The model treats a molecule as a perturbation of a saturated hydrocarbon molecule with the same MSA and uses increments defined for functional groups to quantify the extent to which logP(alk) is perturbed by the introduction each functional group. Interactions between functional groups, such as intramolecular hydrogen bonds are also parameterized within a perturbation framework. The functional groups and interactions between them are specified substructurally in a transparent and reproducible manner using SMARTS notation. The ClogP(alk) model was parameterized using data measured for structurally prototypical compounds that dominate the literature on alkane/water partition coefficients and then validated using an external test set of 100 alkane/water logP measurements, the majority of which were for drugs.

  20. Stimulation of the midkine/ALK axis renders glioma cells resistant to cannabinoid antitumoral action

    PubMed Central

    Lorente, M; Torres, S; Salazar, M; Carracedo, A; Hernández-Tiedra, S; Rodríguez-Fornés, F; García-Taboada, E; Meléndez, B; Mollejo, M; Campos-Martín, Y; Lakatosh, S A; Barcia, J; Guzmán, M; Velasco, G

    2011-01-01

    Identifying the molecular mechanisms responsible for the resistance of gliomas to anticancer treatments is an issue of great therapeutic interest. Δ9-Tetrahydrocannabinol (THC), the major active ingredient of marijuana, and other cannabinoids inhibit tumor growth in animal models of cancer, including glioma, an effect that relies, at least in part, on the stimulation of autophagy-mediated apoptosis in tumor cells. Here, by analyzing the gene expression profile of a large series of human glioma cells with different sensitivity to cannabinoid action, we have identified a subset of genes specifically associated to THC resistance. One of these genes, namely that encoding the growth factor midkine (Mdk), is directly involved in the resistance of glioma cells to cannabinoid treatment. We also show that Mdk mediates its protective effect via the anaplastic lymphoma kinase (ALK) receptor and that Mdk signaling through ALK interferes with cannabinoid-induced autophagic cell death. Furthermore, in vivo Mdk silencing or ALK pharmacological inhibition sensitizes cannabinod-resistant tumors to THC antitumoral action. Altogether, our findings identify Mdk as a pivotal factor involved in the resistance of glioma cells to THC pro-autophagic and antitumoral action, and suggest that selective targeting of the Mdk/ALK axis could help to improve the efficacy of antitumoral therapies for gliomas. PMID:21233844

  1. Genome-wide RNAi screen reveals ALK1 mediates LDL uptake and transcytosis in endothelial cells

    PubMed Central

    Kraehling, Jan R.; Chidlow, John H.; Rajagopal, Chitra; Sugiyama, Michael G.; Fowler, Joseph W.; Lee, Monica Y.; Zhang, Xinbo; Ramírez, Cristina M.; Park, Eon Joo; Tao, Bo; Chen, Keyang; Kuruvilla, Leena; Larriveé, Bruno; Folta-Stogniew, Ewa; Ola, Roxana; Rotllan, Noemi; Zhou, Wenping; Nagle, Michael W.; Herz, Joachim; Williams, Kevin Jon; Eichmann, Anne; Lee, Warren L.; Fernández-Hernando, Carlos; Sessa, William C.

    2016-01-01

    In humans and animals lacking functional LDL receptor (LDLR), LDL from plasma still readily traverses the endothelium. To identify the pathways of LDL uptake, a genome-wide RNAi screen was performed in endothelial cells and cross-referenced with GWAS-data sets. Here we show that the activin-like kinase 1 (ALK1) mediates LDL uptake into endothelial cells. ALK1 binds LDL with lower affinity than LDLR and saturates only at hypercholesterolemic concentrations. ALK1 mediates uptake of LDL into endothelial cells via an unusual endocytic pathway that diverts the ligand from lysosomal degradation and promotes LDL transcytosis. The endothelium-specific genetic ablation of Alk1 in Ldlr-KO animals leads to less LDL uptake into the aortic endothelium, showing its physiological role in endothelial lipoprotein metabolism. In summary, identification of pathways mediating LDLR-independent uptake of LDL may provide unique opportunities to block the initiation of LDL accumulation in the vessel wall or augment hepatic LDLR-dependent clearance of LDL. PMID:27869117

  2. ALK1 signalling analysis identifies angiogenesis related genes and reveals disparity between TGF-β and constitutively active receptor induced gene expression

    PubMed Central

    Lux, Andreas; Salway, Fiona; Dressman, Holly K; Kröner-Lux, Gabriele; Hafner, Mathias; Day, Philip JR; Marchuk, Douglas A; Garland, John

    2006-01-01

    Background TGF-β1 is an important angiogenic factor involved in the different aspects of angiogenesis and vessel maintenance. TGF-β signalling is mediated by the TβRII/ALK5 receptor complex activating the Smad2/Smad3 pathway. In endothelial cells TGF-β utilizes a second type I receptor, ALK1, activating the Smad1/Smad5 pathway. Consequently, a perturbance of ALK1, ALK5 or TβRII activity leads to vascular defects. Mutations in ALK1 cause the vascular disorder hereditary hemorrhagic telangiectasia (HHT). Methods The identification of ALK1 and not ALK5 regulated genes in endothelial cells, might help to better understand the development of HHT. Therefore, the human microvascular endothelial cell line HMEC-1 was infected with a recombinant constitutively active ALK1 adenovirus, and gene expression was studied by using gene arrays and quantitative real-time PCR analysis. Results After 24 hours, 34 genes were identified to be up-regulated by ALK1 signalling. Analysing ALK1 regulated gene expression after 4 hours revealed 13 genes to be up- and 2 to be down-regulated. Several of these genes, including IL-8, ET-1, ID1, HPTPη and TEAD4 are reported to be involved in angiogenesis. Evaluation of ALK1 regulated gene expression in different human endothelial cell types was not in complete agreement. Further on, disparity between constitutively active ALK1 and TGF-β1 induced gene expression in HMEC-1 cells and primary HUVECs was observed. Conclusion Gene array analysis identified 49 genes to be regulated by ALK1 signalling and at least 14 genes are reported to be involved in angiogenesis. There was substantial agreement between the gene array and quantitative real-time PCR data. The angiogenesis related genes might be potential HHT modifier genes. In addition, the results suggest endothelial cell type specific ALK1 and TGF-β signalling. PMID:16594992

  3. Neurological Findings in Early Syphilis: a Comparison Between HIV Positive and Negative Patients.

    PubMed

    González-Duarte, Alejandra; López, Zaira Medina

    2013-01-01

    After a decade of steady decline, syphilis has reemerged within the past few years and it is seeping back into the HIV negative population. We describe herein 16 consecutive cases of neurosyphilis and compare its clinical characteristics. Of the 16 patients, 14 (87%) were men. Mean age at onset was 43 years old (range: 23-82). Twelve patients (75%) were HIV positive; stage was B2 in 2 patients, B3 and C2 in one patient each, and C3 in 8 patients. The clinical presentation was meningitis in 6 (40%), stroke in 3 (18%), ocular manifestations in 4 (27%), and psychiatric manifestations in 2 (13%) cases. Five additional patients had ocular involvement after a formal ophthalmologic examination. High venereal disease research laboratory test (VDRL) titers in serum and cerebrospinal fluid (CSF) were found. Patients in C3 stage of HIV had less CSF pleocytosis (<5 cells/mm(3)) than patients in earlier stages (P=0.018). Disease onset was earlier in patients older than 50 years old with HIV (P=0.049). We found that meningitis, ocular manifestations and stroke were the most common clinical findings in early syphilis. Moreover, stroke included the carotid and cerebrobasilar vascular territories. CSF VDRL continues to be a crucial test in all idiopathic cases of meningitis, stroke and uveitis, regardless of the HIV status or CSF pleocytosis. Except for less pleocytosis, there were no important differences between HIV positive and HIV negative patients.

  4. Rheumatic manifestations of euthyroid, anti-thyroid antibody-positive patients.

    PubMed

    Tagoe, Clement E; Zezon, Anna; Khattri, Saakshi; Castellanos, Patricia

    2013-07-01

    The aim of this study is to define the rheumatic manifestations of euthyroid patients with chronic lymphocytic thyroiditis (CLT) but without a well-defined connective tissue disease. Forty-six consecutive patients with anti-thyroid peroxidase (αTPO) and/or anti-thyroglobulin antibodies (αTG), and normal thyroid function in the absence of a well-defined connective tissue disease were included in a case-cohort study. Arthralgias were a presenting complaint in 98 % of patients. Fibromyalgia syndrome was found in 59 % of patients. Raynaud's phenomenon occurred in 28 % and sicca symptoms in 26 % of patients. Two patients had seronegative arthritis resembling rheumatoid arthritis. Arthritis was radiographically present in 88 %, affecting the spine in 45 % of patients. Thyroid-stimulating hormone (TSH) levels positively correlated with levels of αTPO, but not with erythrocyte sedimentation rate (ESR) or αTG levels. A positive ANA was found in 24 % of patients. One patient developed subclinical hypothyroidism during the study. Rheumatic manifestations frequently occur in patients with CLT in the absence of overt thyroid dysfunction and mimic the presentation of the well-defined connective tissue diseases.

  5. Thyroid metastasis from lung adenocarcinoma with EML4-ALK rearrangement

    PubMed Central

    Kawamoto, Hironori; Kaneko, Yugo; Ryu, Kai; Kuwano, Kazuyoshi

    2016-01-01

    Thyroid metastases from lung cancer are very rare. A woman aged 42 years with a tumour in the lower lobe of the right lung was diagnosed as having lung adenocarcinoma positive for echinoderm microtubule-associated proteinlike 4-anaplastic lymphoma kinase. Positron emission tomography demonstrated fluorodeoxyglucose accumulation in the lower lobe of the right lung, the right thyroid lobe and both adrenal glands. We performed fine-needle aspiration biopsy (FNAB) and used reverse transcriptase-PCR (RT-PCR) to diagnose the patient as having metastatic lung adenocarcinoma to the thyroid gland. We believe that FNAB combined with RT-PCR can be an effective method for diagnosing metastatic lung adenocarcinoma to the thyroid gland. PMID:27872133

  6. Evaluation of vertebrobasilar artery changes in patients with benign paroxysmal positional vertigo.

    PubMed

    Zhang, Daopei; Zhang, Shuling; Zhang, Hongtao; Xu, Yuming; Fu, Shengqi; Yu, Meng; Ji, Peng

    2013-09-11

    The aim of this study was to investigate vertebrobasilar artery (VBA) lesions in elderly patients with benign paroxysmal positional vertigo (BPPV) by magnetic resonance angiography. VBA lesions in patients older than 65 years of age with BPPV were prospectively investigated by magnetic resonance angiography. Vascular risk factors, blood vessel changes, and vertigo severity were recorded. Age-matched individuals without BPPV were included in the control group. Of 126 patients screened for this study, 104 were included. Relevant comorbidities included diabetes (12 patients), hypertension (23 patients), and dyslipidemia (20 patients). Findings included left or right vertebral artery (VA) stenosis or occlusion (22 patients, 21.2%), VA tortuosity (25 patients, 24.0%), VA dominance (20 patients, 19.2%), basilar artery (BA) stenosis or occlusion (nine patients, 8.6%), and BA tortuosity (12 patients, 11.5%). These abnormal vessels differed between BPPV patients and the control group (all P<0.05). The severity of Vertigo did not differ between the abnormal VA and abnormal BA groups (P>0.05), but did differ between the normal group and the abnormal VA or BA group (P<0.05). Vertigo severity correlated with VA stenosis or occlusion, VA dominance, and unilateral or bilateral VA tortuosity. VBA tortuosity and VA dominance were common in BPPV patients and may contribute toward BPPV.

  7. Positive Psychological Interventions for Patients with Type 2 Diabetes: Rationale, Theoretical Model, and Intervention Development

    PubMed Central

    Huffman, Jeff C.; DuBois, Christina M.; Millstein, Rachel A.; Celano, Christopher M.; Wexler, Deborah

    2015-01-01

    Most patients with type 2 diabetes (T2D) have suboptimal adherence to recommended diet, physical activity, and/or medication. Current approaches to improve health behaviors in T2D have been variably effective, and successful interventions are often complex and intensive. It is therefore vital to develop interventions that are simple, well-accepted, and applicable to a wide range of patients who suffer from T2D. One approach may be to boost positive psychological states, such as positive affect or optimism, as these constructs have been prospectively and independently linked to improvements in health behaviors. Positive psychology (PP) interventions, which utilize systematic exercises to increase optimism, well-being, and positive affect, consistently increase positive states and are easily delivered to patients with chronic illnesses. However, to our knowledge, PP interventions have not been formally tested in T2D. In this paper, we review a theoretical model for the use of PP interventions to target health behaviors in T2D, describe the structure and content of a PP intervention for T2D patients, and describe baseline data from a single-arm proof-of-concept (N = 15) intervention study in T2D patients with or without depression. We also discuss how PP interventions could be combined with motivational interviewing (MI) interventions to provide a blended psychological-behavioral approach. PMID:26064980

  8. Incidence of positive peritoneal cytology in patients with endometrial carcinoma after hysteroscopy vs. dilatation and curettage

    PubMed Central

    Crnobrnja, Bojana; Zegura, Branka; Takac, Iztok; Pakiz, Maja

    2017-01-01

    Abstract Background The aim of the study was to compare the frequency of positive peritoneal washings in endometrial cancer patients after either hysteroscopy (HSC) or dilatation and curettage (D&C). Patients and methods We performed a retrospective analysis of 227 patients who underwent either HSC (N = 144) or D&C (N = 83) and were diagnosed with endometrial carcinoma at the University Medical Centre Maribor between January 2008 and December 2014. The incidence of positive peritoneal cytology was evaluated in each group. Results There was no overall difference in the incidence of positive peritoneal washings after HSC or D&C (HSC = 13.2%; D&C = 12.0%; p = 0.803). However, a detailed analysis of stage I disease revealed significantly higher rates of positive peritoneal washings in the HSC group (HSC = 12.8%; D&C = 3.4%; p = 0.046). Among these patients, there was no difference between both groups considering histologic type (chi-square = 0.059; p = 0.807), tumour differentiation (chi-square = 3.709; p = 0.156), the time between diagnosis and operation (t = 0.930; p = 0.357), and myometrial invasion (chi-square = 5.073; p = 0.079). Conclusions Although the diagnostic procedure did not influence the overall incidence of positive peritoneal washings, HSC was associated with a significantly higher rate of positive peritoneal cytology in stage I endometrial carcinoma compared to D&C. PMID:28265237

  9. Partner notification and focused intervention as a means of identifying HIV-positive patients.

    PubMed

    Jordan, W C; Tolbert, L; Smith, R

    1998-09-01

    Partner notification as a means of contact tracing human immunodeficiency virus (HIV)-infected persons remains controversial. It is argued against by many gay activists, while primary public health officials and leaders in ethnic communities continue to support this as a means of identifying unknown cases. Human immunodeficiency virus-positive patients were interviewed to determine if partner notification could be a useful instrument. Based on interviews, patients at risk of infection through heterosexual contact were able to identify most of their sexual partners; the majority of these patients were women. Twenty-two of 22 women infected heterosexually were able to identify all of their sexual partners. Five of 8 heterosexual men were able to identify all of their sexual partners, but these men were infected through intravenous drug use. Six of 44 homosexual men interviewed were able to make these identifications. Two focus groups of homosexual men who were HIV-positive patients were organized; each was asked one question. Men in group B were asked if they could identify HIV-positive persons whom they suspected were not in a treatment program. Men in group A were asked if they they thought they knew HIV-positive persons still practicing unsafe sex. Thirteen of the 14 patients in group A were able to identify 30 persons they felt were still practicing unsafe sex; 17 of 30 tested HIV-positive and 9 were unaware of their status. The 14 patients in group B identified 15 persons they felt were HIV-positive; 11 were found to be HIV-positive and 8 were unaware of their status. These findings suggest that partner notification definitely has a role in heterosexual contact tracing, and focused intervention is a more cost-effective approach to early intervention.

  10. Preliminary Results on Setup Precision of Prone-Lateral Patient Positioning for Whole Breast Irradiation

    SciTech Connect

    Veldeman, Liv; Speleers, Bruno; Bakker, Marlies; Jacobs, Filip; Coghe, Marc; De Gersem, Werner; Impens, Aline; Nechelput, Sarah; De Wagter, Carlos

    2010-09-01

    Purpose: The aim of this study was to develop a rapid and reproducible technique for prone positioning and to compare dose-volume indices in prone and supine positions. Methods and Materials: Eighteen patients underwent computed tomography imaging for radiotherapy planning in prone and supine position. Experience was gained in the first eight patients, which lead to modifications of the Horizon prone breast board (Civco Medical Solutions, Orange City, Iowa, USA) and the patient setup technique. A unilateral breast holder (U-BH) was developed (Van de Velde, Schellebelle, Belgium) to retract the contralateral breast away from the treated breast. The technique was then applied to an additional 10 patients. The setup precision was evaluated using daily cone-beam CT. Results: Modifications to the breast board were made to secure a prone-lateral rather then a pure prone position. We evolved from a classical setup using laser marks on the patients' body to a direct breast setup using marks on the breast only. The setup precision of the direct positioning procedure with the modified breast board and the U-BH is comparable to supine setup data in the literature. Dose-volume indices for heart and lung show significantly better results for prone than for supine position, and dose homogeneity within the treated breast did not differ according to the treatment position. Conclusions: The setup precision of our prone-lateral positioning technique is comparable to supine data in literature. Our data show the advantage of prone radiotherapy to spare the lung and heart. Further research is necessary to reduce the duration of prone setup.

  11. [The National Danish Survey of Patient Experiences has a small positive bias].

    PubMed

    Rosenstjerne Andersen, Angelo; Fuglsang, Marie; Kyed, Daisy

    2012-10-01

    The response rate in The National Danish Survey of Patient Experiences in 2009 was 54%. In order to evaluate bias due to non-responders, The Unit of Patient-perceived Quality merged survey data and data on patient background from Statistics Denmark. The relationships between the responding patients' background and their answers to six questions in the survey questionnaire are estimated with logistic regression analysis and subsequently used for predicting the answers of the non-responders. Results indicate a small positive bias in four of the questions and no bias in the remaining two.

  12. [Management of patients receiving home respiratory care with tracheostomy and positive-pressure ventilation].

    PubMed

    Aoki, Masashi

    2013-01-01

    On March 11, 2011, the Great East Japan Earthquake occurred and a massive tsunami hit the northeastern coast of Japan. In Miyagi prefecture in Tokoku district, 49 patients with amyotrophic lateral sclerosis were supported by home respiratory care with tracheostomy and positive-pressure ventilation at that time. Among them, two patients were died in the tsunami and 25 patients were forced to evacuate to hospitals. We should hurry to submit a guideline for medical transportation for patients with neuromuscular diseases requiring artificial ventilation. We also should research the disaster medicine in the field of neurology.

  13. Efficacy of prone position in acute respiratory distress syndrome patients: A pathophysiology-based review

    PubMed Central

    Koulouras, Vasilios; Papathanakos, Georgios; Papathanasiou, Athanasios; Nakos, Georgios

    2016-01-01

    Acute respiratory distress syndrome (ARDS) is a syndrome with heterogeneous underlying pathological processes. It represents a common clinical problem in intensive care unit patients and it is characterized by high mortality. The mainstay of treatment for ARDS is lung protective ventilation with low tidal volumes and positive end-expiratory pressure sufficient for alveolar recruitment. Prone positioning is a supplementary strategy available in managing patients with ARDS. It was first described 40 years ago and it proves to be in alignment with two major ARDS pathophysiological lung models; the “sponge lung” - and the “shape matching” -model. Current evidence strongly supports that prone positioning has beneficial effects on gas exchange, respiratory mechanics, lung protection and hemodynamics as it redistributes transpulmonary pressure, stress and strain throughout the lung and unloads the right ventricle. The factors that individually influence the time course of alveolar recruitment and the improvement in oxygenation during prone positioning have not been well characterized. Although patients’ response to prone positioning is quite variable and hard to predict, large randomized trials and recent meta-analyses show that prone position in conjunction with a lung-protective strategy, when performed early and in sufficient duration, may improve survival in patients with ARDS. This pathophysiology-based review and recent clinical evidence strongly support the use of prone positioning in the early management of severe ARDS systematically and not as a rescue maneuver or a last-ditch effort. PMID:27152255

  14. Predictive Factors of Spontaneous Bacterial Peritonitis Caused by Gram-Positive Bacteria in Patients With Cirrhosis.

    PubMed

    Kim, Jung Ho; Jeon, Yong Duk; Jung, In Young; Ahn, Mi Young; Ahn, Hea Won; Ahn, Jin Young; Ku, Nam Su; Han, Sang Hoon; Choi, Jun Yong; Ahn, Sang Hoon; Song, Young Goo; Han, Kwang Hyub; Kim, June Myung

    2016-04-01

    Spontaneous bacterial peritonitis (SBP) in patients with cirrhosis is typically caused by gram-negative bacteria. However, the number of SBP cases due to gram-positive bacteria is steadily increasing. To date, little is known about the predictive factors involved in SBP infections.We performed a retrospective cohort study of patients (>18 years) with SBP due to gram-positive and -negative bacteria who were enrolled from January 2006 to December 2013 at Severance Hospital in Seoul, Korea where the incidences of hepatitis B virus associated chronic liver disease, cirrhosis, and hepatocellular carcinoma are high. Only the 1st SBP episode for each patient within the study period was included in our analysis.We identified 77 patients with cirrhosis and SBP. Of these, 27 patients (35%) had gram-positive bacterial infections and 50 patients (65%) had gram-negative bacterial infections. Our univariate analysis revealed that an early stage of cirrhosis (P = 0.004), lower creatinine level (P = 0.011), lower Sequential Organ Failure Assessment (SOFA) score (P = 0.001), lower Model for End-Stage Liver Disease score (P = 0.005), and use of systemic antibiotics within 30 days before SBP diagnosis (P = 0.03) were significantly associated with gram-positive bacterial infections. Our multivariate analysis indicated that the use of systemic antibiotics within 30 days before SBP diagnosis (odds ratio, 3.94; 95% CI, 1.11-13.96; P = 0.033) and a lower SOFA score (odds ratio, 0.56; 95% CI, 0.37-0.86; P = 0.007) were independent predictive factors of SBP caused by gram-positive bacterial infections in patients with cirrhosis. However, we did not observe a statistically significant difference in the 28-day mortality between the gram-positive and -negative bacterial infection groups (40.7% vs 46.0%, respectively; P = 0.407).In this study, the incidence rate of SBP caused by gram-positive bacteria in patients with cirrhosis was similar to the rates reported

  15. Alkane hydroxylase gene (alkB) phylotype composition and diversity in northern Gulf of Mexico bacterioplankton

    PubMed Central

    Smith, Conor B.; Tolar, Bradley B.; Hollibaugh, James T.; King, Gary M.

    2013-01-01

    Natural and anthropogenic activities introduce alkanes into marine systems where they are degraded by alkane hydroxylases expressed by phylogenetically diverse bacteria. Partial sequences for alkB, one of the structural genes of alkane hydroxylase, have been used to assess the composition of alkane-degrading communities, and to determine their responses to hydrocarbon inputs. We present here the first spatially extensive analysis of alkB in bacterioplankton of the northern Gulf of Mexico (nGoM), a region that experiences numerous hydrocarbon inputs. We have analyzed 401 partial alkB gene sequences amplified from genomic extracts collected during March 2010 from 17 water column samples that included surface waters and bathypelagic depths. Previous analyses of 16S rRNA gene sequences for these and related samples have shown that nGoM bacterial community composition and structure stratify strongly with depth, with distinctly different communities above and below 100 m. Although we hypothesized that alkB gene sequences would exhibit a similar pattern, PCA analyses of operational protein units (OPU) indicated that community composition did not vary consistently with depth or other major physical-chemical variables. We observed 22 distinct OPUs, one of which was ubiquitous and accounted for 57% of all sequences. This OPU clustered with AlkB sequences from known hydrocarbon oxidizers (e.g., Alcanivorax and Marinobacter). Some OPUs could not be associated with known alkane degraders, however, and perhaps represent novel hydrocarbon-oxidizing populations or genes. These results indicate that the capacity for alkane hydrolysis occurs widely in the nGoM, but that alkane degrader diversity varies substantially among sites and responds differently than bulk communities to physical-chemical variables. PMID:24376439

  16. Study of Bortezomib and Panobinostat in Treating Patients With Relapsed/Refractory Peripheral T-cell Lymphoma or NK/T-cell Lymphoma

    ClinicalTrials.gov

    2014-06-26

    Peripheral T-cell Lymphoma (Not Otherwise Specified); Angioimmunoblastic T-cell Lymphoma; Extranodal NK/T-cell Lymphoma Nasal Type; Enteropathy- Type T-cell Lymphoma; Hepatosplenic T-cell Lymphoma; Anaplastic Large Cell Lymphoma (ALCL) (ALK-1 Negative); Relapsed ALCL (ALK-1 Positive) Post Autologous Transplant

  17. Body positions and movement patterns in female patients with congenital adrenal hyperplasia.

    PubMed

    Dittmann, R W

    1992-12-01

    Female patients with congenital adrenal hyperplasia (CAH; N = 33; 11-41 years), simple-virilizing (SV) patients (N = 19), salt-wasting (SW) patients (N = 13), and sister controls (N = 14) were compared with regard to their body positions and movement patterns. Data collection comprised both self assessments and mothers' assessments using 20 sex-dimorphic items with corresponding "more masculine" and "more feminine" versions for each variable, represented in photographs (forced-choice approach). Primarily based on mothers' assessments, single-item results suggested slightly more masculine positions and patterns for female CAH patients compared to sisters, for SW patients more distinct than for SV patients. Results from an 11-item scale ("motor behavior", alpha = 0.59) revealed differences between SW (more masculine) and SV patients for self assessments (P, one-tailed, < 0.09); sisters were in an intermediate position closer to the SV patients. According to mothers' assessments, the CAH patient group as a whole differed (more masculine) from sisters (P < 0.06); this finding was mainly accounted for by the SW group (P < 0.04). Complex analyses on the relationship of motor behavior and intervening variables (e.g., postnatal androgenization, onset of puberty, menarche, height, weight, sexual orientation) revealed very few significant results. Findings rather suggested organizational hormonal effects on body positions and movements prenatally; they are in line with main results from the interview section of the Hamburg CAH study (e.g., "Gender-related behavior"). An approach of this kind seems to be justified for investigating motor behavior in future psychoendocrine studies.

  18. Recurrent focal epithelial hyperplasia due to HPV13 in an HIV-positive patient.

    PubMed

    Moerman, M; Danielides, V G; Nousia, C S; Van Wanzeele, F; Forsyth, R; Vermeersch, H

    2001-01-01

    There are few reports on focal epithelial hyperplasia (FEH) in association with human immunodeficiency virus (HIV) infection; thus the relationship between them has not been completely clarified yet. We present a case of recurrent FEH in an HIV-positive man (the first described in Belgium), which, according to the PCR-DNA testing, was due to human papilloma virus type 13 (HPV13). To our knowledge, based on the accessible literature, this type of HPV has not been detected in any other documented study of FEH in HIV-positive patients before. Our patient experienced three recurrences of FEH in 1 year. It is therefore suggested that immunodeficiency due to HIV infection is responsible for the HPV-related FEH and the subsequent recurrences. In order to support the consideration of FEH as an oral manifestation of an HIV-related opportunistic infection, every new 'HPV-type' oral lesion in HIV-positive patients must be completely documented.

  19. Albumin induces excitatory synaptogenesis through astrocytic TGF-β/ALK5 signaling in a model of acquired epilepsy following blood-brain barrier dysfunction

    PubMed Central

    Weissberg, Itai; Wood, Lydia; Kamintsky, Lyn; Vazquez, Oscar; Milikovsky, Dan Z.; Alexander, Allyson; Oppenheim, Hannah; Ardizzone, Carolyn; Becker, Albert; Frigerio, Federica; Vezzani, Annamaria; Buckwalter, Marion S.; Huguenard, John; Friedman, Alon; Kaufer, Daniela

    2015-01-01

    Post injury epilepsy (PIE) is a common complication following brain insults, including ischemic and traumatic brain injuries. At present there are no means to identify the patients at-risk to develop PIE or to prevent its development. Seizures can occur months or years after the insult, do not respond to anti-seizure medications in over third of the patients, and are often associated with significant neuropsychiatric morbidities. We have previously established the critical role of blood-brain barrier dysfunction in PIE, demonstrating that exposure of brain tissue to extravasated serum albumin induces activation of inflammatory transforming growth factor beta (TGF-β) signaling in astrocytes and eventually seizures. However, the link between the acute astrocytic inflammatory responses and reorganization of neural networks that underlie recurrent spontaneous seizures, remains unknown. Here we demonstrate in-vitro and in-vivo that activation of the astrocytic ALK5/TGF-β-pathway induces excitatory, but not inhibitory, synaptogenesis that precedes the appearance of seizures. Moreover, we show that treatment with SJN2511, a specific ALK5/TGF-β inhibitor, prevents synaptogenesis and epilepsy. Our findings point to astrocyte-mediated synaptogenesis as a key epileptogenic process, and highlight manipulation of the TGF-β-pathway as a potential strategy for the prevention of PIE. PMID:25836421

  20. Albumin induces excitatory synaptogenesis through astrocytic TGF-β/ALK5 signaling in a model of acquired epilepsy following blood-brain barrier dysfunction.

    PubMed

    Weissberg, Itai; Wood, Lydia; Kamintsky, Lyn; Vazquez, Oscar; Milikovsky, Dan Z; Alexander, Allyson; Oppenheim, Hannah; Ardizzone, Carolyn; Becker, Albert; Frigerio, Federica; Vezzani, Annamaria; Buckwalter, Marion S; Huguenard, John R; Friedman, Alon; Kaufer, Daniela

    2015-06-01

    Post-injury epilepsy (PIE) is a common complication following brain insults, including ischemic, and traumatic brain injuries. At present, there are no means to identify the patients at risk to develop PIE or to prevent its development. Seizures can occur months or years after the insult, do not respond to anti-seizure medications in over third of the patients, and are often associated with significant neuropsychiatric morbidities. We have previously established the critical role of blood-brain barrier dysfunction in PIE, demonstrating that exposure of brain tissue to extravasated serum albumin induces activation of inflammatory transforming growth factor beta (TGF-β) signaling in astrocytes and eventually seizures. However, the link between the acute astrocytic inflammatory responses and reorganization of neural networks that underlie recurrent spontaneous seizures remains unknown. Here we demonstrate in vitro and in vivo that activation of the astrocytic ALK5/TGF-β-pathway induces excitatory, but not inhibitory, synaptogenesis that precedes the appearance of seizures. Moreover, we show that treatment with SJN2511, a specific ALK5/TGF-β inhibitor, prevents synaptogenesis and epilepsy. Our findings point to astrocyte-mediated synaptogenesis as a key epileptogenic process and highlight the manipulation of the TGF-β-pathway as a potential strategy for the prevention of PIE.

  1. HIV positive patients first presenting with an AIDS defining illness: characteristics and survival.

    PubMed Central

    Poznansky, M. C.; Coker, R.; Skinner, C.; Hill, A.; Bailey, S.; Whitaker, L.; Renton, A.; Weber, J.

    1995-01-01

    OBJECTIVES--To study the presentation and survival of patients who present with their first diagnosis of being HIV positive at the same time as their AIDS defining illness. DESIGN--Retrospective study of patients presenting with AIDS between 1991 and 1993. SETTING--Department of genitourinary medicine, St Mary's Hospital, London. MAIN OUTCOME MEASURES--AIDS defining illness at presentation and survival after diagnosis of AIDS. RESULTS--Between January 1991 and December 1993, 97 out of 436 patients (22%) presented with their first AIDS defining illness coincident with their first positive result of an HIV test (group B). The remaining 339 patients (78%) had tested positive for HIV-1 infection within the previous eight years and had consequently been followed up in clinics before developing their first AIDS defining illness (group A). The two groups of patients did not differ in age and sex distribution, risk factors for HIV-1 infection, nationality, country of origin, or haematological variables determined at the time of the AIDS defining illness. However, the defining illnesses differed between the two groups. Illnesses associated with severe immunodeficiency (the wasting syndrome, cryptosporidiosis, and cytomegalovirus infection) were seen almost exclusively in group A whereas extrapulmonary tuberculosis and Pneumocystis carinii pneumonia were more common in group B. The survival of patients in group B after the onset of AIDS was significantly longer than that of patients in group A as determined by Kaplan-Meier log rank analysis (P = 0.0026). CONCLUSIONS--Subjects who are HIV positive and present late are a challenge to the control of the spread of HIV infection because they progress from asymptomatic HIV infection to AIDS without receiving health care. The finding that presentation with an AIDS defining illness coincident with a positive result in an HIV test did not have a detrimental effect on survival gives insights into the effects of medical intervention on

  2. A positive Babinski reflex predicts delayed neuropsychiatric sequelae in Chinese patients with carbon monoxide poisoning.

    PubMed

    Zou, Jian-Fang; Guo, Qiming; Shao, Hua; Li, Bin; Du, Yuxiu; Liu, Maofeng; Liu, Fengling; Dai, Lixin; Chung, Min-Hsien; Lin, Hung-Jung; Guo, How-Ran; Yang, Tzu-Meng; Huang, Chien-Cheng; Hsu, Chien-Chin

    2014-01-01

    As the human population increased in China, the carbon monoxide is a serious environmental toxin in public health. However, predicting the delayed neuropsychiatric sequelae (DNS) of carbon monoxide poisoning (COP) has not been well studied. We investigated the independent predictors of DNS in patients with COP. This study was conducted at four hospitals in China. Data were retrospectively collected from 258 patients with COP between November 1990 and October 2011. DNS was the primary endpoint. A positive Babinski reflex was the independent predictor for DNS: sensitivity = 53.8% (95% confidence interval [CI]: 26.1-79.6), specificity = 88.6% (95% CI: 83.7-92.1), positive predictive value (PPV) = 20.0% (95% CI: 9.1-37.5), and negative predictive value (NPV) = 97.3% (95% CI: 94.0-98.9). The area under the receiver operating characteristic curve = 0.712 (95% CI: 0.544-0.880). A positive Babinski reflex was very memorable, immediately available, and applicable in clinical practice. Even when the sensitivity and PPV of a positive Babinski reflex were unsatisfactory, it had a good specificity and NPV for excluding the risk of DNS. In patients without a positive Babinski reflex, the risk for DNS was only 2.7%. This finding may help physicians make decisions about dispositions for patients with COP.

  3. Cytokeratin-positive cells in bone marrow of breast cancer patients and noncancer donors

    PubMed Central

    Krag, David N.; Kusminsky, Roberto; Manna, Edward; Weaver, Donald; Harlow, Seth P.; Covelli, Michael; Stanley, Mary A.; McCahill, Laurence; Ittleman, Frank; Leavitt, Bruce; Krag, Martin; Amarante, Patricia

    2009-01-01

    Detection of disseminated tumor cells in the bone marrow may provide important prognostic information in breast cancer patients. With few exceptions the number of stained cells scored as cancer is very low; there may be only one cell per slide. This makes definitive interpretation of cancer in marrow challenging. False-positive staining of marrow cells with cytokeratin (CK) antibody is relatively common and makes interpretation more difficult. In this report we focus on false-positive staining of marrow specimens from breast cancer patients and noncancer controls and demonstrate that the frequency of false positive events is common. Bone marrow was collected from 23 cancer-free donors and 60 breast cancer patients. Samples were processed by Ficoll density gradient centrifugation and slides were prepared for immunocytochemical staining with CK and irrelevant (IR) antibody. Slides were evaluated manually and positive cells were categorized as tumor cells (TCs), hematopoetic cells (HCs), or questionable cells (QCs). False-positive staining events were commonly observed in noncancer cases stained with CK or IR antibodies and in breast cancer cases stained with IR antibody. There was little difference in the number of breast cancer marrow specimens scored as tumor cells regardless of whether the antibody used was CK or IR. It is important to devise improved criteria and methods for accurate detection and interpretation of disseminated tumor cells in the marrow of breast cancer patients. PMID:19417625

  4. The Universal Patient Centeredness Questionnaire: scaling approaches to reduce positive skew

    PubMed Central

    Bjertnaes, Oyvind; Iversen, Hilde Hestad; Garratt, Andrew M

    2016-01-01

    Purpose Surveys of patients’ experiences typically show results that are indicative of positive experiences. Unbalanced response scales have reduced positive skew for responses to items within the Universal Patient Centeredness Questionnaire (UPC-Q). The objective of this study was to compare the unbalanced response scale with another unbalanced approach to scaling to assess whether the positive skew might be further reduced. Patients and methods The UPC-Q was included in a patient experience survey conducted at the ward level at six hospitals in Norway in 2015. The postal survey included two reminders to nonrespondents. For patients in the first month of inclusion, UPC-Q items had standard scaling: poor, fairly good, good, very good, and excellent. For patients in the second month, the scaling was more positive: poor, good, very good, exceptionally good, and excellent. The effect of scaling on UPC-Q scores was tested with independent samples t-tests and multilevel linear regression analysis, the latter controlling for the hierarchical structure of data and known predictors of patient-reported experiences. Results The response rate was 54.6% (n=4,970). Significantly lower scores were found for all items of the more positively worded scale: UPC-Q total score difference was 7.9 (P<0.001), on a scale from 0 to 100 where 100 is the best possible score. Differences between the four items of the UPC-Q ranged from 7.1 (P<0.001) to 10.4 (P<0.001). Multivariate multilevel regression analysis confirmed the difference between the response groups, after controlling for other background variables; UPC-Q total score difference estimate was 8.3 (P<0.001). Conclusion The more positively worded scaling significantly lowered the mean scores, potentially increasing the sensitivity of the UPC-Q to identify differences over time and between providers. However, none of the groups exhibited large positive skew and ceiling effects, implying that such effects might not be a big

  5. Listeria monocytogenes meningitis in a human immunodeficiency virus-positive patient undergoing hemodialysis.

    PubMed

    Calubiran, O V; Horiuchi, J; Klein, N C; Cunha, B A

    1990-01-01

    Listeria monocytogenes bacteremia without meningitis has been reported in patients who have undergone long-term hemodialysis and have transfusional iron overload. On the other hand, cases of Listeria bacteremia without meningitis have occurred sporadically among the acquired immunodeficiency syndrome population, mostly homosexuals. There have been no reports of Listeria meningitis occurring among persons who are antibody positive to human immunodeficiency virus or are intravenous drug abusers having chronic renal failure and undergoing hemodialysis. This patient represents the first case of Listeria bacteremia and meningitis to occur in an intravenous drug abuser who is human immunodeficient antibody positive, is receiving hemodialysis, and has transfusional iron overload.

  6. Correlation between sperm DNA fragmentation index and CMA3 positive spermatozoa in globozoospermic patients.

    PubMed

    Hosseinifar, H; Yazdanikhah, S; Modarresi, T; Totonchi, M; Sadighi Gilani, M A; Sabbaghian, M

    2015-05-01

    The absence of the acrosome causes the situation which is called globozoospermia. There are a few studies, mostly as case reports, about correlation between levels of sperm DNA damage in patients with total round-headed spermatozoa. We investigated this correlation as well as CMA3 positive spermatozoa in 20 globozoospermic men (with more than 90% round-headed spermatozoa) attending to Royan Institute. Semen samples divided into three parts to semen analysis, to measure DNA fragmentation index (DFI) using sperm chromatin structure assay (SCSA) and to detect CMA3(+) sperm cells by chromomycin A3 staining and fluorescent microscopy. Our results showed that there were significant differences in sperm concentration, total sperm motility, and normal morphology between patients and controls group (p < 0.001). Moreover, the average of DFI and CMA3 positive spermatozoa in patients group significantly increases compared with control group (p < 0.001). A significant correlation between DFI and CMA3(+) in total population was also detected in patients group (r = 0.45, p = 0.046). To our knowledge, this is the largest study about correlation between DNA damage levels and CMA3 positive spermatozoa with round head sperm cells in total globozoospermic men. It seems that the increase in DNA damage may be because of defective sperm DNA compaction, as we detected CMA3 positive sperm cells in these patients.

  7. Dasatinib and low-intensity chemotherapy in elderly patients with Philadelphia chromosome–positive ALL

    PubMed Central

    Coudé, Marie Magdelaine; Gokbuget, Nicola; Gambacorti Passerini, Carlo; Hayette, Sandrine; Cayuela, Jean-Michel; Huguet, Françoise; Leguay, Thibaut; Chevallier, Patrice; Salanoubat, Celia; Bonmati, Caroline; Alexis, Magda; Hunault, Mathilde; Glaisner, Sylvie; Agape, Philippe; Berthou, Christian; Jourdan, Eric; Fernandes, José; Sutton, Laurent; Banos, Anne; Reman, Oumedaly; Lioure, Bruno; Thomas, Xavier; Ifrah, Norbert; Lafage-Pochitaloff, Marina; Bornand, Anne; Morisset, Laure; Robin, Valérie; Pfeifer, Heike; Delannoy, Andre; Ribera, Josep; Bassan, Renato; Delord, Marc; Hoelzer, Dieter; Dombret, Herve; Ottmann, Oliver G.

    2016-01-01

    Prognosis of Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) in the elderly has improved during the imatinib era. We investigated dasatinib, another potent tyrosine kinase inhibitor, in combination with low-intensity chemotherapy. Patients older than age 55 years were included in the European Working Group on Adult ALL (EWALL) study number 01 for Ph+ ALL (EWALL-PH-01 international study) and were treated with dasatinib 140 mg/day (100 mg/day over 70 years) with intrathecal chemotherapy, vincristine, and dexamethasone during induction. Patients in complete remission continued consolidation with dasatinib, sequentially with cytarabine, asparaginase, and methotrexate for 6 months. Maintenance therapy was dasatinib and vincristine/dexamethasone reinductions for 18 months followed by dasatinib until relapse or death. Seventy-one patients with a median age of 69 years were enrolled; 77% had a high comorbidity score. Complete remission rate was 96% and 65% of patients achieved a 3-log reduction in BCR-ABL1 transcript levels during consolidation. Only 7 patients underwent allogeneic hematopoietic stem cell transplantation. At 5 years, overall survival was 36% and up to 45% taking into account deaths unrelated to disease or treatment as competitors. Thirty-six patients relapsed, 24 were tested for mutation by Sanger sequencing, and 75% were T315I-positive. BCR-ABL1T315I was tested by allele-specific oligonucleotide reverse transcription–quantitative polymerase chain reaction in 43 patients and detection was associated with short-term relapses. Ten patients (23%) were positive before any therapy and 8 relapsed, all with this mutation. In conclusion, dasatinib combined with low-intensity chemotherapy was well-tolerated and gave long-term survival in 36% of elderly patients with Ph+ ALL. Monitoring of BCR-ABL1T315I from diagnosis identified patients with at high risk of early relapse and may help to personalize therapy. PMID:27121472

  8. De-escalation, adequacy of antibiotic therapy and culture positivity in septic patients: an observational study

    PubMed Central

    Moraes, Rafael Barberena; Guillén, Julián Alberto Viteri; Zabaleta, William Javier Castillo; Borges, Flavia Kessler

    2016-01-01

    Objective To evaluate the prevalence of antibiotic de-escalation in patients diagnosed with severe sepsis or septic shock at a public academic tertiary hospital and to evaluate antibiotic adequacy and culture positivity. Methods The prevalence of antibiotic de-escalation, the adequacy of antibiotic treatment and the rates of culture positivity were analyzed in patients with severe sepsis and septic shock between April and December 2013 at an intensive care unit in a tertiary university hospital. Results Among the 224 patients included in the study, de-escalation was appropriate in 66 patients (29.4%) but was implemented in 44 patients (19.6%). Among the patients who underwent de-escalation, half experienced narrowing of the antimicrobial spectrum. The mortality rate was 56.3%, with no differences between the patients with or without de-escalation (56.8% versus 56.1%; p = 0.999) nor in the length of hospital stay. Empirical antibiotic therapy was appropriate in 89% of cases. Microorganisms were isolated from total cultures in 30% of cases and from blood cultures in 26.3% of cases. Conclusion The adequacy rate of empirical antibiotic therapy was high, reflecting an active institutional policy of monitoring epidemiological profiles and institutional protocols on antimicrobial use. However, antibiotic de-escalation could have been implemented in a greater number of patients. De-escalation did not affect mortality rates. PMID:27626951

  9. Predicting Likelihood of Having Four or More Positive Nodes in Patient With Sentinel Lymph Node-Positive Breast Cancer: A Nomogram Validation Study

    SciTech Connect

    Unal, Bulent; Gur, Akif Serhat; Beriwal, Sushil; Tang Gong; Johnson, Ronald; Ahrendt, Gretchen; Bonaventura, Marguerite; Soran, Atilla

    2009-11-15

    Purpose: Katz suggested a nomogram for predicting having four or more positive nodes in sentinel lymph node (SLN)-positive breast cancer patients. The findings from this formula might influence adjuvant radiotherapy decisions. Our goal was to validate the accuracy of the Katz nomogram. Methods and Materials: We reviewed the records of 309 patients with breast cancer who had undergone completion axillary lymph node dissection. The factors associated with the likelihood of having four or more positive axillary nodes were evaluated in patients with one to three positive SLNs. The nomogram developed by Katz was applied to our data set. The area under the curve of the corresponding receiver operating characteristics curve was calculated for the nomogram. Results: Of the 309 patients, 80 (25.9%) had four or more positive axillary lymph nodes. On multivariate analysis, the number of positive SLNs (p < .0001), overall metastasis size (p = .019), primary tumor size (p = .0001), and extracapsular extension (p = .01) were significant factors predicting for four or more positive nodes. For patients with <5% probability, 90.3% had fewer than four positive nodes and 9.7% had four or more positive nodes. The negative predictive value was 91.7%, and sensitivity was 80%. The nomogram was accurate and discriminating (area under the curve, .801). Conclusion: The probability of four or more involved nodes is significantly greater in patients who have an increased number of positive SLNs, increased overall metastasis size, increased tumor size, and extracapsular extension. The Katz nomogram was validated in our patients. This nomogram will be helpful to clinicians making adjuvant treatment recommendations to their patients.

  10. EPIDEMIOLOGICAL AND ORAL MANIFESTATIONS OF HIV-POSITIVE PATIENTS IN A SPECIALIZED SERVICE IN BRAZIL

    PubMed Central

    Pedreira, Erick Nelo; Cardoso, Camila Lopes; Barroso, Éder do Carmo; Santos, Jorge André de Souza; Fonseca, Felipe Paiva; Taveira, Luís Antônio de Assis

    2008-01-01

    The purpose of this study was to evaluate the prevalence of oral lesions in HIV-positive patients attending the Specialized Service for Infectious-contagious Diseases and Parasitoses of the Health Secretariat of the State of Pará (URE-DIPE/SESPA), in the city of Belém, PA, Brazil. A total of 79 HIV-positive patients (53 males and 26 females) were examined. Clinical and epidemiological evaluations were done by correlating the lesions with gender, race, chronological age, risk behavior and prevailing immune status (CD4+ cells count). Lesion location and the presence of associated factors, such as alcohol use, smoking and denture wearing, were quantified individually for each type of lesion using a diagnostic pattern based on the clinical aspects. Approximately 47% of the patients (n=37) presented some type of oral lesion. Candidiasis (28%) and periodontal disease (28%) were the most common, followed by cervical-facial lymphadenopathy (17.5%). Other lesions observed were hairy leukoplakia, melanin hyperpigmentation, ulcerative stomatitis (aphthous), herpes simplex, frictional keratosis and pyogenic granuloma. This analysis presented some relevance as to the statistical data. Concerning CD4+ cells, most lesions manifested with the reduction of the CD count. There were a larger number of HIV-positive female heterosexual patients. Alcohol and/or smoking were strongly associated with the occurrence of hairy leukoplakia in these patients. Candidiasis and periodontal disease were the most common oro-regional clinical manifestations in the patients. PMID:19082393

  11. In vivo imaging models of bone and brain metastases and pleural carcinomatosis with a novel human EML4-ALK lung cancer cell line.

    PubMed

    Nanjo, Shigeki; Nakagawa, Takayuki; Takeuchi, Shinji; Kita, Kenji; Fukuda, Koji; Nakada, Mitsutoshi; Uehara, Hisanori; Nishihara, Hiroshi; Hara, Eiji; Uramoto, Hidetaka; Tanaka, Fumihiro; Yano, Seiji

    2015-03-01

    EML4-ALK lung cancer accounts for approximately 3-7% of non-small-cell lung cancer cases. To investigate the molecular mechanism underlying tumor progression and targeted drug sensitivity/resistance in EML4-ALK lung cancer, clinically relevant animal models are indispensable. In this study, we found that the lung adenocarcinoma cell line A925L expresses an EML4-ALK gene fusion (variant 5a, E2:A20) and is sensitive to the ALK inhibitors crizotinib and alectinib. We further established highly tumorigenic A925LPE3 cells, which also have the EML4-ALK gene fusion (variant 5a) and are sensitive to ALK inhibitors. By using A925LPE3 cells with luciferase gene transfection, we established in vivo imaging models for pleural carcinomatosis, bone metastasis, and brain metastasis, all of which are significant clinical concerns of advanced EML4-ALK lung cancer. Interestingly, crizotinib caused tumors to shrink in the pleural carcinomatosis model, but not in bone and brain metastasis models, whereas alectinib showed remarkable efficacy in all three models, indicative of the clinical efficacy of these ALK inhibitors. Our in vivo imaging models of multiple organ sites may provide useful resources to analyze further the pathogenesis of EML4-ALK lung cancer and its response and resistance to ALK inhibitors in various organ microenvironments.

  12. First-referral presentations of patients with benign paroxysmal positional vertigo who were negative on positional testing and who lacked nystagmus.

    PubMed

    Tan, Jun; Yu, Dongzhen; Feng, Yanmei; Song, Qiang; You, Jin; Shi, Haibo; Yin, Shankai

    2015-11-01

    The aim of the present study was to explore the demographic, clinical, and pathogenetic features; and treatment outcomes of patients with benign paroxysmal positional vertigo (BPPV) who were negative upon positional testing at their first referral. A total of 133 patients presented with histories of BPPV but were negative, in our hands, upon positional testing. Patients were told to cease taking vestibular suppressant medication (if any) and were to return for re-examination when positional vertigo symptoms recurred. If BPPV was diagnosed, the appropriate repositioning maneuver was applied and patients were re-examined weekly until the characteristic nystagmus and vertigo disappeared. Follow-up was performed 1 week, 4 weeks, 3 months, 6 months, and 1 year after diagnosis. The 133 patients were compared with a group of 250 patients with typical BPPV. Sixty-five of the 133 patients (termed the n-BPPV group) were subsequently identified with typical BPPV. Such diagnoses were made within 10 days of the first referral in 37 (56.9%) cases. Patients of the n-BPPV group had a longer duration of the last episode of vertigo than did others (39.7 ± 38.4 vs. 26.1 ± 36.7 days, p < 0.001), and a higher proportion used vestibular suppressant medication prior to first referral (75.4 vs. 54.8%, p = 0.003). The n-BPPV and typical BPPV patients responded similarly to treatment and exhibited similar recurrence rates. BPPV patients who were negative upon positional testing at first referral were quite common, accounting for 26% of all typical BPPV patients. No significant difference in either treatment outcome or recurrence rate was evident between n-BPPV and typical BPPV positions. Positional vertigo and nystagmus are not always present as BPPV progresses.

  13. Clinical characteristics of patients who test positive for Clostridium difficile by repeat PCR.

    PubMed

    Green, Daniel A; Stotler, Brie; Jackman, Dana; Whittier, Susan; Della-Latta, Phyllis

    2014-11-01

    The high sensitivity of PCR assays for diagnosing Clostridium difficile infection (CDI) has greatly reduced the need for repeat testing after a negative result. Nevertheless, a small subset of patients do test positive within 7 days of a negative test. The aim of this study was to evaluate the clinical characteristics of these patients to determine when repeat testing may be appropriate. The results of all Xpert C. difficile PCR (Cepheid, Sunnyvale CA) tests performed in the clinical microbiology laboratory at New York-Presbyterian Hospital, Columbia University Medical Center (NYPH/CUMC) from 1 May 2011 through 6 September 2013, were reviewed. A retrospective case-control study was performed, comparing patients who tested positive within 7 days of a negative test result to a random selection of 50 controls who tested negative within 7 days of a negative test result. During the study period, a total of 14,875 tests were performed, of which 1,066 were repeat tests (7.2%). Eleven of these repeat tests results were positive (1.0%). The only risk factor independently associated with repeat testing positive was history of a prior CDI (odds ratio [OR], 19.6 [95% confidence interval {CI}, 4.0 to 19.5], P < 0.001). We found that patients who test positive for C. difficile by PCR within 7 days of a negative test are more likely to have a history of CDI than are patients who test negative with repeat PCR. This finding may be due to the high rate of disease relapse or the increased likelihood of empirical therapy leading to false-negative results in these patients.

  14. Class, type and position of 9148 surgically removed third molars in 3206 patients: A retrospective study

    PubMed Central

    Rocha-Navarro, Miriam L.; Acosta-Veloz, Anselmo L.; Juárez-Hernández, Angélica

    2012-01-01

    Objective: To investigate the class, type, position, diagnosis and most common procedures used in the surgical removal of third molars, and evaluate the sex and age distribution in a representative sample of Mexican patients. Study Design: A retrospective descriptive study was made covering the period 1993-2008 in relation to 9148 extracted third molars in 3206 patients treated in the Dental School of Salle Bajío University, A.C. (Mexico). Patients of either sex and aged 11-59 years, with at least one third molar programmed for surgical removal, were included in the study. A descriptive statistical study was made. Results: The mean patient age was 27.6 ± 10.6 years. There were 2093 females (65.3%) and 1111 males (34.6%). In relation to the 4025 upper molars, extraction was decided for prophylactic reasons in 3827 cases (95.08%). Type A presentations were recorded in 1929 cases (47.9%), with a vertical position in 1931 teeth (48%). In relation to the 5123 lower third molars, extraction was likewise most often indicated for prophylactic reasons (4424 cases, 86.36%). A total of 2353 teeth corresponded to type A (45.9%), 2545 were class I cases (49.7%), and a mesioangular position was observed in 1850 cases (36.1%). Conclusions: The present study shows that in Mexican patients, upper third molars most often correspond to type A and class I, with a vertical position, while lower third molars predominantly correspond to type A and class I, with a mesioangular position. This information can help dental surgeons take better decisions before and after surgery, to the benefit of their patients. Key words:Third molars, retrospective review, surgical removal. PMID:22143723

  15. A mapping of people's positions regarding the breaking of bad news to patients.

    PubMed

    Igier, Valérie; Muñoz Sastre, María Teresa; Sorum, Paul Clay; Mullet, Etienne

    2015-01-01

    The objective of this study was to map people's positions regarding the breaking of bad news to patients. One hundred forty adults who had in the past received bad medical news or whose elderly relatives had in the past received bad news, 25 nurses, and 28 nurse's aides indicated the acceptability of physicians' conduct in 72 vignettes of giving bad news to elderly patients. Vignettes were all combinations of five factors: (a) the severity of the disease (severe but not lethal, extremely severe and possibly lethal, or incurable), (b) the patient's wishes (insists on knowing the full truth vs. does not insist), (c) the level of social support during hospitalization, (d) the patient's psychological robustness, and (e) the physician's decision about communicating bad news (tell the patient that the illness is not severe and minimize the severity of the illness when talking to the patient's relatives, tell the full truth to her relatives, or tell the full truth to both the elderly patient and her relatives). Four qualitatively different positions were found. Twenty-eight percent of participants preferred the full truth to be told; 36% preferred the truth to be told but understood that the physician would inform the family first; 13% did not think that telling the full truth is best for patients; and 23% understood that the full truth would be told in some cases and not in others, depending on the physician's perception of the situation. The present mapping could be used to detect the position held by each patient and act accordingly. This would be made easier if breaking bad news was conceived as a communication process involving a range of health care professionals, rather than as a single occurrence in time.

  16. A novel method for interactive multi-objective dose-guided patient positioning

    NASA Astrophysics Data System (ADS)

    Haehnle, Jonas; Süss, Philipp; Landry, Guillaume; Teichert, Katrin; Hille, Lucas; Hofmaier, Jan; Nowak, Dimitri; Kamp, Florian; Reiner, Michael; Thieke, Christian; Ganswindt, Ute; Belka, Claus; Parodi, Katia; Küfer, Karl-Heinz; Kurz, Christopher

    2017-01-01

    In intensity-modulated radiation therapy (IMRT), 3D in-room imaging data is typically utilized for accurate patient alignment on the basis of anatomical landmarks. In the presence of non-rigid anatomical changes, it is often not obvious which patient position is most suitable. Thus, dose-guided patient alignment is an interesting approach to use available in-room imaging data for up-to-date dose calculation, aimed at finding the position that yields the optimal dose distribution. This contribution presents the first implementation of dose-guided patient alignment as multi-criteria optimization problem. User-defined clinical objectives are employed for setting up a multi-objective problem. Using pre-calculated dose distributions at a limited number of patient shifts and dose interpolation, a continuous space of Pareto-efficient patient shifts becomes accessible. Pareto sliders facilitate interactive browsing of the possible shifts with real-time dose display to the user. Dose interpolation accuracy is validated and the potential of multi-objective dose-guided positioning demonstrated for three head and neck (H&N) and three prostate cancer patients. Dose-guided positioning is compared to replanning for all cases. A delineated replanning CT served as surrogate for in-room imaging data. Dose interpolation accuracy was high. Using a 2 % dose difference criterion, a median pass-rate of 95.7% for H&N and 99.6% for prostate cases was determined in a comparison to exact dose calculations. For all patients, dose-guided positioning allowed to find a clinically preferable dose distribution compared to bony anatomy based alignment. For all H&N cases, mean dose to the spared parotid glands was below 26~\\text{Gy} (up to 27.5~\\text{Gy} with bony alignment) and clinical target volume (CTV) {{V}95 % } above 99.1% (compared to 95.1%). For all prostate patients, CTV {{V}95 % } was above 98.9% (compared to 88.5%) and {{V}50~\\text{Gy}} to the rectum below 50 % (compared to 56

  17. Treatment outcome of new smear positive pulmonary tuberculosis patients in Penang, Malaysia

    PubMed Central

    2014-01-01

    Background According to the World Health Organization’s recent report, in Malaysia, tuberculosis (TB) treatment success rate for new smear positive pulmonary tuberculosis (PTB) patients is still below the global success target of 85%. In this study, we evaluated TB treatment outcome among new smear positive PTB patients, and identified the predictors of unsuccessful treatment outcome and longer duration of treatment (i.e., > 6 months). Methods The population in this study consisted of all new smear positive PTB patients who were diagnosed at the chest clinic of Penang General Hospital between March 2010 and February 2011. During the study period, a standardized data collection form was used to obtain socio-demographic, clinical and treatment related data of the patients from their medical charts and TB notification forms (Tuberculosis Information System; TBIS). These data sources were reviewed at the time of the diagnosis of the patients and then at the subsequent follow-up visits until their final treatment outcomes were available. The treatment outcomes of the patients were reported in line with six outcome categories recommended by World Health Organization. Multiple logistic regression analysis was used to find the independent risk factors for unsuccessful treatment outcome and longer treatment duration. Data were analyzed using the PASW (Predictive Analysis SoftWare, version 19.0. Armonk, NY: IBM Corp). Results Among the 336 PTB patients (236 male and 100 female) notified during the study period, the treatment success rate was 67.26% (n = 226). Out of 110 patients in unsuccessful outcome category, 30 defaulted from the treatment, 59 died and 21 were transferred to other health care facilities. The mean duration of TB treatment was 8.19 (SD 1.65) months. In multiple logistic regression analysis, risk factors for unsuccessful treatment outcome were foreign nationality, male gender and being illiterate. Similarly, risk factors for mortality due to TB

  18. Mixed Infection Caused by Two Species of Fusarium in a Human Immunodeficiency Virus-Positive Patient

    PubMed Central

    Guarro, Josep; Nucci, Marcio; Akiti, Tiyomi; Gené, Josepa

    2000-01-01

    We report on a case of mixed infection caused by two species of Fusarium in a human immunodeficiency virus-positive patient with lymphoma who was neutropenic due to chemotherapy. The patient showed the typical signs of a disseminated fusarial infection, with Fusarium solani isolated from skin lesions and F. verticillioides isolated from blood. The report discusses how difficult it is to make an accurate diagnosis when an immunosuppressed patient is infected with more than one fungal species, especially when the species are morphologically very similar. PMID:10970404

  19. Is Radiation Indicated in Patients With Ductal Carcinoma In Situ and Close or Positive Mastectomy Margins?

    SciTech Connect

    Chan, Linda W.; Rabban, Joseph; Hwang, E. Shelley; Bevan, Alison; Alvarado, Michael; Ewing, Cheryl; Esserman, Laura; Fowble, Barbara

    2011-05-01

    Purpose: Resection margin status is one of the most significant factors for local recurrence in patients with ductal carcinoma in situ (DCIS) treated with breast-conserving surgery with or without radiation. However, its impact on chest wall recurrence in patients treated with mastectomy is unknown. The purpose of this study was to determine chest wall recurrence rates in women with DCIS and close (<5 mm) or positive mastectomy margins in order to evaluate the potential role of radiation therapy. Methods and Materials: Between 1985 and 2005, 193 women underwent mastectomy for DCIS. Fifty-five patients had a close final margin, and 4 patients had a positive final margin. Axillary surgery was performed in 17 patients. Median follow-up was 8 years. Formal pathology review was conducted to measure and verify margin status. Nuclear grade, architectural pattern, and presence or absence of necrosis was recorded. Results: Median pathologic size of the DCIS in the mastectomy specimen was 4.5 cm. Twenty-two patients had DCIS of >5 cm or diffuse disease. Median width of the close final margin was 2 mm. Nineteen patients had margins of <1 mm. One of these 59 patients experienced a chest wall recurrence with regional adenopathy, followed by distant metastases 2 years following skin-sparing mastectomy. The DCIS was high-grade, 4 cm, with a 5-mm deep margin. A second patient developed an invasive cancer in the chest wall 20 years after her mastectomy for DCIS. This cancer was considered a new primary site arising in residual breast tissue. Conclusions: The risk of chest wall recurrence in this series of patients is 1.7% for all patients and 3.3% for high-grade DCIS. One out of 20 (5%) patients undergoing skin sparing or total skin-sparing mastectomy experienced a chest wall recurrence. This risk of a chest wall recurrence appears sufficiently low not to warrant a recommendation for postmastectomy radiation therapy for patients with margins of <5 mm. There were too few patients

  20. Prevalence of thyroid disorders in hepatitis C virus positive patients on interferon and antiviral therapy

    PubMed Central

    Goyal, Gitanjali; Panag, KMDS; Garg, Ravinder

    2016-01-01

    Background: Hepatitis C virus (HCV) infection is common worldwide. The treatment typically involves a combination of interferon-alpha (IFN-α) and ribavirin (RBV) therapy; however, the use of IFN-α is well documented to be associated with thyroid disease, the most common autoimmune disorder associated with IFN-α. Aim: The aim of the present study was to know the prevalence of thyroid abnormality in the HCV-positive patients on IFN and antiviral therapy. Materials and Methods: Fifty known HCV positive patients were enrolled for the study. All the patients were on IFN (3 million unit subcutaneously 3 times/week) and antiviral therapy (oral RBV 1000–1200 mg/day). Thyroid function tests were performed first at the start of treatment and then after 12 weeks of treatment. Results: 13 (26%) of the patients were found to develop hypothyroidism, and 1 (2%) patient developed hyperthyroidism in the course of 12 weeks therapy. Conclusion: HCV patients on IFN and antiviral therapy have an effect on the thyroid gland, so these patients should be regularly screened for thyroid disorders and appropriately treated to maintain euthyroid status. PMID:27857890

  1. [The variety of symptoms in patients with benign paroxysmal positional vertigo--revision].

    PubMed

    Pollak, Lea

    2013-02-01

    Despite its frequent occurrence and effective treatment options, benign paroxysmal positional vertigo (BPPV) still remains underestimated in the community. Acquaintance of the physician with the various presentation symptoms assists in recognition of the entity. We report the complaints and subjective outcome in our cohort of BPPV patients and discuss the possible origin of the atypical, but common, symptoms.

  2. Assessing Riverside Community College Nursing Student Attitudes toward Exposure to AIDS/HIV-Positive Patients.

    ERIC Educational Resources Information Center

    Kross, Carolyn Sue

    In fall 1990, a study was conducted to assess the attitudes of nursing students who were attending Riverside Community College (RCC), in California, toward exposure to Acquired Immune Deficiency Syndrome/Human Immunodeficiency Virus (AIDS/HIV) positive patients in a hospital setting. All students enrolled in RCC's associate degree nursing program…

  3. Is patient confidentiality compromised with the electronic health record?: a position paper.

    PubMed

    Wallace, Ilse M

    2015-02-01

    In order for electronic health records to fulfill their expected benefits, protection of privacy of patient information is key. Lack of trust in confidentiality can lead to reluctance in disclosing all relevant information, which could have grave consequences. This position paper contemplates whether patient confidentiality is compromised by electronic health records. The position that confidentiality is compromised was supported by the four bioethical principles and argued that despite laws and various safeguards to protect patients' confidentiality, numerous data breaches have occurred. The position that confidentiality is not compromised was supported by virtue ethics and a utilitarian viewpoint and argued that safeguards keep information confidential and the public feels relatively safe with the electronic health record. The article concludes with an ethically superior position that confidentiality is compromised with the electronic health record. Although organizational and governmental ways of enhancing the confidentiality of patient information within the electronic health record facilitate confidentiality, the ultimate responsibility of maintaining confidentiality rests with the individual end-users and their ethical code of conduct. The American Nurses Association Code of Ethics for nurses calls for nurses to be watchful with data security in electronic communications.

  4. The Patient Protection and Affordable Care Act: The Role of the School Nurse. Position Statement

    ERIC Educational Resources Information Center

    Combe, Laurie G.; Sharpe, Susan; Feeser, Cynthia Jo; Ondeck, Lynnette; Fekaris, Nina

    2015-01-01

    It is the position of the National Association of School Nurses (NASN) that the registered professional school nurse (hereinafter referred to as school nurse) serves a vital role in the delivery of health care to our nation's students within the healthcare system reshaped by the Patient Protection and Affordable Care Act of 2010, commonly known as…

  5. Persistent Positional Vertigo in a Patient with Sudden Sensorineural Hearing Loss: A Case Report

    PubMed Central

    Kim, Yong Won; Shin, Jung Eun; Lee, Yong-Sik

    2015-01-01

    Because inner ear organs are interconnected through the endolymph and surrounding endolymphatic membrane, the patients with sudden sensorineural hearing loss (SSNHL) often complain of vertigo. In this study, we report a patient with SSNHL accompanied by persistent positional vertigo, and serial findings of head-roll tests are described. At acute stage, head-roll test showed persistent geotropic direction-changing positional nystagmus (DCPN), which led to a diagnosis of SSNHL and ipsilateral light cupula. Although vertigo symptom gradually improved, positional vertigo lasted for more than 3 weeks. At this chronic stage, persistent apogeotropic DCPN was observed in a head roll test, which led to a diagnosis of the heavy cupula. Although the mechanism for the conversion of nystagmus direction from geotropic to apogeotropic persistent DCPN is unclear, the change of specific gravity of the endolymph might be one of the plausible hypothetical explanations. PMID:26413578

  6. A positive concept of health - interviews with patients and practitioners in an integrative medicine clinic.

    PubMed

    Hunter, Jennifer; Marshall, Jack; Corcoran, Katherine; Leeder, Stephen; Phelps, Kerryn

    2013-11-01

    Using the phenomenography method, interviews with patients and practitioners were undertaken to explore their understanding of 'health that is more than the absence of disease'. The question was challenging and stimulating for all interviewees. A few were unable to conceptualise this positive definition of health, some perceived it as an optimum end-state, whereas others saw it as an ongoing process. Many positive attributes of health and its influencers were identified. The more advanced understandings of this concept were of a holistic, multidimensional, expansive state where the all dimensions of health are interdependent and positively reinforcing. The results affirmed that wellness is more than psychological wellbeing, 'happiness' and life satisfaction. Optimum physical and cognitive capacities along with spiritual, social and occupational wellness were equally as important. 'Energy and vitality' were sufficiently emphasised by patients and some practitioners to support the inclusion of the principles of vitalism in any discussion about health.

  7. Early-developed hand osteoarthritis in treated HIV-positive patients: Four cases.

    PubMed

    Larcher, Romaric; Mauboussin, Jean-Marc; Rouanet, Isabelle; Sotto, Albert

    2015-10-01

    We describe four cases of hand osteoarthritis in patients with HIV infection under antiretroviral treatment. A 36-year-old HIV-infected man came for consultation in 2007 with hand osteoarthritis. He was diagnosed HIV positive by sexual transmission in 1997. A 52-year-old HIV-infected woman came for consultation with hand osteoarthritis started in 2006. She was diagnosed HIV positive in 1986 by sexual transmission. A 57-year-old man presented hand osteoarthritis. This former IV drug user was diagnosed HIV positive in 1989. A 61-year-old HIV-infected man presented with hand osteoarthritis started in 2010. He had been contaminated with HIV in 1990 by sexual transmission. For all patients, there were neither clinical nor biological manifestations suggesting inflammatory arthritis. X-rays showed signs of hand osteoarthritis. CD4 cell count was over 500/mm(3) and the viral load was below 20 copies/mL under treatments. These four cases show osteoarthritis in HIV-infected patients. Hand osteoarthritis did not seem to be linked to aging or to an antiretroviral treatment's side effect, but rather to the HIV infection itself, and it may pass through a metabolic syndrome. We described a possible association between early-developed hand osteoarthritis and HIV-infected patients. Clinicians should consider osteoarthritis when they are confronted with HIV-infected patients with chronic hand pain.

  8. Positioning patient-perceived medical services to develop a marketing strategy.

    PubMed

    Jung, Minsoo; Hong, Myung-Sun

    2012-01-01

    In today's medical market, marketing philosophy is being rapidly transformed from customer searching to patient satisfaction and service improvement. The principal objective of this study was to contribute to the establishment of a desirable medical marketing strategy, through the factors of customer satisfaction and the positioning of patients' perceptions by marketing institutions. The data were collected from 282 students of the College of Public Health and Medicine in Seoul. The survey tools were developed using the SERVQUAL scale. Analysis in this study involved both statistical and network analysis. The former was used to verify the determinants of service satisfaction as perceived by respondents, via factor analysis and multiple regression analysis. The latter was obtained using a positioning map and 2-mode network analysis with the matrix data converted from raw data. The determining factors for patient satisfaction were identified as facilities, accessibility, process, physicians, and medical staff. The regression equation was significant (R = 0.606), and the most influential variable was the service quality of physicians (β = .569). According to multidimensional scaling, the positioning of medical institutions indicated that patients' perceptions were affected by hospital size and specialization. By recognizing and managing patient satisfaction, medical institutions are able to foster customer loyalty and, in turn, to enhance service quality. It is necessary to develop an adequate marketing mix to provide better medical services and to overcome medical competition among institutions.

  9. Raising positive expectations helps patients with minor ailments: A cross-sectional study

    PubMed Central

    Fassaert, Thijs; van Dulmen, Sandra; Schellevis, François; van der Jagt, Liesbeth; Bensing, Jozien

    2008-01-01

    Background Consultations for minor ailments constitute a large part of the workload of general practitioners (GPs). As medical interventions are not always available, specific communication strategies, such as active listening and positive communication, might help GPs to handle these problems adequately. This study examines to what extent GPs display both strategies during consultations for minor ailments and investigates how each of these relate to the patients' perceived health, consultation frequency and medication adherence. Methods 524 videotaped consultations between Dutch GPs and patients aged 18 years or older were selected. All patients presented a minor ailment, and none of them suffered from a diagnosed chronic illness. The observation protocol included the validated Active Listening Observation Scale (ALOS-global), as well as three domains of positive communication, i.e. providing reassurance, a clear explanation, and a favourable prognosis. Patients completed several questionnaires before, immediately after, and two weeks after the consultation. These included measures for state anxiety (STAI), functional health status (COOP/WONCA charts) and medication adherence (MAQ). Consultation frequency was available from an ongoing patient registration. Data were analysed using multivariate regression analyses. Results Reassurance was related to patients' better overall health. Providing a favourable prognosis was linked to patients feeling better, but only when accompanied by a clear explanation of the complaints. A clear explanation was also related to patients feeling better and less anxious, except when patients reported a low mood pre-visit. Active listening alone was positively associated with patients feeling worse. Among patients in a good mood state, active listening was associated with less adherence. Conclusion To some extent, it seems helpful when GPs are at the same time clear and optimistic about the nature and course of minor ailments. Yet, it

  10. Novel alkane hydroxylase gene (alkB) diversity in sediments associated with hydrocarbon seeps in the Timor Sea, Australia.

    PubMed

    Wasmund, Kenneth; Burns, Kathryn A; Kurtböke, D Ipek; Bourne, David G

    2009-12-01

    Hydrocarbon seeps provide inputs of petroleum hydrocarbons to widespread areas of the Timor Sea. Alkanes constitute the largest proportion of chemical components found in crude oils, and therefore genes involved in the biodegradation of these compounds may act as bioindicators for this ecosystem's response to seepage. To assess alkane biodegradation potential, the diversity and distribution of alkane hydroxylase (alkB) genes in sediments of the Timor Sea were studied. Deduced AlkB protein sequences derived from clone libraries identified sequences only distantly related to previously identified AlkB sequences, suggesting that the Timor Sea maybe a rich reservoir for novel alkane hydroxylase enzymes. Most sequences clustered with AlkB sequences previously identified from marine Gammaproteobacteria though protein sequence identities averaged only 73% (with a range of 60% to 94% sequence identities). AlkB sequence diversity was lower in deep water (>400 m) samples off the continental slope than in shallow water (<100 m) samples on the continental shelf but not significantly different in response to levels of alkanes. Real-time PCR assays targeting Timor Sea alkB genes were designed and used to quantify alkB gene targets. No correlation was found between gene copy numbers and levels of hydrocarbons measured in sediments using sensitive gas chromatography-mass spectrometry techniques, probably due to the very low levels of hydrocarbons found in most sediment samples. Interestingly, however, copy numbers of alkB genes increased substantially in sediments exposed directly to active seepage even though only low or undetectable concentrations of hydrocarbons were measured in these sediments in complementary geochemical analyses due to efficient biodegradation.

  11. The emerging role of multiple antiphospholipid antibodies positivity in patients with antiphospholipid syndrome.

    PubMed

    Forastiero, Ricardo; Martinuzzo, Marta

    2015-01-01

    Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by clinical symptoms of vascular thrombosis and/or pregnancy morbidity in the presence of autoimmune antiphospholipid antibodies (aPL). Current laboratory APS criteria include the presence of at least one of the three relevant aPL: lupus anticoagulant, anticardiolipin antibodies and anti-β2 glycoprotein I antibodies. Therefore, patients could have a single aPL pattern or combinations of aPL. Evidence arising from clinical experience indicates that patients having the highest aPL titer and simultaneous aPL detected by different tests have a worse prognosis and a higher probability of recurrence of the APS clinical features. In recent years, an emerging role of multiple aPL positivity in the identification of high-risk patients with aPL/APS is evident. This paper will review the current knowledge on the clinical relevance of having single or multiple aPL positivity.

  12. Electromagnetic Tracking of Intrafraction Prostate Displacement in Patients Externally Immobilized in the Prone Position

    SciTech Connect

    Bittner, Nathan; Wallner, Kent E.; Merrick, Gregory S.

    2010-06-01

    Purpose: To evaluate intrafraction prostate displacement among patients immobilized in the prone position using real-time monitoring of implanted radiofrequency transponders. Methods and Materials: The Calypso localization system was used to track prostate motion in patients receiving external beam radiation therapy (XRT) for prostate cancer. All patients were treated in the prone position and immobilized with a thermoplastic immobilization device. Real-time measurement of prostate displacement was recorded for each treatment fraction. These measurements were used to determine the duration and magnitude of displacement along the three directional axes. Results: The calculated centroid of the implanted transponders was offset from the treatment isocenter by >=2 mm, >=3 mm, and >=4 mm for 38.0%, 13.9%, and 4.5% of the time. In the lateral dimension, the centroid was offset from the treatment isocenter by >=2 mm, >=3 mm, and >=4 mm for 2.7%, 0.4%, and 0.06% of the time. In the superior-inferior dimension, the centroid was offset from the treatment isocenter by >=2 mm, >=3 mm, and >=4 mm for 16.1%, 4.7%, and 1.5% of the time, respectively. In the anterior-posterior dimension, the centroid was offset from the treatment isocenter by >=2 mm, >=3 mm, and >=4 mm for 13.4%, 3.0%, and 0.5% of the time. Conclusions: Intrafraction prostate displacement in the prone position is comparable to that in the supine position. For patients with large girth, in whom the supine position may preclude accurate detection of implanted radiofrequency transponders, treatment in the prone position is a suitable alternative.

  13. Learning from positively deviant wards to improve patient safety: an observational study protocol

    PubMed Central

    Baxter, Ruth; Taylor, Natalie; Kellar, Ian; Lawton, Rebecca

    2015-01-01

    Introduction Positive deviance is an asset-based approach to improvement which has recently been adopted to improve quality and safety within healthcare. The approach assumes that solutions to problems already exist within communities. Certain groups or individuals identify these solutions and succeed despite having the same resources as others. Within healthcare, positive deviance has previously been applied at individual or organisational levels to improve specific clinical outcomes or processes of care. This study explores whether the positive deviance approach can be applied to multidisciplinary ward teams to address the broad issue of patient safety among elderly patients. Methods and analysis Preliminary work analysed National Health Service (NHS) Safety Thermometer data from 34 elderly medical wards to identify 5 ‘positively deviant’ and 5 matched ‘comparison’ wards. Researchers are blinded to ward status. This protocol describes a multimethod, observational study which will (1) assess the concurrent validity of identifying positively deviant elderly medical wards using NHS Safety Thermometer data and (2) generate hypotheses about how positively deviant wards succeed. Patient and staff perceptions of safety will be assessed on each ward using validated surveys. Correlation and ranking analyses will explore whether this survey data aligns with the routinely collected NHS Safety Thermometer data. Staff focus groups and researcher fieldwork diaries will be completed and qualitative thematic content analysis will be used to generate hypotheses about the strategies, behaviours, team cultures and dynamics that facilitate the delivery of safe patient care. The acceptability and sustainability of strategies identified will also be explored. Ethics and dissemination The South East Scotland Research Ethics Committee 01 approved this study (reference: 14/SS/1085) and NHS Permissions were granted from all trusts. Findings will be published in peer

  14. Positive Glucose Breath Tests in Patients with Hysterectomy, Gastrectomy, and Cholecystectomy

    PubMed Central

    Kim, Dae Bum; Paik, Chang-Nyol; Kim, Yeon Ji; Lee, Ji Min; Jun, Kyong-Hwa; Chung, Woo Chul; Lee, Kang-Moon; Yang, Jin-Mo; Choi, Myung-Gyu

    2017-01-01

    Background/Aims This study aimed to investigate the prevalence and characteristics of small intestinal bacterial overgrowth (SIBO) in patients undergoing abdominal surgeries, such as gastrectomy, cholecystectomy, and hysterectomy. Methods One hundred seventy-one patients with surgery (50 hysterectomy, 14 gastrectomy, and 107 cholecystectomy), 665 patients with functional gastrointestinal disease (FGID) and 30 healthy controls undergoing a hydrogen (H2)-methane (CH4) glucose breath test (GBT) were reviewed. Results GBT positivity (+) was significantly different among the surgical patients (43.9%), FGID patients (31.9%), and controls (13.3%) (p<0.01). With respect to the patients, 65 (38.0%), four (2.3%), and six (3.5%) surgical patients and 150 (22.6%), 30 (4.5%), and 32 (4.8%) FGID patients were in the GBT (H2)+, (CH4)+ and (mixed)+ groups, respectively (p<0.01). The gastrectomy group had a significantly increased preference in GBT+ (71.4% vs 42.0% or 41.1%, respectively) and GBT (H2)+ (64.3% vs 32.0% or 37.4%, respectively) compared with the hysterectomy or cholecystectomy groups (p<0.01). During GBT, the total H2 was significantly increased in the gastrectomy group compared with the other groups. Conclusions SIBO producing H2 is common in abdominal surgical patients. Different features for GBT+ may be a result of the types of abdominal surgery. PMID:27965476

  15. SU-C-19A-04: Evaluation of Patient Positioning Reproducibility with Three Supine Breast Boards

    SciTech Connect

    Zhang, Y; Brinkmann, D; Pafundi, D; Park, S; Yan, E; Choo, R; Petersen, I; Childs, S; Pisansky, T; Remmes, N; Mutter, R

    2014-06-15

    Purpose: To evaluate positioning reproducibility using three commercially available breast board immobilization systems for whole breast radiation therapy. Methods: Weekly pre-treatment cone beam CT images from 18 free-breathing breast radiotherapy patients, each immobilized with one of three breast boards, were retrospectively registered to the planning CT. Relative shifts between breast tissue and sternum/chest wall (CW), and breast tissue and spine compared to planning CT were obtained for each board. Positioning reproducibility, inter-patient variation and intra-patient variation were evaluated by group mean (M), standard deviation of group mean (Σ) and standard deviation of random shift (σ). Margins to account for setup uncertainties were calculated based on shift uncertainties in x, y, and z directions. Results: For breast positioning relative to sternum/CW, the average shift from planned positioning was 4.5mm (95% CI: 3.5 – 5.3), 3.3mm (CI: 2.9 - 3.8) and 2.6mm (CI: 1.8 - 3.5) for Breast Boards I, II, and III, respectively. The respective numbers for breast positioning relative to spine were 7.2 mm (CI: 4.1 – 10.3), 6.4 mm (CI: 4.3 – 8.3) and 4.3 mm (CI: 2.5 – 6.2). Localizing to the sternum/CW as a surrogate for the breast tissue, margins for setup uncertainties were 5.7mm, 5.5mm, and 6.0mm for Breast Board I, 5.0mm, 4.0mm and 4.3mm for Breast Board II, and 3.8mm, 3.5mm and 4.8mm for Breast Board III, in the lateral, anterior/posterior, and superior/inferior directions, respectively. Conclusion: Better patient positioning reproducibility was observed with Boards II and III compared to Board I. Inter- and intra-patient set-up uncertainties were also improved with Boards II and III, which requires smaller PTV margins. Independent of breast board, breast cancer patient positioning to the sternum/CW is a better surrogate than the spine. Our findings have potential dosimetric consequences from set-up uncertainties when employing IMRT or proton

  16. Influence of the prosthetic arm length (palatal position) of zygomatic implants upon patient satisfaction

    PubMed Central

    Pellicer-Chover, Hilario; Cervera-Ballester, Juan; Peñarrocha-Oltra, David; Bagán, Leticia; Peñarrocha-Diago, María

    2016-01-01

    Background To assess the influence of the prosthetic arm length (palatal position) of zygomatic implants upon patient comfort and stability, speech, functionality and overall satisfaction. Material and Methods A retrospective clinical study was made of patients subjected to rehabilitation of atrophic maxilla with complete maxillary implant-supported fixed prostheses involving a minimum of two zygomatic implants (one on each side) in conjunction with premaxillary implants, and with 12 months of follow-up after implant loading. Subjects used a VAS to score general satisfaction, comfort and stability, speech and functionality, and the results were analyzed in relation to the prosthetic arm length of the zygomatic implants 12 months after prosthetic delivery. Results Twenty-two patients participated in the study, receiving 22 prostheses anchored on 148 implants (44 were zygomatic and 94 were conventional implants). The mean right and left prosthetic arm length was 5.9±2.4 mm and 6.1±2.7 mm, respectively, with no statistically significant differences between them (p=0.576). The mean scores referred to comfort/retention, speech, functionality and overall satisfaction were high - no correlation being found between prosthetic arm length and patient satisfaction (p=0.815). Conclusions No relationship could be identified between prosthetic arm length (palatal position) and patient satisfaction. Key words:Zygomatic implants, patient satisfaction, zygomatic prosthesis, prosthetic arm length. PMID:26946206

  17. Positional stretching of the coracohumeral ligament on a patient with adhesive capsulitis: a case report.

    PubMed

    Ruiz, Jose Orlando

    2009-01-01

    Idiopathic frozen shoulder is a common medical diagnosis for patients seeking physical therapy. Radiographic and surgical evidence exists that describes the coracohumeral ligament (CHL) as a major contributor to lack of external rotation in patients diagnosed with frozen shoulder. No stretching techniques targeting the anatomical fiber orientation of the CHL have been reported in the literature. This single-patient case-report describes the use of a positional stretching technique of the CHL on a 51-year-old female diagnosed with phase I frozen shoulder. The patient completed 8 in-office visits and 17 home exercise program sessions of positional CHL stretching combined with a simple volitional rotator cuff exercise program in a 4-week period. The patient's Disabilities of the Arm Shoulder and hand (DASH) scores improved from 65 to 36 and Shoulder Pain and Disability Index (SPADI) scores improved from 72 to 8 and passive external rotation from 20 degrees to 71 degrees . While a cause-and-effect relationship cannot be inferred from a single case, this report may foster further investigation regarding the role of the CHL in patients with stage-I and stage-II frozen shoulder as well as therapeutic strategies to help reduce loss of mobility and function.

  18. Toxicity of Head-and-Neck Radiation Therapy in Human Immunodeficiency Virus-Positive Patients

    SciTech Connect

    Sanfilippo, Nicholas J.; Mitchell, James; Grew, David; DeLacure, Mark

    2010-08-01

    Purpose: To examine the acute morbidity of high dose head and neck RT and CRT in patients with infected with HIV. Methods and Materials: All HIV-positive patients who underwent radiation therapy for head and neck cancer in our department between 2004 and 2008 were reviewed. Treatment related data were examined. All treatments were delivered with megavoltage photon beams or electron beams. Patients were evaluated by an attending radiation oncologist for toxicity and response on a weekly basis during therapy and monthly after treatment in a multidisciplinary clinic. Acute toxicities were recorded using the Radiation Therapy and Oncology Group (RTOG) common toxicity criteria. Response to treatment was based on both physical exam as well as post-treatment imaging as indicated. Results: Thirteen patients who underwent RT with a diagnosis of HIV were identified. Median age was 53 years and median follow-up was 22 months. Twelve had squamous cell carcinoma and one had lymphoproliferative parotiditis. Median radiation dose was 66.4 Gy and median duration of treatment was 51 days. The median number of scheduled radiotherapy days missed was zero (range 0 to 7). One patient (8%) developed Grade 4 confluent moist desquamation. Eight patients (61%) developed Grade 3 toxicity. Conclusion: Based on our results, HIV-positive individuals appear to tolerate treatment for head and neck cancer, with toxicity similar to that in HIV-negative individuals.

  19. Positive psychology group intervention for breast cancer patients: a randomised trial.

    PubMed

    Victoria Cerezo, M; Ortiz-Tallo, Margarita; Cardenal, Violeta; De La Torre-Luque, Alejandro

    2014-08-01

    This study assessed the effects of a psychological group intervention based on positive psychology in women with breast cancer. 175 women were randomly assigned either to an experimental group, receiving the 14-session intervention (n = 87), or to a wait list group (n = 88) that did not receive any type of intervention. For treatment, a group intervention was applied, based on improving psychological strengths and enhancing positive psychology-based styles of coping. Strength-related outcomes, self-esteem, well-being, and happiness were assessed before and after the intervention. The experimental group showed higher scores on all of the study variables after the intervention. Participants reported improved self-esteem, emotional intelligence-related abilities, resilience, and optimism, as well as positive affectivity, well-being, and happiness. The results show a beneficial effect of this psychological intervention based on positive psychology on female breast cancer patients' psychological health.

  20. SU-E-J-184: Stereo Time-Of-Flight System for Patient Positioning in Radiotherapy

    SciTech Connect

    Wentz, T; Gilles, M; Visvikis, D; Le Fur, E; Pradier, O

    2014-06-01

    Purpose: The objective of this work is to test the advantage of using the surface acquired by two stereo Time-of-Flight (ToF) cameras in comparison of the use of one camera only for patient positioning in radiotherapy. Methods: A first step consisted on validating the use of a stereo ToFcamera system for positioning management of a phantom mounted on a linear actuator producing very accurate and repeatable displacements. The displacements between two positions were computed from the surface point cloud acquired by either one or two cameras thanks to an iterative closest point algorithm. A second step consisted on determining the displacements on patient datasets, with two cameras fixed on the ceiling of the radiotherapy room. Measurements were done first on voluntary subject with fixed translations, then on patients during the normal clinical radiotherapy routine. Results: The phantom tests showed a major improvement in lateral and depth axis for motions above 10 mm when using the stereo-system instead of a unique camera (Fig1). Patient measurements validate these results with a mean real and measured displacement differences in the depth direction of 1.5 mm when using one camera and 0.9 mm when using two cameras (Fig2). In the lateral direction, a mean difference of 1 mm was obtained by the stereo-system instead of 3.2 mm. Along the longitudinal axis mean differences of 5.4 and 3.4 mm with one and two cameras respectively were noticed but these measurements were still inaccurate and globally underestimated in this direction as in the literature. Similar results were also found for patient subjects with a mean difference reduction of 35%, 7%, and 25% for the lateral, depth, and longitudinal displacement with the stereo-system. Conclusion: The addition of a second ToF-camera to determine patient displacement strongly improved patient repositioning results and therefore insures better radiation delivery.

  1. Prevalence of antineutrophil cytoplasmic antibody positivity in patients with Hodgkin's and non-Hodgkin lymphoma: a single center experience.

    PubMed

    Cil, Timucin; Altintas, Abdullah; Isikdogan, Abdurrahman; Batun, Sabri

    2009-07-01

    Hematological malignancies are associated with the release of different autoantibodies and rheumatological manifestations. Systemic vasculitides are rare in hematological malignancies, and antineutrophil cytoplasmic antibodies (ANCA) have not been described sufficiently in hematological malignancies. In this present prospective study, we examined the prevalence of ANCA and related disease in Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) patients in the southeast region of Turkey. We examined 119 patients with previously or newly diagnosed NHL and 60 patients with HL for the presence of ANCA and related autoimmune diseases between December 2002 and February 2007. ANCA positivity was detected in only 8 patients (4.4%); and all of these ANCA positivities were detected in patients in the HL group (13.3%); p-ANCA positivity was detected in 6 patients (3.3%); and c-ANCA positivity was detected in 2 patients (1.1%). There was statistically significant difference between patients with HL and NHL in terms of p-ANCA (p = 0.001) but none in c-ANCA (p = 0.111) positivity. None of the ANCA positive patients had vasculitides or rheumatic manifestations. In addition, we did not detect any ANCA positivity in the NHL group. In conclusion, ANCA positivities were detected only in HL patients; but we did not detect the association between ANCA positivities and rheumatic manifestations or vasculitis and also the different treatment responses in HL patients.

  2. Positive Contrast MRI Techniques for Visualization of Iron-Loaded Hernia Mesh Implants in Patients

    PubMed Central

    Ciritsis, Alexander; Truhn, Daniel; Hansen, Nienke L.; Otto, Jens; Kuhl, Christiane K.; Kraemer, Nils A.

    2016-01-01

    Object In MRI, implants and devices can be delineated via susceptibility artefacts. To discriminate susceptibility voids from proton-free structures, different positive contrast techniques were implemented. The purpose of this study was to evaluate a pulse sequence-based positive contrast technique (PCSI) and a post-processing susceptibility gradient mapping algorithm (SGM) for visualization of iron loaded mesh implants in patients. Material and Methods Five patients with iron-loaded MR-visible inguinal hernia mesh implants were examined at 1.5 Tesla. A gradient echo sequence (GRE; parameters: TR: 8.3ms; TE: 4.3ms; NSA:2; FA:20°; FOV:350mm²) and a PCSI sequence (parameters: TR: 25ms; TE: 4.6ms; NSA:4; FA:20°; FOV:350mm²) with on-resonant proton suppression were performed. SGM maps were calculated using two algorithms. Image quality and mesh delineation were independently evaluated by three radiologists. Results On GRE, the iron-loaded meshes generated distinct susceptibility-induced signal voids. PCSI exhibited susceptibility differences including the meshes as hyperintense signals. SGM exhibited susceptibility differences with positive contrast. Visually, the different algorithms presented no significant differences. Overall, the diagnostic value was rated best in GRE whereas PCSI and SGM were barely “sufficient”. Conclusion Both “positive contrast” techniques depicted implanted meshes with hyperintense signal. SGM comes without additional acquisition time and can therefore be utilized in every patient. PMID:27192201

  3. Oral ranula in an HIV-positive patient: case report and literature review.

    PubMed

    Kinshuck, Andrew Jon; Schober, Marianne; Kokai, George; Clarke, Ray

    2012-07-10

    We describe the presentation and treatment of an HIV-positive patient with an oral ranula, and review the literature. Ranulas are mucoceles or retention cysts formed by the extravasation of mucus from the sublingual gland, presumably due to continued production of saliva in the presence of ductal obstruction. Oral ranulas in children are rare and the overall prevalence of mucoceles has been reported as 0.08% in children aged 0-12 years. However, there has been a documented increased occurrence in HIV-positive patients. This has been attributed to a blockage of the salivary gland by inflammation and peri-ductal fibrosis following HIV-associated salivary gland disease. Oral lesions may indicate infection with HIV and can also predict progression of HIV to AIDS. The most common oral manifestation is oral candidiasis occurring in 67% of children with HIV. Following this salivary gland disease, periodontal and gingival disease and herpes simplex are the next most common. The exact prevalence of ranulas in an HIV population is not known but the occurrence of a paediatric patient with HIV having at least one oral lesion has been documented as high as 63% and salivary gland disease at 50%. The true extent of the relationship between HIV and ranula is as yet unknown. This represents the only reported case of oral ranula in an HIV-positive patient in the UK.

  4. Exogenous Magnesium Chloride Reduces the Activated Partial Thromboplastin Times of Lupus Anticoagulant-Positive Patients

    PubMed Central

    Tokutake, Takayoshi; Baba, Hisami; Shimada, Yuji; Takeda, Wataru; Sato, Keijiro; Hiroshima, Yuki; Kirihara, Takehiko; Shimizu, Ikuo; Nakazawa, Hideyuki; Kobayashi, Hikaru; Ishida, Fumihiro

    2016-01-01

    The activated partial thromboplastin time (APTT) assay is a basic hemostatic assay based on the time it takes for clots to form in plasma samples after the addition of calcium chloride. It is used to screen for various coagulation disorders. Several previous reports have suggested that magnesium (Mg) might contribute to coagulation reactions by binding to specific coagulation proteins. We investigated the effects of Mg on the APTT. In healthy controls, the APTT was significantly prolonged in proportion to the increase in the concentration of magnesium chloride in the range from 2.1 to 16.7 mmol/L. Among eight samples from patients with various disorders that exhibited prolonged APTT, two samples demonstrated shorter APTT when Mg was added, both of which were from patients that were positive for lupus anticoagulant. When we examined 206 clinical APTT samples, we found that Mg shortened the APTT of two samples. These two samples were also from lupus anticoagulant-positive patients (p-value: <0.003). Our findings regarding the unique effects of exogenous Mg on the APTT of lupus anticoagulant-positive patients might shed light on the role of Mg in APTT assays and lead to the development of a novel screening method for lupus anticoagulant. PMID:27355205

  5. Error types and error positions in neglect dyslexia: comparative analyses in neglect patients and healthy controls.

    PubMed

    Weinzierl, Christiane; Kerkhoff, Georg; van Eimeren, Lucia; Keller, Ingo; Stenneken, Prisca

    2012-10-01

    Unilateral spatial neglect frequently involves a lateralised reading disorder, neglect dyslexia (ND). Reading of single words in ND is characterised by left-sided omissions and substitutions of letters. However, it is unclear whether the distribution of error types and positions within a word shows a unique pattern of ND when directly compared to healthy controls. This question has been difficult to answer so far, given the usually low number of reading errors in healthy controls. Therefore, the present study compared single word reading of 18 patients with left-sided neglect, due to right-hemisphere stroke, and 11 age-matched healthy controls, and adjusted individual task difficulty (by varying stimulus presentation times in participants) in order to reach approximately equal error rates between neglect patients and controls. Results showed that, while both omission and substitution errors were frequently produced in neglect patients and controls, only omissions appeared neglect-specific when task difficulty was adapted between groups. Analyses of individual letter positions within words revealed that the spatial distribution of reading errors in the neglect dyslexic patients followed an almost linear increase from the end to the beginning of the word (right-to-left-gradient). Both, the gradient in error positions and the predominance of omission errors presented a neglect-specific pattern. Consistent with current models of visual word processing, these findings suggest that ND reflects sublexical, visuospatial attentional mechanisms in letter string encoding.

  6. Arm position does not attenuate visual loss in patients with homonymous field deficits.

    PubMed

    Smith, Daniel T; Lane, Alison R; Schenk, Thomas

    2008-01-01

    One of the most common and debilitating consequences of stroke is the loss of vision in the contralesional visual field. Clinicians typically regard this loss as irreversible and attempts at visual restoration have delivered only small and unreliable improvements. However, Schendel and Robertson [Schendel, K., & Robertson, L. C. (2004). Reaching out to see: Arm position can attenuate human visual loss. Journal of Cognitive Neuroscience, 16(6), 935-943] reported that the visual abilities of a hemianopic patient (WM) were significantly improved when the left arm was extended into the blind field. They suggest that visual stimuli near the arm recruited bimodal visual-tactile neurons, and this activity was sufficient to bring the stimulus into awareness. This result has enormous potential therapeutic value, but given that it is a single case study there are a number of reasons to be cautious about interpreting the data. Here, we investigate the effects of manipulating arm position on visual loss in a sample of five patients with homonymous field deficits. None of our patients showed any evidence of improved implicit or explicit visual ability in the blind field as a consequence of moving the arm. We suggest that WMs improvement was the consequence of a spatial bias towards the space containing his extended arm rather than the recruitment of bimodal neurons, and conclude that manipulating arm position is of little therapeutic value to patients with dense hemianopia.

  7. Atrophy, fibrosis, and increased PAX7-positive cells in pharyngeal muscles of oculopharyngeal muscular dystrophy patients.

    PubMed

    Gidaro, Teresa; Negroni, Elisa; Perié, Sophie; Mirabella, Massimiliano; Lainé, Jeanne; Lacau St Guily, Jean; Butler-Browne, Gillian; Mouly, Vincent; Trollet, Capucine

    2013-03-01

    Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominant inherited dystrophy caused by an abnormal trinucleotide repeat expansion in the poly(A)-binding-protein-nuclear 1 (PABPN1) gene. Primary muscular targets of OPMD are the eyelid elevator and pharyngeal muscles, including the cricopharyngeal muscle (CPM), the progressive involution of which leads to ptosis and dysphagia, respectively. To understand the consequences of PABPN1 polyalanine expansion in OPMD, we studied muscle biopsies from 14 OPMD patients, 3 inclusion body myositis patients, and 9 healthy controls. In OPMD patient CPM (n = 6), there were typical dystrophic features with extensive endomysial fibrosis and marked atrophy of myosin heavy-chain IIa fibers. There were more PAX7-positive cells in all CPM versus other muscles (n = 5, control; n = 3, inclusion body myositis), and they were more numerous in OPMD CPM versus control normal CPM without any sign of muscle regeneration. Intranuclear inclusions were present in all OPMD muscles but unaffected OPMD patient muscles (i.e. sternocleidomastoid, quadriceps, or deltoid; n = 14) did not show evidence of fibrosis, atrophy, or increased PAX7-positive cell numbers. These results suggest that the specific involvement of CPM in OPMD might be caused by failure of the regenerative response with dysfunction of PAX7-positive cells and exacerbated fibrosis that does not correlate with the presence of PABPN1 inclusions.

  8. [Effects of stepped counseling intervention on quality of life among newly diagnosed HIV-positive patients].

    PubMed

    Hsiao, Ching-Fang; Chao, Shu-Ling; Tsai, Tsui-Ching; Chuang, Peing

    2004-04-01

    The purpose of this research was to understand how stepped counseling intervention affects quality of life in newly diagnosed HIV-positive patients. The study made use of quasi-experimental methodology that included a three-step interview process over 45 days. The theoretical framework supporting interviews with 32 newly diagnosed HIV-positive patients in northern Taiwan included a combination of rational-emotive therapy, cognitive-behavior therapy, and health education. Participants were divided into an experimental and control group of equal size. Data collection also included responses to the WHOQOL-HIV instrument at the beginning and end of each interview session. Responses were analyzed with the SPSS software package. The results showed a 25-point difference between pre- and post-test scores in the experimental group (SD = 3.2) and a 6 point difference in the control group (SD = 4.3). The results indicate that stepped counseling techniques are effective in helping this patient population to adjust to the physical, emotional, social, and environmental stresses associated with their newly diagnosis. The researchers suggest that stepped counseling be used with all newly diagnosed HIV-positive Taiwanese patients in all hospitals and clinics to promote adaptive abilities and to control the further spread of HIV.

  9. Endoscopic Calcaneoplasty and Achilles Tendoscopy With the Patient in Supine Position.

    PubMed

    Lui, Tun Hing

    2016-12-01

    Insertional and non-insertional Achilles tendinopathy is usually treated conservatively. Surgery is indicated if conservative treatment fails to relieve the pain. Endoscopic surgery has the advantages of less morbidity, a shorter operating time, reduced postoperative pain, and a lower rate of wound and soft-tissue healing problems. Patients will have a short recovery time and quickly resume work and sports because of less soft-tissue disruption. Moreover, the pathology can be better differentiated and precisely treated. Achilles tendoscopy is classically performed with the patient in the prone position, whereas endoscopic calcaneoplasty can be performed with the patient in the prone or supine position. This technical note describes the technique of Achilles tendoscopy and endoscopic calcaneoplasty with the patient in the supine position. This has the advantages of more ergonomic hand motion for the Achilles tendon debridement, easier access to the ventral surface of the Achilles tendon, and better orientation of the inside structures; moreover, concomitant chondral lesions of the ankle can be dealt with arthroscopically.

  10. ALK5 inhibition blocks TGFβ-induced CCN1 expression in human foreskin fibroblasts.

    PubMed

    Thompson, Katherine; Murphy-Marshman, Hannah; Leask, Andrew

    2014-03-01

    The potent profibrotic cytokine TGFβ induces connective tissue growth factor (CCN2/CTGF) is induced in fibroblasts in a fashion sensitive to SB-431542, a specific pharmacological inhibitor of TGFβ type I receptor (ALK5). In several cell types, TGFβ induces CCN1 but suppresses CCN3, which opposes CCN1/CCN2 activities. However, whether SB-431542 alters TGFβ-induced CCN1 or CCN3 in human foreskin fibroblasts in unclear. Here we show that TGFβ induces CCN1 but suppresses CCN3 expression in human foreskin fibroblasts in a SB-431542-sensitive fashion. These results emphasize that CCN1/CCN2 and CCN3 are reciprocally regulated and support the notion that blocking ALK5 or addition of CCN3 may be useful anti-fibrotic approaches.

  11. SMARCE1 suppresses EGFR expression and controls responses to MET and ALK inhibitors in lung cancer.

    PubMed

    Papadakis, Andreas I; Sun, Chong; Knijnenburg, Theo A; Xue, Yibo; Grernrum, Wipawadee; Hölzel, Michael; Nijkamp, Wouter; Wessels, Lodewyk F A; Beijersbergen, Roderick L; Bernards, Rene; Huang, Sidong

    2015-04-01

    Recurrent inactivating mutations in components of SWI/SNF chromatin-remodeling complexes have been identified across cancer types, supporting their roles as tumor suppressors in modulating oncogenic signaling pathways. We report here that SMARCE1 loss induces EGFR expression and confers resistance to MET and ALK inhibitors in non-small cell lung cancers (NSCLCs). We found that SMARCE1 binds to regulatory regions of the EGFR locus and suppresses EGFR transcription in part through regulating expression of Polycomb Repressive Complex component CBX2. Addition of the EGFR inhibitor gefitinib restores the sensitivity of SMARCE1-knockdown cells to MET and ALK inhibitors in NSCLCs. Our findings link SMARCE1 to EGFR oncogenic signaling and suggest targeted treatment options for SMARCE1-deficient tumors.

  12. Dental Health Status of HIV-Positive Patients and Related Variables in Southeast Iran

    PubMed Central

    Saravani, Shirin; Nosrat Zehi, Tahereh; Kadeh, Hamideh; Mir, Sarvar

    2016-01-01

    Background Different factors can be responsible for the increased prevalence of dental caries and missing teeth in HIV-positive patients. Objectives This study evaluates dental health status and its relationship with social, behavioral, and medical factors in HIV-positive patients under the coverage of Zahedan University of Medical Sciences in Southeast Iran. Patients and Methods In a cross-sectional study, the dental health status of 119 HIV-positive patients was assessed in accordance with WHO indices and included decayed, missing, and filled teeth (DMFT). A questionnaire on different social, behavioral, and medical variables was filled out for every case and the relationship and correlation of the variables to dental health status were investigated using One-way ANOVA, the Kruskal Wallis test, the t-test, the Mann-Whitney test, Spearman’s rho correlation coefficient, and Pearson correlation. Results The mean value of DMFT index was 11.87 ± 8.08, where the mean values of decayed and missing teeth were 8.42 ± 5.44 and 3.43 ± 4.07, respectively. DMFT index, decayed, and missing teeth correlated only with age (P < 0.0001, P = 0.009, P < 0.0001) and duration of HIV involvement (P = 0.004, P = 0.031, P = 0.007). Conclusions The dental health status of HIV-positive patients in this region was almost inappropriate. Most social, behavioral, and medical factors had no influence on dental health; only a correlation between dental health, age, and duration of HIV involvement was observed. PMID:27622173

  13. Thinking differently about thinking positive: a discursive approach to cancer patients' talk.

    PubMed

    Wilkinson, S; Kitzinger, C

    2000-03-01

    There is an extensive social science and psycho-oncology literature on coping with cancer which claims that "thinking positive" is correlated with--and, by extension, causally implicated in--individuals' morbidity and mortality rates, and their overall level of mental health. Drawing on our own data, in which groups of women with breast cancer talk about "thinking positive", this paper interrogates the basis of such claims from a discursive perspective, by challenging the data analyses upon which they are based. We show that previous literature overwhelmingly relies on self-report data, which are taken as offering more or less accurate depictions of speakers' psychological states (i.e. their mental adjustment or coping style). A discursive approach, by contrast, explores talk as a form of action designed for its local interactional context, and pays detailed attention to what statements about "thinking positive" actually mean for speakers in the contexts in which they occur. We show that "thinking positive" functions not as an accurate report of a internal cognitive state, but rather as a conversational idiom, characterised by vagueness and generality, and summarising a socially normative moral requirement; we also show that even those breast cancer patients who report "thinking positive" can also actively resist its moral prescriptions. Finally, we sketch out the implications of our analysis for analyses of cancer patients' talk more generally and for future research on coping with cancer.

  14. Positive predictive value of diagnosis coding for hemolytic anemias in the Danish National Patient Register

    PubMed Central

    Hansen, Dennis Lund; Overgaard, Ulrik Malthe; Pedersen, Lars; Frederiksen, Henrik

    2016-01-01

    Purpose The nationwide public health registers in Denmark provide a unique opportunity for evaluation of disease-associated morbidity if the positive predictive values (PPVs) of the primary diagnosis are known. The aim of this study was to evaluate the predictive values of hemolytic anemias registered in the Danish National Patient Register. Patients and methods All patients with a first-ever diagnosis of hemolytic anemia from either specialist outpatient clinic contact or inpatient admission at Odense University Hospital from January 1994 through December 2011 were considered for inclusion. Patients with mechanical reason for hemolysis such as an artificial heart valve, and patients with vitamin-B12 or folic acid deficiency were excluded. Results We identified 412 eligible patients: 249 with a congenital hemolytic anemia diagnosis and 163 with acquired hemolytic anemia diagnosis. In all, hemolysis was confirmed in 359 patients, yielding an overall PPV of 87.1% (95% confidence interval [CI]: 83.5%–90.2%). A diagnosis could be established in 392 patients of whom 355 patients had a hemolytic diagnosis. Diagnosis was confirmed in 197 of the 249 patients with congenital hemolytic anemia, yielding a PPV of 79.1% (95% CI: 73.5%–84.0%). Diagnosis of acquired hemolytic anemia could be confirmed in 136 of the 163 patients, resulting in a PPV of 83.4% (95% CI: 76.8%–88.8%). For hemoglobinopathy PPV was 84.1% (95% CI: 77.4%–89.4%), for hereditary spherocytosis PPV was 80.6% (95% CI: 69.5%–88.9%), and for autoimmune hemolytic anemia PPV was 78.4% (95% CI: 70.4%–85.0%). Conclusion The PPV of hemolytic anemias was moderately high. The PPVs were comparable in the three main categories of overall hemolysis, and congenital and acquired hemolytic anemia. PMID:27445504

  15. Does the position of conus medullaris change with increased thoracolumbar kyphosis in ankylosing spondylitis patients?

    PubMed Central

    Qu, Zhe; Qian, Bang-ping; Qiu, Yong; Zhang, Yun-peng; Hu, Jun; Zhu, Ze-zhang

    2017-01-01

    Abstract To date, only a few reports described the potential factors influencing the position of conus medullaris. One previous study revealed no significant change of conus locations in patients with idiopathic scoliosis; however, the effect of ankylosing spondylitis (AS)-related thoracolumbar kyphosis on conus position remains unexplored. Therefore, we aimed to investigate the variation of conus medullaris terminations in patients with thoracolumbar kyphosis secondary to AS when compared with normal subjects, and evaluated the relationship between conus positions and the magnitude of kyphosis. In this study, MR images of 96 AS patients with thoracolumbar kyphosis, including 86 males and 10 females with an average of 34.6 years (range, 17–65 years), and 100 age-matched normal controls were reviewed to determine the conus terminations in relation to spinal levels. Sagittal parameters of the AS group measured on radiograph included: global kyphosis (GK), thoracic kyphosis (TK), lumbar lordosis (LL), and thoracolumbar junction (TLJ). Finally, conus tips located at the mean level of the lower 3rd of L1 in both groups, there was no significant difference of the conus distributions between AS and control group (P = 0.49). In addition, conus medullaris displayed similar positions in AS patients among various apical region groups (P = 0.88), and no significant difference was found when AS population was stratified into GK ranges of 30° (P = 0.173). Also, no remarkable correlation of the conus positions with GK (r = −0.15, P = 0.15), TK (r = −0.10, P = 0.34), LL (r = −0.10, P = 0.32), and TLJ (r = −0.06, P = 0.54) was identified. This study showed the conus terminations displayed a wide range of distributions in AS patients with thoracolumbar kyphosis, which was similar to normal subjects. Moreover, the conus located at a relatively fixed position and would not be affected by the change of kyphosis magnitude, which is

  16. A Study Of Oral PF-02341066, A C-Met/Hepatocyte Growth Factor Tyrosine Kinase Inhibitor, In Patients With Advanced Cancer

    ClinicalTrials.gov

    2017-04-04

    Non-Small Cell Lung Cancer (ALK-positive); Non-Small Cell Lung Cancer (c-Met Dependent); Non-Small Cell Lung Cancer (ROS Marker Positive); Systemic Anaplastic Large-Cell Lymphoma; Advanced Malignancies (Except Leukemia)

  17. Brentuximab Vedotin or Crizotinib and Combination Chemotherapy in Treating Patients With Newly Diagnosed Stage II-IV Anaplastic Large Cell Lymphoma

    ClinicalTrials.gov

    2017-04-06

    Anaplastic Large Cell Lymphoma, ALK-Positive; CD30-Positive Neoplastic Cells Present; Stage II Childhood Anaplastic Large Cell Lymphoma; Stage III Childhood Anaplastic Large Cell Lymphoma; Stage IV Childhood Anaplastic Large Cell Lymphoma

  18. Utilization of n-alkanes by a newly isolated strain of Acinetobacter venetianus: the role of two AlkB-type alkane hydroxylases.

    PubMed

    Throne-Holst, Mimmi; Markussen, Sidsel; Winnberg, Asgeir; Ellingsen, Trond E; Kotlar, Hans-Kristian; Zotchev, Sergey B

    2006-09-01

    A bacterial strain capable of utilizing n-alkanes with chain lengths ranging from decane (C10H22) to tetracontane (C40H82) as a sole carbon source was isolated using a system for screening microorganisms able to grow on paraffin (mixed long-chain n-alkanes). The isolate, identified according to its 16S rRNA sequence as Acinetobacter venetianus, was designated A. venetianus 6A2. Two DNA fragments encoding parts of AlkB-type alkane hydroxylase homologues, designated alkMa and alkMb, were polymerase chain reaction-amplified from the genome of A. venetianus 6A2. To study the roles of these two alkM paralogues in n-alkane utilization in A. venetianus 6A2, we constructed alkMa, alkMb, and alkMa/alkMb disruption mutants. Studies on the growth patterns of the disruption mutants using n-alkanes with different chain lengths as sole carbon source demonstrated central roles for the alkMa and alkMb genes in utilization of C10 to C18 n-alkanes. Comparative analysis of these patterns also suggested different substrate preferences for AlkMa and AlkMb in n-alkane utilization. Because both single and double mutants were able to grow on n-alkanes with chain lengths of C20 and longer, we concluded that yet another enzyme(s) for the utilization of these n-alkanes must exist in A. venetianus 6A2.

  19. Eosinophilic acute appendicitis caused by Strongyloides stercoralis and Enterobius vermicularis in an HIV-positive patient

    PubMed Central

    Cruz, Dennis Baroni; Friedrisch, Bruno Kras; Fontanive Junior, Vilmar; da Rocha, Vívian Wünderlich

    2012-01-01

    A 29 year old female HIV-positive patient presented in emergency with acute right lower quadrant abdominal pain, fever, tenderness and positive Blumberg sign. Laboratorial tests revealed eosinophilia, anaemia and leukocytosis. She underwent exploratory laparotomy followed by appendectomy. The pathological analysis of the appendix revealed acute appendicitis, accentuated eosinophilia and infestation by Strongyloides stercoralis and Enterobius vermicularis. She did well after surgery and adequate treatment. To the authors’ knowledge, this is the first case of eosinophilic acute appendicitis caused by these two parasitic worms reported in the medical literature. PMID:22605801

  20. Illness Representations of HIV Positive Patients Are Associated with Virologic Success

    PubMed Central

    Leone, Daniela; Borghi, Lidia; Lamiani, Giulia; Barlascini, Luca; Bini, Teresa; d’Arminio Monforte, Antonella; Vegni, Elena

    2016-01-01

    Introduction: It is important for HIV positive patients to be engaged in their care and be adherent to treatment in order to reduce disease progression and mortality. Studies found that illness representations influence adherence through the mediating role of coping behaviors. However, no study has ever tested if patient engagement to the visits mediate the relationship between illness perceptions and adherence. This study aimed to explore illness representations of HIV positive patients and test the hypothesis that illness representations predict adherence through the mediating role of a component of behavioral engagement. Methods: HIV-positive patients treated with highly active antiretroviral therapy (HAART) for at least one year and presenting to a check-up visit were eligible to participate in the study. Patients completed the Illness Perception Questionnaire-Revised. Behavioral engagement was measured based on the patients’ clinical attendance to the check-up visits; adherence to HAART was measured by viral load. Undetectable viral load or HIV-RNA < 40 copies/ml were considered indexes of virologic success. Results: A total of 161 patients participated in the study. Most of them coherently attributed the experienced symptoms to HIV/HAART; perceived their condition as chronic, stable, coherent, judged the therapy as effective, and attributed their disease to the HIV virus and to their behavior or bad luck. The majority of patients (80.1%) regularly attended check-up visits and 88.5% of them reached virologic success. The mediation model did not show good fit indexes. However, a significant direct effect of two independent variables on virologic success was found. Specifically, the perception that the disease does not have serious consequences on patient’s life and the prevalence of negative emotions toward HIV were associated with virologic success. On the contrary, the patient’s perception that the disease has serious consequences on his/her life and

  1. Retreatment with brentuximab vedotin in patients with CD30-positive hematologic malignancies

    PubMed Central

    2014-01-01

    Background Brentuximab vedotin is a CD30-directed antibody-drug conjugate. Retreatment with brentuximab vedotin monotherapy was investigated in patients with CD30-positive Hodgkin lymphoma (HL) or systemic anaplastic large cell lymphoma (ALCL) who relapsed after achieving complete or partial remission (CR or PR) with initial brentuximab vedotin therapy in a previous study (ClinicalTrials.gov NCT00947856). Methods Twenty-one patients with HL and 8 patients with systemic ALCL were retreated; 3 patients with systemic ALCL were retreated twice. Patients generally received brentuximab vedotin 1.8 mg/kg intravenously approximately every 3 weeks over 30 minutes as an outpatient infusion. The primary objectives of this study were to assess safety and to estimate antitumor activity of brentuximab vedotin retreatment. Results The objective response rate was 60% (30% CR) in HL patients and 88% (63% CR) in systemic ALCL patients. The estimated median duration of response for patients with an objective response was 9.5 months (range, 0.0+ to 28.0+ months) at the time of study closure. Of the 19 patients with objective response, 7 patients had not had an event of disease progression or death at the time of study closure; duration of response for these patients ranged from 3.5 to 28 months. Of the 11 patients with CR, 45% had response durations of over 1 year. Adverse events (AEs) occurring in ≥25% of patients during the retreatment period were generally similar in type and frequency to those observed in the pivotal trials of brentuximab vedotin monotherapy, with the exception of peripheral neuropathy, which is known to have a cumulative effect. Grade 3 or higher events were observed in 48% of patients; these were generally transient and managed by dose modifications or delays. Deaths due to AEs occurred in 3 HL patients; none were considered to be related to brentuximab vedotin retreatment. Discussion With the exception of a higher rate of peripheral motor neuropathy

  2. BMP type I receptor ALK2 is required for angiotensin II-induced cardiac hypertrophy.

    PubMed

    Shahid, Mohd; Spagnolli, Ester; Ernande, Laura; Thoonen, Robrecht; Kolodziej, Starsha A; Leyton, Patricio A; Cheng, Juan; Tainsh, Robert E T; Mayeur, Claire; Rhee, David K; Wu, Mei X; Scherrer-Crosbie, Marielle; Buys, Emmanuel S; Zapol, Warren M; Bloch, Kenneth D; Bloch, Donald B

    2016-04-15

    Bone morphogenetic protein (BMP) signaling contributes to the development of cardiac hypertrophy. However, the identity of the BMP type I receptor involved in cardiac hypertrophy and the underlying molecular mechanisms are poorly understood. By using quantitative PCR and immunoblotting, we demonstrated that BMP signaling increased during phenylephrine-induced hypertrophy in cultured neonatal rat cardiomyocytes (NRCs), as evidenced by increased phosphorylation of Smads 1 and 5 and induction of Id1 gene expression. Inhibition of BMP signaling with LDN193189 or noggin, and silencing of Smad 1 or 4 using small interfering RNA diminished the ability of phenylephrine to induce hypertrophy in NRCs. Conversely, activation of BMP signaling with BMP2 or BMP4 induced hypertrophy in NRCs. Luciferase reporter assay further showed that BMP2 or BMP4 treatment of NRCs repressed atrogin-1 gene expression concomitant with an increase in calcineurin protein levels and enhanced activity of nuclear factor of activated T cells, providing a mechanism by which BMP signaling contributes to cardiac hypertrophy. In a model of cardiac hypertrophy, C57BL/6 mice treated with angiotensin II (A2) had increased BMP signaling in the left ventricle. Treatment with LDN193189 attenuated A2-induced cardiac hypertrophy and collagen deposition in left ventricles. Cardiomyocyte-specific deletion of BMP type I receptor ALK2 (activin-like kinase 2), but not ALK1 or ALK3, inhibited BMP signaling and mitigated A2-induced cardiac hypertrophy and left ventricular fibrosis in mice. The results suggest that BMP signaling upregulates the calcineurin/nuclear factor of activated T cell pathway via BMP type I receptor ALK2, contributing to cardiac hypertrophy and fibrosis.

  3. Echocardiographic assessment of systolic pulmonary arterial pressure in HIV-positive patients.

    PubMed

    Rasoulinejad, Mehrnaz; Moradmand Badie, Sina; Salehi, Mohammad Reza; Seyed Alinaghi, Seyed Ahmad; Dehghan Manshadi, Seyed Ali; Zakerzadeh, Nahid; Foroughi, Maryam; Jahanjo Amin Abad, Fatemeh; Moradmand Badie, Banafsheh

    2014-01-01

    Pulmonary hypertension is rare but is one of the complications that occur due to HIV infection. Symptoms of HIV-associated pulmonary arterial hypertension are often non-specific but the main symptom of the disease is dyspnea. In this cross-sectional study, we measured systolic pulmonary arterial pressure (SPAP) by echocardiographic methods among HIV-positive patients who received ART. This research is a descriptive, cross-sectional study of 170 HIV-positive patients that was conducted in Imam-Khomeini hospital, Tehran, Iran during 2011-2013. All patients regularly received antiretroviral therapy at least for recent 2 years. There were not any cardiopulmonary symptoms (cough, dyspnea, exertional fatigue and chest discomfort) in these patients. All participants underwent echocardiography to estimate SPAP. The participants comprised 108 males (63.5%) and 62 females (46.5%). The mean age of patients was 41 years old, and the mean duration of HIV infection was 5.5 years. The mean CD4 cell count was 401 cell/µl. The principal regimen of antiretroviral therapy included two nucleoside reverse transcriptase inhibitor (NRTI) and one non-nucleoside reverse transcriptase inhibitor (NNRTI) in the hospital. The mean of systolic pulmonary arterial pressure was 25 mmHg in the participants; 156 (93.4%) of them had SPAP ≤ 30 mmHg (normal), six (3.6%) had SPAP: 31-35 mmHg (borderline) and five (3%) had SPAP > 35 mmHg (pulmonary hypertension). Our results indicated a significant increase of pulmonary hypertension in asymptomatic HIV-positive patients that had no association with any other risk factor. Also, antiretroviral therapy was not a risk factor for pulmonary hypertension in this study.

  4. Electromyography of symmetrical trunk movements and trunk position sense in chronic stroke patients

    PubMed Central

    Liao, Chien-Fen; Liaw, Lih-Jiun; Wang, Ray-Yau; Su, Fong-Chin; Hsu, Ar-Tyan

    2015-01-01

    [Purpose] To explore the differences in bilateral trunk muscle activation between chronic stroke patients and healthy controls, this study investigated the symmetry index and cross-correlation of trunk muscles during trunk flexion and extension movements. This study also assessed the differences in trunk reposition error between groups and the association between trunk reposition error and bilateral trunk muscle activation. [Subjects and Methods] Fifteen stroke patients and 15 age- and gender-matched healthy subjects participated. Bilateral trunk muscle activations were collected by electromyography during trunk flexion and extension. Trunk reposition errors in trunk flexion and extension directions were recorded by a Qualisys motion capture system. [Results] Compared with the healthy controls, the stroke patients presented lower symmetrical muscle activation of the bilateral internal oblique and lower cross-correlation of abdominal muscles during trunk flexion, and lower symmetry index and cross-correlation of erector spinae in trunk extension. They also showed a larger trunk extension reposition error. A smaller trunk reposition error was associated with higher cross-correlation of bilateral trunk muscles during trunk movements in all subjects. [Conclusion] Trunk muscle function during symmetrical trunk movements and trunk reposition sense were impaired in the chronic stroke patients, and trunk position sense was associated with trunk muscle functions. Future studies should pay attention to symmetrical trunk movements as well as trunk extension position sense for patients with chronic stroke. PMID:26504267

  5. Relapsing inappropriate antidiuretic hormone secretion in an anti-aquaporin-4 antibody positive paediatric patient.

    PubMed

    Kravljanac, Ruzica; Martinović, Vanja; Dujmović, Irena; Djurić, Milena; Kuzmanović, Miloš; Weinshenker, Brian G; Drulović, Jelena

    2014-09-01

    Paediatric patients with the syndrome of an inappropriate antidiuretic hormone secretion (SIADH), as a manifestation of inflammatory demyelinating disorders of the central nervous system, have been rarely described until now, in only a few cases of neuromyelitis optica spectrum disorders (NMOSDs). We present a case of relapsing SIADH associated with NMOSD, in an anti-aquaporin-4 antibody positive 14-year-old girl, who is, to our best knowledge, the first reported paediatric patient with relapsing SIADH and NMOSD. Additionally, our case further supports the notion that paediatric encephalomyelitis associated with SIADH should suggest the diagnosis of NMOSD.

  6. Benign lymphoepithelial cysts of parotid and submandibular glands in a HIV-positive patient

    PubMed Central

    Shivhare, Peeyush; Shankarnarayan, Lata; Jambunath, Usha; Basavaraju, Sowbhagya Malligere

    2015-01-01

    Patients with human immunodeficiency virus (HIV) infection have been reported to have parotid swellings of various types such as diffuse infiltrative lymphocytosis syndrome, parotitis, intraparotid lymphadenopathy, benign lymphoepithelial cyst (BLEC), as well as salivary gland neoplasms such as adenoid cystic carcinoma, Kaposi sarcoma and lymphoma. LECs in the parotid gland are uncommon benign entities with increased incidence associated with HIV infection. We are presenting a case of 28-year-old HIV-positive patient with BLECs in the parotid and submandibular glands. PMID:26097320

  7. AlkB homolog 3-mediated tRNA demethylation promotes protein synthesis in cancer cells

    PubMed Central

    Ueda, Yuko; Ooshio, Ikumi; Fusamae, Yasuyuki; Kitae, Kaori; Kawaguchi, Megumi; Jingushi, Kentaro; Hase, Hiroaki; Harada, Kazuo; Hirata, Kazumasa; Tsujikawa, Kazutake

    2017-01-01

    The mammalian AlkB homolog (ALKBH) family of proteins possess a 2-oxoglutarate- and Fe(II)-dependent oxygenase domain. A similar domain in the Escherichia coli AlkB protein catalyzes the oxidative demethylation of 1-methyladenine (1-meA) and 3-methylcytosine (3-meC) in both DNA and RNA. AlkB homolog 3 (ALKBH3) was also shown to demethylate 1-meA and 3-meC (induced in single-stranded DNA and RNA by a methylating agent) to reverse the methylation damage and retain the integrity of the DNA/RNA. We previously reported the high expression of ALKBH3 in clinical tumor specimens and its involvement in tumor progression. In this study, we found that ALKBH3 effectively demethylated 1-meA and 3-meC within endogenously methylated RNA. Moreover, using highly purified recombinant ALKBH3, we identified N6-methyladenine (N6-meA) in mammalian transfer RNA (tRNA) as a novel ALKBH3 substrate. An in vitro translation assay showed that ALKBH3-demethylated tRNA significantly enhanced protein translation efficiency. In addition, ALKBH3 knockdown in human cancer cells impaired cellular proliferation and suppressed the nascent protein synthesis that is usually accompanied by accumulation of the methylated RNAs. Thus, our data highlight a novel role for ALKBH3 in tumor progression via RNA demethylation and subsequent protein synthesis promotion. PMID:28205560

  8. Structural and mechanistic insight into alkane hydroxylation by Pseudomonas putida AlkB.

    PubMed

    Alonso, Hernan; Kleifeld, Oded; Yeheskel, Adva; Ong, Poh C; Liu, Yu C; Stok, Jeanette E; De Voss, James J; Roujeinikova, Anna

    2014-06-01

    Pseudomonas putida GPo1 alkane hydroxylase (AlkB) is an integral membrane protein that catalyses the hydroxylation of medium-chain alkanes (C3-C12). 1-Octyne irreversibly inhibits this non-haem di-iron mono-oxygenase under turnover conditions, suggesting that it acts as a mechanism-based inactivator. Upon binding to the active site, 1-octyne is postulated to be oxidized to an oxirene that rapidly rearranges to a reactive ketene which covalently acylates nearby residues, resulting in enzyme inactivation. In analysis of inactivated AlkB by LC-MS/MS, several residues exhibited a mass increase of 126.1 Da, corresponding to the octanoyl moiety derived from oxidative activation of 1-octyne. Mutagenesis studies of conserved acylated residues showed that Lys18 plays a critical role in enzyme function, as a single-point mutation of Lys18 to alanine (K18A) completely abolished enzymatic activity. Finally, we present a computational 3D model structure of the transmembrane domain of AlkB, which revealed the overall packing arrangement of the transmembrane helices within the lipid bilayer and the location of the active site mapped by the 1-octyne modifications.

  9. Silicone implant and primary breast ALK1-negative anaplastic large cell lymphoma, fact or fiction?

    PubMed Central

    Li, Shiyong; Lee, Andrew K

    2010-01-01

    The safety of silicone-based implant for mammoplasty has been debated for decades. A series of anecdotal case reports and a recent epidemiological case-control study have suggested a possible association between silicone implant and the development of primary breast ALK1-negative anaplastic large cell lymphoma (ALCL), a rare type of peripheral T-cell lymphoma. In this report, we describe an additional case of primary breast ALK1-negative ALCL in the fibrous capsule and cystic fluid of silicone breast implant in a 58 year old woman who underwent breast reconstructive surgery after lumpectomy for her infiltrating breast adenocarcinoma. Morphologically and immunohistochemically, the lymphoma cells may be confused with recurrent infiltrating breast adenocarcinoma or other non-hematolymphoid malignancies. Molecular studies were needed to determine T-lineage differentiation of the malignant lymphoma cells. We will also review the case reports and case series published in the English literature and discuss our current understanding of silicone implant in primary breast ALK1-negative ALCL. PMID:19918336

  10. Structure of Escherichia coli AlkA in Complex with Undamaged DNA*

    PubMed Central

    Bowman, Brian R.; Lee, Seongmin; Wang, Shuyu; Verdine, Gregory L.

    2010-01-01

    Because DNA damage is so rare, DNA glycosylases interact for the most part with undamaged DNA. Whereas the structural basis for recognition of DNA lesions by glycosylases has been studied extensively, less is known about the nature of the interaction between these proteins and undamaged DNA. Here we report the crystal structures of the DNA glycosylase AlkA in complex with undamaged DNA. The structures revealed a recognition mode in which the DNA is nearly straight, with no amino acid side chains inserted into the duplex, and the target base pair is fully intrahelical. A comparison of the present structures with that of AlkA recognizing an extrahelical lesion revealed conformational changes in both the DNA and protein as the glycosylase transitions from the interrogation of undamaged DNA to catalysis of nucleobase excision. Modeling studies with the cytotoxic lesion 3-methyladenine and accompanying biochemical experiments suggested that AlkA actively interrogates the minor groove of the DNA while probing for the presence of lesions. PMID:20843803

  11. A novel immunohistochemical classifier to distinguish Hodgkin lymphoma from ALK anaplastic large cell lymphoma.

    PubMed

    Döring, Claudia; Hansmann, Martin-Leo; Agostinelli, Claudio; Piccaluga, Pier P; Facchetti, Fabio; Pileri, Stefano; Küppers, Ralf; Newrzela, Sebastian; Hartmann, Sylvia

    2014-10-01

    Classical Hodgkin lymphoma and ALK(-) anaplastic large cell lymphoma share many features like strong CD30 expression and usually loss of B- and T-cell markers. However, their clinical course is dramatically different with curability rates of >90% for classical Hodgkin lymphoma and an unfavorable prognosis for anaplastic large cell lymphoma. Classical Hodgkin lymphoma and ALK(-) anaplastic large cell lymphoma can usually be distinguished by PAX5 expression in the Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma and expression of cytotoxic molecules in tumor cells of anaplastic large cell lymphoma. However, in some cases the differential diagnosis is difficult owing to absence of established markers. To be able to better classify these cases, we reevaluated gene expression data of microdissected tumor cells of both lymphomas for differentially expressed genes. A classifier was established, comprising four genes strongly expressed in Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma (MDC/CCL22, CD83, STAT3, and TUBB2B). Applying this classifier to a test cohort, Hodgkin lymphoma was successfully distinguished from ALK(-) anaplastic large cell lymphoma with an accuracy of 97% (43/44). MDC/CCL22, CD83, and STAT3 have also been found to be expressed in antigen-presenting cells. Therefore, based on our established classifier, Hodgkin and Reed-Sternberg cells differ from tumor cells of anaplastic large cell lymphoma, which can successfully be applied for practical purposes in histopathologic diagnostics.

  12. Structure of Escherichia coli AlkA in Complex with Undamaged DNA

    DOE PAGES

    Bowman, Brian R.; Lee, Seongmin; Wang, Shuyu; ...

    2010-11-22

    Because DNA damage is so rare, DNA glycosylases interact for the most part with undamaged DNA. Whereas the structural basis for recognition of DNA lesions by glycosylases has been studied extensively, less is known about the nature of the interaction between these proteins and undamaged DNA. Here we report the crystal structures of the DNA glycosylase AlkA in complex with undamaged DNA. The structures revealed a recognition mode in which the DNA is nearly straight, with no amino acid side chains inserted into the duplex, and the target base pair is fully intrahelical. A comparison of the present structures withmore » that of AlkA recognizing an extrahelical lesion revealed conformational changes in both the DNA and protein as the glycosylase transitions from the interrogation of undamaged DNA to catalysis of nucleobase excision. Modeling studies with the cytotoxic lesion 3-methyladenine and accompanying biochemical experiments suggested that AlkA actively interrogates the minor groove of the DNA while probing for the presence of lesions.« less

  13. [Ophthalmic manifestations of toxoplasmosis in a human immunodeficiency virus-positive patient. Description of a case].

    PubMed

    Hermida Pérez, J A; Bermejo Hernandez, Á; Sobenes Gutierrez, R

    2014-03-01

    Toxoplasmosis is an infection of worldwide distribution caused by Toxoplasma gondii, and infects a large proportion of the world population. Only under certain circumstances of severe immunosuppression can the parasite reactivate and cause disease. The most common form of presentation of this pathology in patients with positive HIV is the brain abscess. One of the extra-cerebral forms is toxoplasmic chorioretinitis, which could lead to a chronic active form of a slowly progressive retinitis. Diagnosis is made by observing the eye fundus and confirmed by the scarring obtained after specific treatment. We report a case of a patient with diabetes and positive HIV, in whom a toxoplasmic scar injury was detected in the annual retinography follow-up. A conservative therapeutic approach was decided, with regular check-ups for possible detection of disease activation.

  14. Orofacial manifestations of histoplasmosis in HIV-positive patients: a case report.

    PubMed

    Gomes Ferreira, O; Vieira Fernandes, A; Sebastião Borges, A; Simão Ferreira, M; Mota Loyola, A

    2001-01-01

    Amongst the main opportunistic diseases that affect the HIV-positive patient, histoplasmosis is found. This systemic mycosis caused by the fungus Histoplasma capsulatum has the capacity to disseminate from the lung to the skin and oral mucosa. Oral lesions of histoplasmosis can be found with ulcerated or nodular aspect, being always very painful and infiltrating the mucosa. When they are present in the mouth, they strongly indicate the presence of some kind of immunosuppression. This study shows the disease's evolution in an HIV-positive patient, who presented several ulcerated lesions in the oral cavity and facial skin. The symptomatology and clinical aspects of the lesions were not specific for the disease, and due to this, the diagnosis was obtained by cytological smear and oral biopsy. The results of the exams defined the disseminated picture of the infection. The treatment plan involved the use of amphotericin B for the lesions' remission, and, following this, itraconazole was administered in the maintenance phase.

  15. Applying positioning theory to examine interactions between simulated patients and medical students: a narrative analysis.

    PubMed

    Sargeant, Sally; McLean, Michelle; Green, Patricia; Johnson, Patricia

    2017-03-01

    In their journey to becoming doctors, students engage with a range of teachers and trainers. Among these are simulated patients (SPs), who, through role-playing, assist students to develop their communication and physical examination skills, in contexts of formative and summative assessments. This paper explores the teaching and learning relationship between medical students and SPs, and considers how this might affect feedback and assessment. 14 SPs were interviewed on the subject of medical students' professional identity development in 2014. Data were examined using narrative analysis in conjunction with positioning theory to identify the positions that SPs assigned to themselves and to students. Narrative analysis yielded three interpretative positioning themes: Occupational, familial and cultural and discursive and embodied positioning. The interview process revealed that SPs adopt different positions intra-and interpersonally. SPs appear to hold dissonant perceptions of students in terms relating to their emerging professional identities, which may confound assessment and feedback. Training should include reflections on the SP/student relationship to uncover potential biases and positions, giving SPs the opportunity to reflect on and manage their individual and occupational selves.

  16. High Incidence of Germline BRCA Mutation in Patients with ER low positive/PR low positive/HER-2 neu negative Tumors

    PubMed Central

    Sanford, Rachel Ann; Song, Juhee; Gutierrez-Barrera, Angelica M.; Profato, Jessica; Woodson, Ashley; Litton, Jennifer Keating; Bedrosian, Isabelle; Albarracin, Constance T.; Valero, Vicente; Arun, Banu

    2016-01-01

    Purpose 2015 NCCN guidelines recommend genetic counseling and germline BRCA mutation testing be offered to women under age 60 with triple negative breast cancer (TNBC). As a result of the 2010 ASCO/CAP guidelines in breast cancer, patients with breast cancers that are ER or PR low-positive (1–9% on immunohistochemistry) are no longer strictly considered to have TNBC and may not be referred for genetic counseling. However, the incidence of BRCA mutation in patients with hormone receptor (HR) low-positive breast cancers remains unknown, and current ASCO/CAP guidelines may result in under-testing for BRCA mutation. Methods We reviewed a prospectively maintained research database of breast cancer patients evaluated at UT MD Anderson Cancer Center between 2004 and 2014, identifying 314 patients with ER<10%, PR<10%, HER-2 neu negative breast cancers with known BRCA mutation status. Results 314 patients had breast cancers expressing ER and PR <10%; 238 (75.8%) had HR negative (ER and PR <1%) cancers and 76 (24.2%) had HR low-positive (ER and/or PR 1–9%) cancers. Among patients with HR negative tumors, 86 of 238 (36.1%) had a BRCA 1/2 mutation, while among the HR low-positive group, 30 of 76 (39.5%) had a BRCA 1/2 mutation. In multivariate analysis, HR status (HR<1% vs. HR 1–9%) was not significantly associated with BRCA 1/2 mutation. Conclusion The incidence of BRCA 1/2 mutation is similar in patients with HR low-positive and HR negative breast cancers. We recommend offering genetic counseling and BRCA testing to patients under age 60 with ER low-positive breast cancers. PMID:26280679

  17. A software tool of digital tomosynthesis application for patient positioning in radiotherapy.

    PubMed

    Yan, Hui; Dai, Jian-Rong

    2016-03-08

    Digital Tomosynthesis (DTS) is an image modality in reconstructing tomographic images from two-dimensional kV projections covering a narrow scan angles. Comparing with conventional cone-beam CT (CBCT), it requires less time and radiation dose in data acquisition. It is feasible to apply this technique in patient positioning in radiotherapy. To facilitate its clinical application, a software tool was developed and the reconstruction processes were accelerated by graphic process-ing unit (GPU). Two reconstruction and two registration processes are required for DTS application which is different from conventional CBCT application which requires one image reconstruction process and one image registration process. The reconstruction stage consists of productions of two types of DTS. One type of DTS is reconstructed from cone-beam (CB) projections covering a narrow scan angle and is named onboard DTS (ODTS), which represents the real patient position in treatment room. Another type of DTS is reconstructed from digitally reconstructed radiography (DRR) and is named reference DTS (RDTS), which represents the ideal patient position in treatment room. Prior to the reconstruction of RDTS, The DRRs are reconstructed from planning CT using the same acquisition setting of CB projections. The registration stage consists of two matching processes between ODTS and RDTS. The target shift in lateral and longitudinal axes are obtained from the matching between ODTS and RDTS in coronal view, while the target shift in longitudinal and vertical axes are obtained from the matching between ODTS and RDTS in sagittal view. In this software, both DRR and DTS reconstruction algorithms were implemented on GPU environments for acceleration purpose. The comprehensive evaluation of this software tool was performed including geometric accuracy, image quality, registration accuracy, and reconstruction efficiency. The average correlation coefficient between DRR/DTS generated by GPU-based algorithm

  18. Factors Associated With Smoking Status among HIV-Positive Patients in Routine Clinical Care

    PubMed Central

    Zyambo, Cosmas M; Willig, James H; Cropsey, Karen L; Carson, April P; Wilson, Craig; Tamhane, Ashutosh R; Westfall, Andrew O; Burkholder, Greer A

    2015-01-01

    Background Treatment-related reductions in morbidity and mortality among human immunodeficiency virus (HIV)-positive patients have been attenuated by cigarette smoking, which increases risk of cardiovascular, respiratory, and neoplastic diseases. This study investigated factors associated with smoking status among HIV-positive patients. Methods This cross-sectional study included 2,464 HIV-positive patients attending the HIV Clinic at the University of Alabama at Birmingham between April 2008 and December 2013. Smoking status (current, former, never), psychosocial factors, and clinical characteristics were assessed. Multinomial logistic regression was used to obtain unadjusted and adjusted odds ratios (OR) and 95% confidence intervals (CI) for the association of the various factors with smoking status. Results Among HIV-positive patients (mean age 45 years, 75% male, 55% African-American), the majority reported a history of smoking (39% current and 22% former smokers). In adjusted models, patient characteristics associated with increased odds of current smoking were male gender (OR for heterosexual men, 1.8 [95% CI: 1.3–2.6]; for men who have sex with men, 1.5 [1.1–1.9]), history of respiratory diseases (1.5 [1.2–1.9]), unsuppressed HIV viral load (>50 copies/mL) (1.5 [1.1–1.9]), depression (1.6 [1.3–2.0]), anxiety (1.6 [1.2–2.1]), and prior and current substance abuse (4.7 [3.6–6.1] and 8.3 [5.3–13.3] respectively). Male gender, anxiety, and substance abuse were also associated with being a former smoker. Conclusions Smoking was common among HIV-positive patients, with several psychosocial factors associated with current and former smoking. This suggests smoking cessation programs in HIV clinic settings may achieve greater impact by integrating interventions that also address illicit substance abuse and mental health. PMID:26767146

  19. Negative Religious Coping, Positive Religious Coping, and Quality of Life Among Hemodialysis Patients

    PubMed Central

    Taheri-Kharameh, Zahra; Zamanian, Hadi; Montazeri, Ali; Asgarian, Azadeh; Esbiri, Roya

    2016-01-01

    Background Religious coping is known as a main resource influencing how individuals cope with the complications and stressors of chronic disease. Objectives The aim of this study was to assess the relationship between religious coping and quality of life among hemodialysis patients. Methods This cross-sectional study was conducted in Qom, Iran, from June 2012 to July 2013. Ninety-five end-stage renal disease (ESRD) patients undergoing hemodialysis were selected via the convenience sampling method. Data were collected via a questionnaire comprising items on sociodemographic information, quality of life, the anxiety and depression scale, and religious coping. Following this, the data were analyzed using descriptive statistics and logistic regression analysis. Results The mean age of patients was 50.4 (standard deviation [SD] = 15.7) years, and most were male (61%). The mean score for positive religious coping was 23.38 (SD = 4.17), while that for negative religious coping was 11.46 (SD = 4.34). It was found that 53.6% of patients had higher than the mean score of positive religious coping, while those with negative religious coping made up 37.9%. Negative religious coping was associated with worse quality of life, including physical functioning (odds ratio [OR] = 0.72; P = 0.009), role physical (OR = 0.79; P = 0.04), vitality (OR = 0.62; P = 0.005), social functioning (OR = 0.69; P = 0.007), and mental health (OR = 0.58; P = 0.01) after controlling for sociodemographic, clinical, and anxiety and depression variables. Conclusions The results indicated that patients with negative religious coping abilities were at risk of a suboptimal quality of life. Incorporating religious support in the care of hemodialysis patients may be helpful in improving quality of life in this patient population. Further longitudinal studies are needed to determine whether these associations are causal and the direction of effect. PMID:27896237

  20. Decreased PD-1 positive blood follicular helper T cells in patients with psoriasis.

    PubMed

    Shin, Dongyun; Kim, Dae Suk; Kim, Sung Hee; Je, Jung Hwan; Kim, Hee Ju; Young Kim, Do; Kim, Soo Min; Lee, Min-Geol

    2016-10-01

    Follicular helper T (Tfh) cells are recently characterized subset of helper T cells, which are initially found in the germinal centers of B cell follicles. The major role of Tfh cells is helping B cell activation and antibody production during humoral immunity. Recently, blood Tfh cells were shown to be associated with autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, bullous pemphigoid and psoriasis. There is only one study which investigated Tfh cells in psoriasis patients. Therefore, in this study, we evaluated and analyzed blood Tfh cells in Korean patients with psoriasis. A total of 28 psoriasis patients and 16 healthy controls were enrolled. The frequency and absolute number of CXCR5(+)PD-1(+) Tfh cells were decreased in patients with psoriasis compared to healthy controls. CD4(+)CXCR5(+) T cells and CXCR5(+)ICOS(+) Tfh cells did not show differences. The frequency and absolute number of CXCR5(+)PD-1(+) Tfh cells in psoriasis patients negatively correlated with erythrocyte sedimentation rate and positively correlated with disease duration. The absolute number of CXCR5(+)ICOS(+) Tfh cells also showed positive correlation with disease duration. However, the subpopulations of Tfh cells did not correlate with Psoriasis Area and Severity Index. Serum interleukin-21 level was significantly increased in psoriasis patients compared to healthy controls, however, its level did not correlate with clinical and experimental parameters of psoriasis patients. These findings suggest the decreased function of Tfh cells in psoriasis, which could result in attenuated B cell immune responses in the pathogenesis of psoriasis. However, further investigations are necessary to confirm the function of Tfh cells in psoriasis vulgaris.

  1. Trastuzumab improves locoregional control in HER2-positive breast cancer patients following adjuvant radiotherapy

    PubMed Central

    Cao, Lu; Cai, Gang; Xu, Fei; Yang, Zhao-Zhi; Yu, Xiao-Li; Ma, Jin-Li; Zhang, Qian; Wu, Jiong; Guo, Xiao-Mao; Chen, Jia-Yi

    2016-01-01

    Abstract The benefit of adjuvant trastuzumab in disease-free and overall survival for human epidermal receptor 2–positive (HER2+) breast cancer patients is well established. However, the effect of trastuzumab on locoregional control remains unclear, particularly in patients treated with adjuvant radiotherapy (RT). In this study, we investigated the locoregional benefit of trastuzumab in patients with HER2+ breast cancer after adjuvant RT. Using a single institutional database, we identified 278 patients with stage II/III invasive HER2+ breast tumors receiving adjuvant RT between January 2008 and July 2011. We compared the locoregional outcomes of 134 patients who received trastuzumab to 144 patients without trastuzumab within the same period. Clinical and biological factors that might impact on the locoregional benefit of trastuzumab were also assessed. At the median follow-up of 45 months, trastuzumab significantly lowered the risk of locoregional recurrence (LRR) with a 3-year LRR rate of 2.4% versus 7.5% for the cohort with and without trastuzumab (P = 0.019). Trastuzumab was associated with a more significant locoregional benefit in the hormone receptor–positive (HR+)/HER2+ subgroup, with a 3-year LRR of 0% versus 6.7% in the cohort with and without trastuzumab (P = 0.027). For HR−/HER2+ breast tumor patients, the 3-year LRR rate was still lower for the cohort with trastuzumab (4.7% vs 8.6%). However, statistical significance was not found (P = 0.179). Both univariate and multivariate analyses confirmed that trastuzumab treatment was the only significant predictive factor for LRR (hazard ratio, 4.05; 95% confidence interval, 1.07–15.35; P = 0.039). Adjuvant trastuzumab in addition to RT is associated with significant reduced LRR risk in HER2+ breast cancer. PMID:27512838

  2. Unusual manifestation of cutaneous toxoplasmosis in a HIV-positive patient.

    PubMed

    Fong, M Y; Wong, K T; Rohela, M; Tan, L H; Adeeba, K; Lee, Y Y; Lau, Y L

    2010-12-01

    We report a case of unusual cutaneous toxoplasmosis manifestation in a HIV-positive patient. He presented with hard and painful nodular lesions on the arms, hands and chest. Serology tests for anti-Toxoplasma antibody were negative. However, histopathologic examination of the lesion revealed foci of macrophages containing crescent-shaped organisms resembling the zoites of the protozoan parasite Toxoplasma gondii. Ultrastructure examination under electron microscopy and PCR confirmed the organism as T. gondii.

  3. Arnold-Chiari type I malformation presenting as benign paroxysmal positional vertigo in an adult patient.

    PubMed

    Unal, M; Bagdatoglu, C

    2007-03-01

    Arnold-Chiari malformations are a group of congenital hindbrain and spinal cord abnormalities characterized by herniation of the contents of the posterior cranial fossa caudally through the foramen magnum into the upper cervical spine. It is important to recognize Arnold-Chiari type I malformation in the differential diagnosis of adult vertigo cases. We present a 51-year-old patient with Arnold-Chiari type I malformation that was initially diagnosed as posterior semicircular canal benign paroxysmal positional vertigo.

  4. Patients Respond More Positively to Physicians Who Focus on Their Ideal Affect

    PubMed Central

    Sims, Tamara; Tsai, Jeanne L.

    2014-01-01

    Previous findings suggest that patients choose physicians whose affective focus matches how they ideally want to feel (Sims et al., 2014). For instance, the more people wanted to feel excitement, the more likely they were to hypothetically choose a new physician who promoted excitement. What remains unknown is whether this match shapes how patients actually respond to physicians after being assigned to them (i.e., whether they adhere to physicians’ recommendations more and evaluate physicians more positively). To this end, community adults reported their global ideal affect and actual affect (how they ideally want to feel and actually feel during a typical week, respectively), and were randomly assigned to receive health recommendations from either a physician who expressed and promoted high arousal positive states (HAP) (e.g., excitement), or one who expressed and promoted low arousal positive states (LAP) (e.g., calm). For the next five days, participants reported their daily adherence to the recommendations and their daily ideal and actual affect. At the end of the week, participants evaluated their physician. As predicted, the more participants wanted to feel HAP, the more they adhered to the “HAP-focused” physician’s recommendations, and the more participants wanted to feel LAP, the more they adhered to the “LAP-focused” physician’s recommendations. Participants also evaluated their physician more positively when his affective focus matched their ideal affect. Neither global nor daily actual affect systematically predicted how patients responded to their physicians. These findings suggest that patients respond better to physicians whose affective focus matches their ideal affect. PMID:25313670

  5. Automated Patient Positioning Guided by Cone-Beam CT for Prostate Radiotherapy

    DTIC Science & Technology

    2008-01-01

    phantom consisting of bladder, prostate, rectum and bony structures. The study was detailed in the previous annual progress report. We have further...developed and clinically implemented an automated patient positioning strategy and tested with phantom experiments; (2) developed image-to-projection...used. Figure 1 shows an example of uch a plot for the periodically moving phantom . The projections re phase-tagged according to the resultant sinusoidal

  6. False-positive indium-111 labeled leukocyte scintigram in a patient with a painful hip prosthesis

    SciTech Connect

    Feldman, N.; Makler, P.T. Jr.; Alavi, A.

    1986-01-01

    A Tronzo hip prosthesis is designed to elicit an inflammatory reaction in order to promote prosthesis stability. A three-phased bone scan and Ga-67 imaging in conjunction with physical examination and laboratory findings failed to demonstrate evidence for osteomyelitis in a patient with a painful hip prosthesis, in whom images obtained with In-111-labeled leukocytes were positive. This observation demonstrated that the interpretation of the latter technique in demonstrating inflammation can cause a false impression of an infectious process.

  7. Positional convulsant syncope in a pacemaker patient following insulation break of the right ventricular lead

    PubMed Central

    Ben Lassoued, Mehdi; Baatour, Makram; Haggui, Abdeddayem; Lamine, Khaled

    2014-01-01

    In spite of the advances made in the technology of pacemakers which resulted in a decrease in the incidence of pacemaker lead fracture, the latter remains a potential complication of implanted pacemakers manufactured in the early days. In this report, we present a case of fracture of the unipolar electrode diagnosed by an emergency physician in a patient on a pacemaker for 10 years who presented to the emergency department with positional convulsant syncopes. PMID:24827652

  8. Patients respond more positively to physicians who focus on their ideal affect.

    PubMed

    Sims, Tamara; Tsai, Jeanne L

    2015-06-01

    Previous findings suggest that patients choose physicians whose affective focus matches how they ideally want to feel (Sims et al., 2014). For instance, the more people wanted to feel excitement, the more likely they were to hypothetically choose a new physician who promoted excitement. What remains unknown is whether this match shapes how patients actually respond to physicians after being assigned to them (i.e., whether they adhere to physicians' recommendations more and evaluate physicians more positively). To this end, community adults reported their global ideal affect and actual affect (how they ideally want to feel and actually feel during a typical week, respectively), and were randomly assigned to receive health recommendations from either a physician who expressed and promoted high arousal positive states (HAP) (e.g., excitement), or one who expressed and promoted low arousal positive states (LAP) (e.g., calm). For the next 5 days, participants reported their daily adherence to the recommendations and their daily ideal and actual affect. At the end of the week, participants evaluated their physician. As predicted, the more participants wanted to feel HAP, the more they adhered to the "HAP-focused" physician's recommendations, and the more participants wanted to feel LAP, the more they adhered to the "LAP-focused" physician's recommendations. Participants also evaluated their physician more positively when his affective focus matched their ideal affect. Neither global nor daily actual affect systematically predicted how patients responded to their physicians. These findings suggest that patients respond better to physicians whose affective focus matches their ideal affect.

  9. Isolated penile Kaposi's sarcoma in a HIV-positive patient stable on treatment for three years.

    PubMed

    Lebari, Dornubari; Gohil, Jesal; Patnaik, Lipsita; Wasef, Wafaa

    2014-07-01

    Kaposi's sarcoma (KS) is an AIDS-defining condition. Typically, KS affects the skin with or without visceral involvement. The extensive use of antiretroviral therapy (ART) has decreased the incidence of KS amongst the HIV-positive population. We report a case of a 40-year-old man with HIV-1 infection with CD4 count of 551 cells/mm(3)and an undetectable viral load who presented with two skin-coloured KS lesions on the prepuce of the penis. Diagnosis was confirmed by histopathology. He had been commenced on ART three years earlier with a nadir CD4 count of 255 cells/mm(3) He had achieved and maintained viral suppression since commencing ART. The patient was initially treated with cryotherapy and 5% imiquimod as the lesions were presumed to be warts. The lack of response to treatment prompted further investigation. We carried out a literature search of published cases of penile KS over the past 10 years. The majority of articles regarding penile KS were published in the pre-ART era and involved patients with AIDS. Over the past 10 years, published cases of penile KS have almost exclusively been in HIV-negative men. We found 10 published cases of penile KS in HIV-negative men and only one other published case of penile KS in a HIV-positive man, who had severe immune suppression with CD4 count below 200 cells/mm(3) This is the first case report to describe a HIV-positive patient stable on ART with a CD4 count above 200 cells/mm(3)and suppressed HIV-1 viral load, to develop two KS lesions on the penis. Clinicians have to remain suspicious of penile lesions and appreciate the crucial role a biopsy with histopathological analysis plays in confirming a diagnosis. In addition, this case illustrates that unusual presentations of KS can still occur in treated HIV-positive patients with sustained immune recovery.

  10. Evaluation of the optimal positioning of subcutaneous butterfly when administering injectable opioids in cancer patients

    PubMed Central

    MITREA, NICOLETA; MOSOIU, DANIELA; VOSIT-STELLER, JULIE; ROGOZEA, LILIANA

    2016-01-01

    Background and aims The increasing number of cancer patients, together with the development of new palliative care services in Romania, warrants the evaluation of nursing strategies meant to improve the level of comfort of patients who are suffering from advanced cancer. The main objective of the study was to evaluate the optimal positioning of the subcutaneous (sc) butterfly, in accordance with its resistance in the insertion tissue, the local complications that may occur, and the evaluation of the time of resistance at the insertion site (puncture) with the daily frequency of injectable opioid administration. Methods A prospective experimental pilot study was designed and conducted between January and May 2011. Patients admitted to the Hospice Casa Sperantei (Brasov, Romania) with moderate or severe cancer pain, who were receiving subcutaneously opioids, over the age of 18, with normal body index ranging from 18.5 – 22.0, were assigned randomly to one of two groups, after signing the informed consent. In group one, the butterfly was positioned with the needle bevel up – this was considered to be the control group as this modality of inserting the needle is considered standard practice; in group two the butterfly was positioned with the needle bevel down – experimental group. The drugs used for pain relief were sc tramadol for moderate pain and sc morphine for severe pain. Results Our research supported the hypothesis that the occurrence of local complications coincides with the decrease of sc butterfly resistance in time at the place of insertion, and the sc butterfly has a higher rate of resistance in time at the insertion site if the frequency of injectable opioids administration is lower (twice per day). Conclusion The positioning of the butterflies with the bevel down (experimental group) is associated with a longer resistance in time at the site of insertion, and causes fewer local complications compared to the sc butterflies positioned with the bevel

  11. [Effectiveness of intervention by the infection control team for cancer patients with a positive blood culture].

    PubMed

    Yamada, Tomoyuki; Suzuki, Kaoru; Ohi, Yukimasa; Kawanishi, Fumiko; Shibata, Yuriko; Hosomi, Makoto; Goto, Emi; Nishihara, Masami; Katsumata, Takahiro; Ukimura, Akira

    2013-11-01

    Cancer patients at a high risk of acquiring infectious diseases should be maintained in a facility where good infection control practices are followed. At our hospital, the infection control team(ICT)provides expertise, education, and support to the staff, helping them maintain proper standards, thereby minimizing the risks of infection. The ICT(established in 2004)has implemented infection control programs by employing an appropriate number of staff members after the revision of medical treatment fees in 2011. Our intervention program includes 2 general policies, namely, ordering and collection of blood cultures and intervention for the medical care of patients with positive blood cultures. In this study, we evaluated the effectiveness of our intervention for cancer patients with a positive blood culture. During the surveillance period(April 2011 to July 2012), 42 positive cases were determined to be infectious. ICT intervention was required in 37 cases. Our suggestions were accepted in 92%(34/37)of the cases, and improved outcome was estimated in 65%(22/34)of the cases. The results of our study contribute to the scientific bases on which routine clinical practices could be promoted in the future.

  12. Patient-tailored plate for bone fixation and accurate 3D positioning in corrective osteotomy.

    PubMed

    Dobbe, J G G; Vroemen, J C; Strackee, S D; Streekstra, G J

    2013-02-01

    A bone fracture may lead to malunion of bone segments, which gives discomfort to the patient and may lead to chronic pain, reduced function and finally to early osteoarthritis. Corrective osteotomy is a treatment option to realign the bone segments. In this procedure, the surgeon tries to improve alignment by cutting the bone at, or near, the fracture location and fixates the bone segments in an improved position, using a plate and screws. Three-dimensional positioning is very complex and difficult to plan, perform and evaluate using standard 2D fluoroscopy imaging. This study introduces a new technique that uses preoperative 3D imaging to plan positioning and design a patient-tailored fixation plate that only fits in one way and realigns the bone segments as planned. The method is evaluated using artificial bones and renders realignment highly accurate and very reproducible (d(err) < 1.2 ± 0.8 mm and φ(err) < 1.8° ± 2.1°). Application of a patient-tailored plate is expected to be of great value for future corrective osteotomy surgeries.

  13. Unanticipated Disturbance in Somatosensory Evoked Potentials in a Patient in Park-Bench Position.

    PubMed

    Babakhani, Babak; Schott, Martin; Hosseinitabatabaei, Narges; Jantzen, Jan-Peter

    2015-06-01

    Perioperative neuropathy is a known complication of malpositioning during anaesthesia. Somatosensory evoked potentials are used for detecting such a complication in selected surgeries. Most reports of intraoperative nerve injuries due to malpositioning are limited to injuries to the peripheral nervous system, and there have been no previously reported cases of somatosensory evoked potential monitoring disturbance attributable to position-related cerebral ischemia in the park-bench position. We present the case of a patient with glioblastoma in the park-bench position whose somatosensory evoked potential waveforms disappeared after head and neck repositioning. A prompt diagnosis of this complication and elimination of the underlying cause led to the return of somatosensory evoked potential waveforms, and there was no relevant neurologic deficit at the end of the surgery.

  14. Assessment of interfractional prostate motion in patients immobilized in the prone position using a thermoplastic shell.

    PubMed

    Ikeda, Itaru; Mizowaki, Takashi; Sawada, Yohei; Nakata, Manabu; Norihisa, Yoshiki; Ogura, Masakazu; Hiraoka, Masahiro

    2014-01-01

    The aim of this study was to evaluate the interfractional prostate motion of patients immobilized in the prone position using a thermoplastic shell. A total of 24 patients with prostate calcifications detectable using a kilo-voltage X-ray image-guidance system (ExacTrac X-ray system) were examined. Daily displacements of the calcification within the prostate relative to pelvic bony structures were calculated by the ExacTrac X-ray system. The average displacement and standard deviation (SD) in each of the left-right (LR), anterior-posterior (AP), and superior-inferior (SI) directions were calculated for each patient. Based on the results of interfractional prostate motion, we also calculated planning target volume (PTV) margins using the van Herk formula and examined the validity of the PTV margin of our institute (a 9-mm margin everywhere except posteriorly, where a 6-mm margin was applied). In total, 899 data measurements from 24 patients were obtained. The average prostate displacements ± SD relative to bony structures were 2.8 ± 3.3, -2.0 ± 2.0 and 0.2 ± 0.4 mm, in the SI, AP and LR directions, respectively. The required PTV margins were 9.7, 6.1 and 1.4 mm in the SI, AP and LR directions, respectively. The clinical target volumes of 21 patients (87.5%) were located within the PTV for 90% or more of all treatment sessions. Interfractional prostate motion in the prone position with a thermoplastic shell was equivalent to that reported for the supine position. The PTV margin of our institute is considered appropriate for alignment, based on bony structures.

  15. Assessment of interfractional prostate motion in patients immobilized in the prone position using a thermoplastic shell

    PubMed Central

    Ikeda, Itaru; Mizowaki, Takashi; Sawada, Yohei; Nakata, Manabu; Norihisa, Yoshiki; Ogura, Masakazu; Hiraoka, Masahiro

    2014-01-01

    The aim of this study was to evaluate the interfractional prostate motion of patients immobilized in the prone position using a thermoplastic shell. A total of 24 patients with prostate calcifications detectable using a kilo-voltage X-ray image-guidance system (ExacTrac X-ray system) were examined. Daily displacements of the calcification within the prostate relative to pelvic bony structures were calculated by the ExacTrac X-ray system. The average displacement and standard deviation (SD) in each of the left–right (LR), anterior–posterior (AP), and superior–inferior (SI) directions were calculated for each patient. Based on the results of interfractional prostate motion, we also calculated planning target volume (PTV) margins using the van Herk formula and examined the validity of the PTV margin of our institute (a 9-mm margin everywhere except posteriorly, where a 6-mm margin was applied). In total, 899 data measurements from 24 patients were obtained. The average prostate displacements ± SD relative to bony structures were 2.8 ± 3.3, −2.0 ± 2.0 and 0.2 ± 0.4 mm, in the SI, AP and LR directions, respectively. The required PTV margins were 9.7, 6.1 and 1.4 mm in the SI, AP and LR directions, respectively. The clinical target volumes of 21 patients (87.5%) were located within the PTV for 90% or more of all treatment sessions. Interfractional prostate motion in the prone position with a thermoplastic shell was equivalent to that reported for the supine position. The PTV margin of our institute is considered appropriate for alignment, based on bony structures. PMID:23860549

  16. Inter- and Intrafractional Positional Uncertainties in Pediatric Radiotherapy Patients With Brain and Head and Neck Tumors

    SciTech Connect

    Beltran, Chris; Krasin, Matthew J.; Merchant, Thomas E.

    2011-03-15

    Purpose: To estimate radiation therapy planning margins based on inter- and intrafractional uncertainty for pediatric brain and head and neck tumor patients at different imaging frequencies. Methods: Pediatric patients with brain (n = 83) and head and neck (n = 17) tumors (median age = 7.2 years) were enrolled on an internal review board-approved localization protocol and stratified according to treatment position and use of anesthesia. Megavoltage cone-beam CT (CBCT) was performed before each treatment and after every other treatment. The pretreatment offsets were used to calculate the interfractional setup uncertainty (SU), and posttreatment offsets were used to calculate the intrafractional residual uncertainty (RU). The SU and RU are the patient-related components of the setup margin (SM), which is part of the planning target volume (PTV). SU data was used to simulate four intervention strategies using different imaging frequencies and thresholds. Results: The SM based on all patients treated on this study was 2.1 mm (SU = 0.9 mm, RU = 1.9 mm) and varied according to treatment position (supine = 1.8 mm, prone = 2.6 mm) and use of anesthesia (with = 1.7 mm, without = 2.5 mm) because of differences in the RU. The average SU for a 2-mm threshold based on no imaging, once per week imaging, initial five images, and daily imaging was 3.6, 2.1, 2.2, and 0.9 mm, respectively. Conclusion: On the basis of this study, the SM component of the PTV may be reduced to 2 mm for daily CBCT compared with 3.5 mm for weekly CBCT. Considering patients who undergo daily pretreatment CBCT, the SM is larger for those treated in the prone position or smaller for those treated under anesthesia because of differences in the RU.

  17. Implement the RFID position based system of automatic tablets packaging machine for patient safety.

    PubMed

    Chang, Ching-Hsiang; Lai, Yeong-Lin; Chen, Chih-Cheng

    2012-12-01

    Patient safety has been regarded as the most important quality policy of hospital management. The medicine dispensing definitely plays an influential role in the Joint Commission International Accreditation Standards. The problem we are going to discuss in this paper is that the function of detecting mistakes does not exist in the Automatic Tablets packaging machine (ATPM) in the hospital pharmacy department when the pharmacists implement the replenishment of cassettes. In this situation, there are higher possibilities of placing the wrong cassettes back to the wrong positions, so that the human errors will lead to a crucial impact on total inpatients undoubtedly. Therefore, this study aims to design the RFID (Radio frequency identification) position based system (PBS) for the ATPM with passive high frequency (HF) model. At first, we placed the HF tags on each cassette and installed the HF readers on the cabinets for each position. Then, the system works on the reading loop to verify ID numbers and positions on each cassette. Next, the system would detect whether the orbit opens or not and controls the readers' working power consumption for drug storage temperature. Finally, we use the RFID PBS of the ATPM to achieve the goal of avoiding the medication errors at any time for patient safety.

  18. SU-E-J-21: Setup Variability of Colorectal Cancer Patients Treated in the Prone Position and Dosimetric Comparison with the Supine Position

    SciTech Connect

    Kim, A; Foster, J; Chu, W; Karotki, A

    2015-06-15

    Purpose: Many cancer centers treat colorectal patients in the prone position on a belly board to minimize dose to the small bowel. That may potentially Result in patient setup instability with corresponding impact on dose delivery accuracy for highly conformal techniques such as IMRT/VMAT. Two aims of this work are 1) to investigate setup accuracy of rectum patients treated in the prone position on a belly board using CBCT and 2) to evaluate dosimetric impact on bladder and small bowel of treating rectum patients in supine vs. prone position. Methods: For the setup accuracy study, 10 patients were selected. Weekly CBCTs were acquired and matched to bone. The CBCT-determined shifts were recorded. For the dosimetric study, 7 prone-setup patients and 7 supine-setup patients were randomly selected from our clinical database. Various clinically relevant dose volume histogram values were recorded for the small bowel and bladder. Results: The CBCT-determined rotational shifts had a wide variation. For the dataset acquired at the time of this writing, the ranges of rotational setup errors for pitch, roll, and yaw were [−3.6° 4.7°], [−4.3° 3.2°], and [−1.4° 1.4°]. For the dosimetric study: the small bowel V(45Gy) and mean dose for the prone position was 5.6±12.1% and 18.4±6.2Gy (ranges indicate standard deviations); for the supine position the corresponding dose values were 12.9±15.8% and 24.7±8.8Gy. For the bladder, the V(30Gy) and mean dose for prone position were 68.7±12.7% and 38.4±3.3Gy; for supine position these dose values were 77.1±13.7% and 40.7±3.1Gy. Conclusion: There is evidence of significant rotational instability in the prone position. The OAR dosimetry study indicates that there are some patients that may still benefit from the prone position, though many patients can be safely treated supine.

  19. Extreme face-to-face positioning for cataract surgery with patient seated upright in motorized wheelchair.

    PubMed

    Pajaujis, Mykolas; Injarie, Anas; Eke, Tom

    2013-05-01

    We present a case of extreme positioning for cataract surgery. The 68-year-old man was unable to lie flat and found it difficult to transfer from his motorized wheelchair. He had poor mobility due to a stroke, slept upright because of orthopnea, and his neck extension was poor. After the options and risks were discussed, surgery was performed under topical intracameral anesthesia using face-to-face positioning with the patient seated upright in his wheelchair. The operating microscope was rotated toward the horizontal, and the surgeon stood at the patient's side with the patient's face almost upright. The right-handed surgeon used a temporal corneal incision (0 degree) in the left eye and an inferior incision (270 degrees) in the right eye. Surgery and recovery were uneventful. Given a preexisting epiretinal membrane in the left eye, the patient was very happy with the uncorrected distance visual acuity outcome of 6/9 in the right eye and 6/18 in the left eye.

  20. Transfer factor in the attempted treatment of patients with HBsAg-positive chronic liver disease.

    PubMed Central

    Jain, S; Thomas, H C; Sherlock, S

    1977-01-01

    Six patients with hepatitis B surface antigen-positive (HBsAg-pos) chronic liver disease have been treated with transfer factor (TF) prepared from leucocytes of normal blood donors with no history of hepatitis, and with TF from subjects recently recovered from type B hepatitis. In three patients there were transient elevations of aspartate transaminase (AsT) after 'specific' TF, representing damage or destruction of hepatocytes, and in two of these patients there was coincidental complement consumption, suggesting that TF had stimulated production of antibody. In one other patient there was an increase in E-rosetting lymphocyte (ERL) concentration representing a change in T-lymphocyte reactivity. One of the two patients who had no measured response to TF had a primary liver cell carcinoma and was receiving prednisolone therapy. TF prepared from subjects who have recently recovered from type B hepatitis may have temporarily altered the immunological status of patients with HBsAg-pos chronic liver disease, but it did not have a beneficial therapeutic effect. PMID:606432

  1. Herbal product use in non-HIV and HIV-positive Hispanic patients.

    PubMed Central

    Rivera, José O.; González-Stuart, Armando; Ortiz, Melchor; Rodríguez, José C.; Anaya, Jaime P.; Meza, Armando

    2005-01-01

    PURPOSE: The primary endpoint of this study was to determine the prevalence of herbal product use by a sample of Mexican-American patients in the El Paso, TX region. Even though medicinal plants are popularly assumed to be a safe and natural alternative to conventional medications, some herbal products may pose a potential health risk to the consumer. Currently, there are few studies related to herbal use by Mexican Americans and none in HIV patients living on the U.S./México border. METHODS: A prospective observational study was conducted in hospitals and clinics throughout the El Paso region area. A semistructured interview was conducted by trained bilingual interviewers. A 45-item bilingual questionnaire was used to collect the information. RESULTS: A total of 439 non-HIV patients as well as 35 patients afflicted with HIV participated in the study. Seventy-nine percent (347/439) of non-HIV and 71% (25/35) of HIV patients reported using herbal products. The percentages of herbal use among the two groups did not show any statistically significant differences (p=0.29), and both groups reflected that herbal products are commonly used. CONCLUSIONS: The use of herbal products was very common among non-HIV (79%) and HIV-positive (71%) Mexican-Americans patients in the El Paso region. PMID:16396061

  2. microRNA classifiers are powerful diagnostic/prognostic tools in ALK-, EGFR-, and KRAS-driven lung cancers.

    PubMed

    Gasparini, Pierluigi; Cascione, Luciano; Landi, Lorenza; Carasi, Stefania; Lovat, Francesca; Tibaldi, Carmelo; Alì, Greta; D'Incecco, Armida; Minuti, Gabriele; Chella, Antonio; Fontanini, Gabriella; Fassan, Matteo; Cappuzzo, Federico; Croce, Carlo M

    2015-12-01

    microRNAs (miRNAs) can act as oncosuppressors or oncogenes, induce chemoresistance or chemosensitivity, and are major posttranscriptional gene regulators. Anaplastic lymphoma kinase (ALK), EGF receptor (EGFR), and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) are major drivers of non-small cell lung cancer (NSCLC). The aim of this study was to assess the miRNA profiles of NSCLCs driven by translocated ALK, mutant EGFR, or mutant KRAS to find driver-specific diagnostic and prognostic miRNA signatures. A total of 85 formalin-fixed, paraffin-embedded samples were considered: 67 primary NSCLCs and 18 matched normal lung tissues. Of the 67 primary NSCLCs, 17 were echinoderm microtubule-associated protein-like 4-ALK translocated (ALK(+)) lung cancers; the remaining 50 were not (ALK(-)). Of the 50 ALK(-) primary NSCLCs, 24 were EGFR and KRAS mutation-negative (i.e., WT; triple negative); 11 were mutant EGFR (EGFR(+)), and 15 were mutant KRAS (KRAS(+)). We developed a diagnostic classifier that shows how miR-1253, miR-504, and miR-26a-5p expression levels can classify NSCLCs as ALK-translocated, mutant EGFR, or mutant KRAS versus mutation-free. We also generated a prognostic classifier based on miR-769-5p and Let-7d-5p expression levels that can predict overall survival. This classifier showed better performance than the commonly used classifiers based on mutational status. Although it has several limitations, this study shows that miRNA signatures and classifiers have great potential as powerful, cost-effective next-generation tools to improve and complement current genetic tests. Further studies of these miRNAs can help define their roles in NSCLC biology and in identifying best-performing chemotherapy regimens.

  3. Diversity of crude oil-degrading bacteria and alkane hydroxylase (alkB) genes from the Qinghai-Tibet Plateau.

    PubMed

    Long, Haozhi; Wang, Yilin; Chang, Sijing; Liu, Guangxiu; Chen, Tuo; Huo, Guanghua; Zhang, Wei; Wu, Xiukun; Tai, Xisheng; Sun, Likun; Zhang, Baogui

    2017-03-01

    The aim of this study was to survey the response of the microbial community to crude oil and the diversity of alkane hydroxylase (alkB) genes in soil samples from the Qinghai-Tibet Plateau (QTP). The enrichment cultures and clone libraries were used. Finally, 53 isolates and 94 alkB sequences were obtained from 10 pristine soil samples after enrichment at 10 °C with crude oil as sole carbon source. The isolates fell into the phyla Proteobacteria, Actinobacteria, and Bacteroidetes, with the dominance of Pseudomonas and Acinetobacter. The composition of degraders was different from polar habitats where Acinetobacter sp. is not a predominant responder of alkane degradative microbial communities. Phylogenetic analysis showed that the alkB genes from isolates and enrichment communities formed eight clusters and mainly related with alkB genes of Pseudomonas, Rhodococcus, and Acinetobacter. The alkB gene diversity in the QTP was lower than marine environments and polar soil samples. In particular, a total of 10 isolates exhibiting vigorous growth with crude oil could detect no crude oil degradation-related gene sequences, such as alkB, P450, almA, ndoB, and xylE genes. The Shannon-Wiener index of the alkB clone libraries from the QTP ranged from 1.00 to 2.24 which is similar with polar pristine soil samples but lower than that of contaminated soils. These results indicated that the Pseudomonas, Acinetobacter, and Rhodococcus genera are the candidate for in situ bioremediation, and the environment of QTP may be still relatively uncontaminated by crude oil.

  4. Validation of dosimetric field matching accuracy from proton therapy using a robotic patient positioning system.

    PubMed

    Farr, Jonathan B; O'Ryan-Blair, Avril; Jesseph, Frederick; Hsi, Wen-Chien; Allgower, Chris E; Mascia, Anthony E; Thornton, Allan F; Schreuder, Andreas N

    2010-04-12

    Large area, shallow fields are well suited to proton therapy. However, due to beam production limitations, such volumes typically require multiple matched fields. This is problematic due to the relatively narrow beam penumbra at shallow depths compared to electron and photon beams. Therefore, highly accurate dose planning and delivery is required. As the dose delivery includes shifting the patient for matched fields, accuracy at the 1-2 millimeter level in patient positioning is also required. This study investigates the dosimetric accuracy of such proton field matching by an innovative robotic patient positioner system (RPPS). The dosimetric comparisons were made between treatment planning system calculations, radiographic film and ionization chamber measurements. The results indicated good agreement amongst the methods and suggest that proton field matching by a RPPS is accurate and efficient.

  5. Dynamic multidetector computed tomography findings of hepatocellular carcinoma of hepatitis B virus-positive and -negative patients

    PubMed Central

    2014-01-01

    Background The objective of this study was to retrospectively investigate and compare multidetector computed tomography findings of hepatocellular carcinoma (HCC) in hepatitis B virus (HBV)-positive and -negative patients. Methods Triphasic (arterial, portal venous, and delayed phases) dynamic multidetector computed tomography (CT) was performed in 83 patients with HCC, 48 of whom were HBV-positive. The diagnosis of HCC was established with typical CT imaging findings (68 patients) or histopathological evaluation (15 patients). Distribution of solitary, multiple, and diffuse HCC, portal/hepatic vein thrombosis, metastasis, and patients with high alpha-fetoprotein levels in the HBV-positive and -negative groups were compared using the Kolmogorov–Smirnov test. Lesion size, alpha-fetoprotein levels, arterial, portal, delayed enhancement, and washout of lesions were compared using the Student’s t-test. Results Hypervascular tumors were observed in 72 (87%) patients, and hypovascular tumors were found in 11 (13%) patients. The mean alpha-fetoprotein value of HBV-positive patients with HCC was significantly higher than the mean alpha-fetoprotein value of HBV-negative patients (P < 0.05). Portal/hepatic vein thrombosis and metastasis were more frequently observed in HBV-positive patients (P < 0.05). The frequencies of solitary, multiple, and diffuse lesions in HBV-positive and -negative patients were not significantly different (P > 0.05). The mean diameters, arterial, portal, and delayed phase attenuations, and washout of HCC were not significantly different (P > 0.05). Conclusions Multidetector CT imaging findings of HCC in HBV-positive and -negative patients are alike. Portal/hepatic vein thrombosis and metastasis are more frequently observed in HBV-positive patients. Alpha-fetoprotein levels are higher in HBV-positive patients. PMID:25608603

  6. Dihydropteroate synthase gene mutation rates in Pneumocystis jirovecii strains obtained from Iranian HIV-positive and non-HIV-positive patients.

    PubMed

    Sheikholeslami, Maryam-Fatemeh; Sadraei, Javid; Farnia, Parisa; Forozandeh Moghadam, Mehdi; Emadikochak, Hamid

    2015-05-01

    The dihydropteroate sulfate (DHPS) gene is associated with resistance to sulfa/sulfone drugs in Pneumocystis jirovecii. We investigated the DHPS mutation rate in three groups of Iranian HIV-positive and HIV-negative patients by polymerase chain reaction-restricted fragment length polymorphism analysis. Furthermore, an association between P. jirovecii DHPS mutations and strain typing was investigated based on direct sequencing of internal transcribed spacer region 1 (ITS1) and ITS2. The overall P. jirovecii DHPS mutation rate was (5/34; 14.7%), the lowest rate identified was in HIV-positive patients (1/16; 6.25%) and the highest rate was in malignancies patients (3/11; 27.3%). A moderate rate of mutation was detected in chronic obstructive pulmonary disease (COPD) patients (1/7; 14.3%). Most of the isolates were wild type (29/34; 85.3%). Double mutations in DHPS were detected in patients with malignancies, whereas single mutations at codons 55 and 57 were identified in the HIV-positive and COPD patients, respectively. In this study, two new and rare haplotypes were identified with DHPS mutations. Additionally, a positive relationship between P. jirovecii strain genotypes and DHPS mutations was identified. In contrast, no DHPS mutations were detected in the predominant (Eg) haplotype. This should be regarded as a warning of an increasing incidence of drug-resistant P. jirovecii strains.

  7. Growth of a progesterone receptor-positive meningioma in a female patient with congenital adrenal hyperplasia

    PubMed Central

    O’Shea, T; Crowley, R K; Farrell, M; MacNally, S; Govender, P; Feeney, J; Gibney, J

    2016-01-01

    Summary Meningioma growth has been previously described in patients receiving oestrogen/progestogen therapy. We describe the clinical, radiological, biochemical and pathologic findings in a 45-year-old woman with congenital adrenal hyperplasia secondary to a defect in the 21-hydroxylase enzyme who had chronic poor adherence to glucocorticoid therapy with consequent virilisation. The patient presented with a frontal headache and marked right-sided proptosis. Laboratory findings demonstrated androgen excess with a testosterone of 18.1 nmol/L (0–1.5 nmol) and 17-Hydroxyprogesterone >180 nmol/L (<6.5 nmol/L). CT abdomen was performed as the patient complained of rapid-onset increasing abdominal girth and revealed bilateral large adrenal myelolipomata. MRI brain revealed a large meningioma involving the right sphenoid wing with anterior displacement of the right eye and associated bony destruction. Surgical debulking of the meningioma was performed and histology demonstrated a meningioma, which stained positive for the progesterone receptor. Growth of meningioma has been described in postmenopausal women receiving hormone replacement therapy, in women receiving contraceptive therapy and in transsexual patients undergoing therapy with high-dose oestrogen and progestogens. Progesterone receptor positivity has been described previously in meningiomas. 17-Hydroxyprogesterone is elevated in CAH and has affinity and biological activity at the progesterone receptor. Therefore, we hypothesise that patients who have long-standing increased adrenal androgen precursor concentrations may be at risk of meningioma growth. Learning points: Patients with long-standing CAH (particularly if not optimally controlled) may present with other complications, which may be related to long-standing elevated androgen or decreased glucocorticoid levels. Chronic poor control of CAH is associated with adrenal myelolipoma and adrenal rest tissue tumours. Meningiomas are sensitive to

  8. The Role of Positive Personality Traits in Emotion Regulation of Patients with Irritable Bowel Syndrome (IBS)

    PubMed Central

    MAZAHERI, Mina; NIKNESHAN, Shekoufeh; DAGHAGHZADEH, Hamed; AFSHAR, Hamid

    2015-01-01

    Background: Personality traits and emotion regulation processes play an important role in human health. The purpose of this study was to investigate the role of positive personality traits (psychological hardiness and interpersonal forgiveness) in emotion regulation of patients with Irritable Bowel Syndrome. Methods: The research was a cross-sectional study. Statistical population included all of IBS patients referred to the Subspecialty Center of Psychiatry in Isfahan in 2013. Overall, 123 subjects (100 women, 83.3%, and 30 men, 16.7%) were selected by census method, according to criteria of research and during a particular period. To collect data, the Difficulties in Emotion Regulation Scale (DERS), Lang and Goulet Hardiness Scale (LGHS) and Interpersonal forgiveness Inventory (IFI) were used. Data was analyzed using Pearson’s correlation coefficient and Multivariate and Binary Logistic regression analyses. Results: Mean age of patients was 33.82±10.45 years and 83.3% (100) of them were female. Regression analyses showed that both personality traits of hardiness and forgiveness were as protective factors for emotional dysregulation with OR, 95% CI: 0.93 and 0.96 sequentially, with adjusting demographic variables (age, gender, and education level and disease duration). Conclusion: Patients who are more hardy and forgiving toward others, are likely more successful at adaptive emotion regulation. It emphasizes the positive and beneficial role of the personality traits in regulating of emotional problems of IBS patients. Hence, these variables should be considered as effective factors in the treatment process of the patients. PMID:26056675

  9. ALKBH3, a human AlkB homologue, contributes to cell survival in human non-small-cell lung cancer

    PubMed Central

    Tasaki, M; Shimada, K; Kimura, H; Tsujikawa, K; Konishi, N

    2011-01-01

    Background: We have demonstrated for the first time that a novel human AlkB homologue, ALKBH3, contributes to prostate cancer development, but its clinical and biological roles in lung cancer remain unclear. Methods: Expression of both mRNA and protein of PCA-1 was examined by RT–PCR and western blotting. We also assessed association with senescence and in vivo ALKBH3 treatment on orthotopic tumour cell inoculation, and analysed it clinicopathologically. Results: We have since found novel biological roles for ALKBH3 in human lung cancers, particularly in adenocarcinoma. Our immunohistochemical analysis of human adenocarcinomas and squamous cell carcinomas of the lung not only showed overexpression of ALKBH3 in these tumours but the percentage of cells positive for ALKBH3 also correlated statistically to recurrence-free survival in adenocarcinoma. Knockdown of ALKBH3 by siRNA transfection induced expression of p21WAF1/Cip1 and p27Kip1 in the human lung adenocarcinoma cell line A549, resulting in cell cycle arrest, senescence and strong suppression of cell growth in vitro. In vivo, peritoneal tumour growth and dissemination was inhibited in nude mice, previously inoculated with the A549 cell line, by intraperitoneal injection of ALKBH3 siRNA + atelocollagen, as demonstrated by the reduction in both number and diameter of tumours developing in the peritoneum. Conclusion: We suggest that ALKBH3 contributes significantly to cancer cell survival and may be a therapeutic target for human adenocarcinoma of the lung. PMID:21285982

  10. A comparative study on the CT effective dose for various positions of the patient's arm

    NASA Astrophysics Data System (ADS)

    Seong, Ji-Hye; Park, Soon-Ki; Kim, Jung-Sun; Jung, Woo-Young; Kim, Ho-Sung; Dong, Kyung-Rae; Chung, Woon-Kwan; Cho, Jae-Hwan; Cho, Young-Kuk

    2012-10-01

    In a whole body PET/CT (positron emission tomography/computed tomography) scan, lifting the patient's arm to improve the image quality is natural. On the other hand, the arms should be placed lower when the lesion is located in the head and neck. This study compared the CT effective dose for each arm position after applying AEC (automatic exposure control). Forty-five patients who had undergone an 18F-FDG (fluorine-18-fluoro deoxy glucose) whole body PET/CT scan were examined using Biograph Truepoint 40, Biograph Sensation 16, and Discovery STe 8 systems. The CT effective dose of 15 patients for each set of equipment was measured and analyzed comparatively in both the arm-lifted and arm-lowered positions. The ImPACT Ver. 1.0 program was used to measure the CT effective dose. A paired t-test (SPSS 18.0 statistic program) was applied for statistical analysis. In the case of the arm-lifted position, the CT effective dose measured for Biograph 40, Biograph 16, and DSTe 8 systems were 6.33 ± 0.93 mSv, 8.01 ± 1.34 mSv, and 9.69 ± 2.32 mSv, respectively. When the arms were located in the lower position, the respective CT effective doses were 6.97 ± 0.76 mSv, 8.95 ± 1.85 mSv, and 13.07 ± 2.87 mSv, respectively. These results revealed 9.2%, 10.5%, and 25.9% improvement in the CT effective doses for the Biograph 40, Biograph 16 and DSTe 8 systems, respectively, when the arms were raised compared to that when they were lowered (p < 0.05). For the whole body PET/CT case, the CT effective dose applying AEC showed a mean 15.2% decrease in the radiation exposure of the patients when the arm was lifted. The patient with no lesion in the head and neck would show fewer artifacts in the objective part and a lower CT effective dose. For a patient with a lesion in the head and neck, the artifacts in the objective part can be reduced by putting the arms down. The fact that the CT effective dose is increased in a whole-body PET/CT scan should be a concern.

  11. Optimal adjuvant treatment for patients with HER2-positive breast cancer in 2015.

    PubMed

    Zardavas, Dimitrios; Fouad, Tamer M; Piccart, Martine

    2015-11-01

    The introduction of trastuzumab as adjuvant treatment for patients with HER2-positive breast cancer changed the natural course of early-stage disease. Currently, one year of trastuzumab given concurrently with a taxane and following an anthracycline regimen is the preferred standard of care in Europe. The first attempt to escalate this approach, though the implementation of dual HER2 blockade with lapatinib added to trastuzumab, as assessed by the ALTTO trial, failed to improve further clinical outcomes; clinical assessment of the adjuvant trastuzumab/pertuzumab regimen is still ongoing in the APHINITY trial. Negative results were also reported for the addition of bevacizumab to adjuvant trastuzumab treatment within the context of the BETH study. Similarly, efforts to de-escalate through shortening the duration of adjuvant trastuzumab treatment failed (the PHARE trial), whereas others are still ongoing. Of note, evidence supports the use of lighter chemotherapy regimens with one year of adjuvant trastuzumab as backbone, for women with small HER2-positive breast tumors, where the omission of anthracyclines did not compromise the clinical outcome. Despite the successes achieved so far, a proportion of women with early-stage HER2-positive breast cancer, will still experience disease recurrence. The identification of these women is urgently needed, as well as the identification of predictive biomarkers to dictate the optimal treatment strategy. So far, HER2 expression status has been the only validated predictive biomarker for this patient population. Despite the clear association of pCR achieved through neoadjuvant trastuzumab-based chemotherapy with clinical outcome, results from neoadjuvant trials have not been always consistent with what was seen in the adjuvant setting. Similarly, inconsistent results have been reported for the predictive ability of alterations affecting the PI3K signaling pathway or the quantification of tumor infiltrating lymphocytes. In the era

  12. Rehabilitation outcome of hip fracture patients: the importance of a positive albumin gain.

    PubMed

    Mizrahi, E H; Fleissig, Y; Arad, M; Blumstein, T; Adunsky, A

    2008-01-01

    Low serum albumin level is associated with poor functional outcome and predicting a greater functional decline in the elderly. The aim of this study is to determine the interrelation between change of serum albumin level during rehabilitation period and functional outcome in hip fracture patients. We studied 433 consecutive elderly hip fracture patients admitted for rehabilitation. Functional outcome was assessed by the Functional Independence Measure (FIM) at admission and discharge of patients with no albumin gain (<0 g/dl) or with positive albumin gain (>or=0 g/dl). Data were analyzed by t-test, Pearson correlation, chi(2)-test and linear regression. Of patients 66.7% showed no albumin gain. These patients had a higher prevalence of previous stroke (p=0.04), lower Mini Mental State Examination (MMSE) scores (p=0.05) and were less likely to have hyperlipidemia (p=0.008) compared with patients with albumin gains. Admission and discharge FIM parameters and total and motor FIM gain/day were statistically significantly lower among patients with no albumin gain. In a linear regression analysis total FIM at discharge was inversely associated with pre-fracture function (beta=-0.148; p<0.001), Albumin gain (beta=0.047; p=0.005), high MMSE score (beta=0.143; p<0.001), and higher admission total FIM score (beta=0.69; p<0.001) emerged as significant predictors of higher total FIM scores upon discharge. The results suggest that patients with albumin gain have better admission and discharge FIM scores. Albumin gain emerged as a significant predictor for higher discharge FIM scores. We conclude that greater attention and efforts should be made regarding the dietary intervention and protein supplementation, in order to improve the rehabilitation outcome.

  13. Accurate positioning for head and neck cancer patients using 2D and 3D image guidance

    PubMed Central

    Kang, Hyejoo; Lovelock, Dale M.; Yorke, Ellen D.; Kriminiski, Sergey; Lee, Nancy; Amols, Howard I.

    2011-01-01

    Our goal is to determine an optimized image-guided setup by comparing setup errors determined by two-dimensional (2D) and three-dimensional (3D) image guidance for head and neck cancer (HNC) patients immobilized by customized thermoplastic masks. Nine patients received weekly imaging sessions, for a total of 54, throughout treatment. Patients were first set up by matching lasers to surface marks (initial) and then translationally corrected using manual registration of orthogonal kilovoltage (kV) radiographs with DRRs (2D-2D) on bony anatomy. A kV cone beam CT (kVCBCT) was acquired and manually registered to the simulation CT using only translations (3D-3D) on the same bony anatomy to determine further translational corrections. After treatment, a second set of kVCBCT was acquired to assess intrafractional motion. Averaged over all sessions, 2D-2D registration led to translational corrections from initial setup of 3.5 ± 2.2 (range 0–8) mm. The addition of 3D-3D registration resulted in only small incremental adjustment (0.8 ± 1.5 mm). We retrospectively calculated patient setup rotation errors using an automatic rigid-body algorithm with 6 degrees of freedom (DoF) on regions of interest (ROI) of in-field bony anatomy (mainly the C2 vertebral body). Small rotations were determined for most of the imaging sessions; however, occasionally rotations > 3° were observed. The calculated intrafractional motion with automatic registration was < 3.5 mm for eight patients, and < 2° for all patients. We conclude that daily manual 2D-2D registration on radiographs reduces positioning errors for mask-immobilized HNC patients in most cases, and is easily implemented. 3D-3D registration adds little improvement over 2D-2D registration without correcting rotational errors. We also conclude that thermoplastic masks are effective for patient immobilization. PMID:21330971

  14. Pattern of mucocutaneous manifestations in human immunodeficiency virus-positive patients in North India

    PubMed Central

    Kore, Sachin D.; Kanwar, Amrinder J.; Vinay, Keshavamurthy; Wanchu, Ajay

    2013-01-01

    Background: Mucocutaneous diseases are among the first-recognized clinical manifestations of acquired immune deficiency syndrome. They function as visual markers in assessing the progression of human immunodeficiency virus (HIV) infection. Given the relative ease of examination of skin, its evaluation remains an important tool in the diagnosis of HIV infection. Objective: To determine the pattern of mucocutaneous manifestations in HIV-positive patients and to correlate their presence with CD4 counts. Materials and Methods: This cross-sectional study included 352 HIV-infected patients seen at PGIMER, Chandigarh, India, over a period of 1 year. The patients were screened for mucocutaneous disorders by an experienced dermatologist. The patients were classified into different stages according to the World Health Organization clinical and immunological staging system. Results: The most prevalent infection was candidiasis, seen in 57 patients (16.2%). Prevalence of candidiasis, dermatophytosis, herpes simplex, herpes zoster, molluscum contagiosum (MC), seborrheic dermatitis, adverse drug reaction, nail pigmentation, xerosis and diffuse hair loss differed statistically according to the clinical stages of HIV infection. There was a statistically significant association between immunological stages of HIV infection and dermatophytosis. Conclusion: Results of our study suggest that mucocutaneous findings occur throughout the course of HIV infection. Dermatoses like MC and dermatophytosis show an inverse relation with CD4 cell count, and these dermatoses can be used as a proxy indicator of advanced immunosuppression to start highly active anti-retroviral therapy in the absence of facilities to carry out CD4 cell count. PMID:23919050

  15. [Fever of unknown origin in a cohort of HIV-positive patients].

    PubMed

    Genné, D; Chave, J P; Glauser, M P

    1992-11-21

    The purpose of this study was to determine the prevalence of fever of unknown origin (FUO) in a cohort of HIV positive patients and to describe their evolution and the final diagnosis. The clinical records of 412 patients followed from January 1987 to December 1990 at our HIV outpatient clinic were reviewed: in 151 patients 255 episodes of fever had been observed of which 22 (in 21 patients) met the criteria for FUO. 19 patients (90%) presented with a CDC/WHO stage IV HIV infection and the mean CD4+ lymphocyte count was 0.160 G/l. The etiology was ultimately determined in 13/22 episodes (3 Pneumocystis carinii pneumonia, 3 invasive infections due to atypical mycobacteria, 2 bacterial pneumonia, 1 Cytomegalovirus colitis, 1 Isospora belli enteritis, 1 visceral leishmania, 1 candida septicemia and 1 lymphoma). In 6/22 episodes, the fever subsided after zidovudine was started and was therefore attributed to HIV itself. In 3/22 episodes no etiology was found. In conclusion, this series shows that FUO is usually seen in advanced HIV infection and that it often represents an early sign of opportunistic infection. This observation underlines the importance of follow-up, since it finally served to detect the etiology of FUO in 86% of cases. Trial treatment with zidovudine can be useful where no pathology has been discovered despite 3 weeks' follow-up and appropriate investigations.

  16. Thrombosis associated with cytomegalovirus infection in patients with ANCA-positive vasculitis.

    PubMed

    Wolf, G; Porth, J; Stahl, R A

    2001-11-01

    Three cases of venous thrombosis with pulmonary embolism in two patients associated with underlying antineutrophil cytoplasmic autoantibody (ANCA)-positive vasculitis and reactivated cytomegalovirus (CMV) infection are described. In vitro studies previously have shown that infection of endothelium with CMV increases the release of procoagulant factors and stimulates the expression of adhesion molecules. Because the endothelial cell plays a pivotal role in maintaining the equilibrium between procoagulant and anticoagulant states, injury by ANCA-positive vasculitis and additional infection with CMV may ignite a local thrombosis easily. Although venous thrombosis is uncommon in CMV infection (eg, in the immunosuppressed state after organ transplantation), the combination of vasculitis and reactivated CMV infection may have contributed to injury of the vessel wall with subsequent development of thrombosis. A better awareness of this association could improve morbidity and may lead to prevention of potentially life-threatening pulmonary embolism. Patients with ANCA-positive vasculitis and CMV infection may profit from prophylactic anticoagulant therapy with heparin or low-molecular-weight heparin.

  17. Virulence factors of Candida albicans isolates from the oral cavities of HIV-1-positive patients.

    PubMed

    Menezes, Tatiany O A; Gillet, Luciana C S; Menezes, Sílvio A F; Feitosa, Rosimar N M; Ishak, Marluísa O G; Ishak, Ricardo; Marques-da-Silva, Sílvia H; Vallinoto, Antonio C R

    2013-06-01

    The present study assessed the phenotypic aspects of oral-cavity Candida albicans isolates from 300 HIV-1- positive patients, relating the most commonly investigated virulence factors (enzyme typing and germ-tube formation) to the most common morphotypes. The samples were seeded into specific media for isolation and subsequent identification using the automated Vitek 2 system. The following assays were performed for phenotypic characterization: morphotyping, germ-tube formation and enzyme typing. Out of 300 collected samples, 144 tested positive for yeasts of the Candida genus, 98 (32.7 %) of which were identified as C. albicans. The latter samples were attributed to seven different morphotypes; the three most common morphotypes were 7208 (49 %), 7308 (14.3 %) and 3208 (13.3 %). All of the C. albicans isolate samples formed germ tubes and produced the enzymes proteinase and phospholipase, with an activity classified as intermediate to high. Due to the identification of virulence factors among the analyzed samples, monitoring of HIV-1-positive patients colonized by different morphotypes must be established because these morphotypes are extremely pathogenic and can trigger severe fungal infections.

  18. Differences in androgens of HIV positive patients with and without Kaposi sarcoma.

    PubMed Central

    Christeff, N; Winter, C; Gharakhanian, S; Thobie, N; Wirbel, E; Costagliola, D; Nunez, E A; Rozenbaum, W

    1995-01-01

    AIM--Since most forms of Kaposi sarcoma are much more common in men than in women, the aim of this study was to examine serum concentrations of sex steroids in HIV positive men with and without Kaposi sarcoma. METHODS--Blood samples from 34 HIV positive men without Kaposi sarcoma (KS-) and 28 with Kaposi sarcoma (KS+) and from 35 HIV negative men (controls) were analysed for adrenal and gonadal steroids. Further analysis was done in subgroups classified by CD4 lymphocyte counts. RESULTS--KS+ patients had significantly higher serum dehydroepiandrosterone (DHEA) and testosterone concentrations than the KS- patients, and their DHEA, DHEA sulphate, testosterone, and androstenedione values were higher than in the controls. The KS+ patients with more than 500 CD4 lymphocytes per mm3 had significantly higher serum DHEA, DHEA sulphate, and testosterone than the KS- patients with the same CD4 counts; those with 500-200 CD4 cells/mm3 had higher serum DHEA and testosterone than the equivalent KS- men; and those with < 200 CD4 cells/mm3 had raised DHEA only compared with KS- men. Both KS+ and KS- men had higher serum progesterone and oestradiol than the controls. Glucocorticoids were not significantly altered. CONCLUSIONS--The high androgen levels in KS+ patients, particularly in the early stages of the disease (> 500 CD4 cells/mm3), may affect the immune system by inducing an abnormal cytokine profile, or by increasing T8 proliferation and activation, or both. This raises the question of the relationship between androgens and Kaposi sarcoma. PMID:7665693

  19. Expression and prognostic value of estrogen receptor β in patients with triple-negative and triple-positive breast cancer.

    PubMed

    Guo, Liying; Zhu, Qianwen; Aisimutuola, Mulati; Yilamu, Dilimina; Liu, Sha; Jakulin, Adina

    2015-06-01

    The aim of the present study was to investigate the expression of estrogen receptor β (ERβ) in triple-negative and triple-positive breast cancer patients, and evaluate its utility as a prognostic factor. Between January 2000 and December 2010, primary tumor tissue samples were collected from 234 subjects, including 107 triple-negative and 127 triple-positive breast cancer patients. The samples were embedded in paraffin and immunohistochemical staining was conducted to determine the expression levels of ERβ. The Kaplan-Meier method was used to analyze patient survival rates. ERβ expression was observed in 38/107 patients (35.5%) with triple-negative breast cancer and 63/127 patients (49.6%) with triple-positive breast cancer. The ERβ expression rate was significantly decreased in the patients with triple-negative breast cancer, as compared with those with triple-positive breast cancer (P=0.03). Analysis of the survival rates indicated that patients with triple-negative breast cancer and positive ERβ expression exhibited poor disease progression-free survival (DFS) compared with those with negative ERβ expression (P=0.021). However, no statistically significant difference was observed in the DFS between the triple-positive breast cancer patients with positive and negative ERβ expression. Therefore, the expression of ERβ varies between triple-negative and triple-positive breast cancer patients. In addition, positive expression of ERβ indicates a poor prognosis in triple-negative breast cancer patients; however, this is not the case for triple-positive breast cancer patients.

  20. Positive expression of KIF20A indicates poor prognosis of glioma patients

    PubMed Central

    Duan, Jia; Huang, Wei; Shi, Haiping

    2016-01-01

    Glioma patients have a poor overall survival; however, patients can show distinct clinical outcomes due to the high heterogeneity of the tumor, which may be indicated by certain clinicobiological parameters. Kinesin family member 20A (KIF20A), which participates in cytokinesis and intracellular transportation, has been recently reported to be upregulated in pancreatic cancer, breast cancer, and bladder cancer. In the current study, we investigated the expression of KIF20A in gliomas and its significance in predicting the prognosis after surgery. We found that KIF20A positive expression in glioma tissues correlated significantly with Ki67 protein expression and advanced World Health Organization grade. Univariate and multivariate analysis revealed that KIF20A can act as an independent prognostic factor for predicting the overall survival of glioma patients. Moreover, we demonstrated that KIF20A can positively regulate the expression of Ki67 in glioma cell lines. Correspondingly, overexpression of KIF20A can promote cell proliferation and invasion, whereas knockdown of KIF20A can inhibit cell viability and invasion capacity. In vitro study also showed that under the treatment of plumbagin, an anticancer drug, KIF20A expression decreased in a dose-dependent manner. In addition, the overexpression of KIF20A can also increase the drug resistance toward plumbagin, which provided the possibility that KIF20A may contribute to the chemotherapy resistance of gliomas. PMID:27843327

  1. Robot assisted radical prostatectomy: how I do it. Part I: Patient preparation and positioning.

    PubMed

    Valdivieso, Roger F; Hueber, Pierre-Alain; Zorn, Kevin C

    2013-10-01

    Radical prostatectomy remains the standard treatment for long term cure of clinically localized prostate cancer, offering excellent oncologic outcomes, with cancer-specific survival approaching 95% at 15 years after surgery. The introduction of the "da Vinci Robotic Surgical System" (Intuitive Surgical, Sunnyvale, CA, USA) has been another important step toward a minimally invasive approach to radical prostatectomy. Technologic peculiarities, such as three-dimensional vision, wristed instrumentation with seven degrees of freedom of motion, lack of tremor, a 10x-magnification and a comfortable seated position for the surgeon has added value to the surgeon and patient. In this first part of a two article series, we describe preoperative patient preparation and positioning protocols for robot assisted radical prostatectomy (RARP) that are currently used in our institution (University of Montreal Hospital Center (CHUM)-Hopital St-Luc). We use the four-arm da Vinci Si Surgical System. Our experience with RARP is now over 250 cases with the senior surgeon having performed over 1200 RARPs and we have continually refined our technique to improve patient outcomes.

  2. An Abdominal CT may be Safe in Selected Hypotensive Trauma Patients with Positive FAST Exam

    PubMed Central

    Cook, Mackenzie R.; Holcomb, John B.; Rahbar, Mohammad H.; Alarcon, Louis H.; Bulger, Eileen M.; Brasel, Karen J.; Schreiber, Martin A.

    2016-01-01

    Background Positive Focused Assessment with Sonography in Trauma (FAST) and hypotension often indicates urgent surgery. An abdomen/pelvis CT (apCT) may allow less invasive management but the delay may be associated with adverse outcomes. Methods Patients in the Prospective Observational Multicenter Major Trauma Transfusion study with hypotension and a positive FAST (HF+) who underwent a CT (apCT+) were compared to those who did not. Results Of the 92 HF+ identified, 32(35%) underwent apCT during initial evaluation and apCT was associated with decreased odds of an emergency operation, OR 0.11 95% CI (0.001–0.116) and increased odds of angiographic intervention, OR 14.3 95% CI (1.5–135). There was no significant difference in 30 day mortality or need for dialysis. Conclusion An apCt in HF+ patients is associated with reduced odds of emergency surgery, but not mortality. Select HF+ patients can safely undergo apCT to obtain clinically useful information. PMID:25805456

  3. Nutritional status of HIV-positive patients in Niterói, Rio de Janeiro, Brazil.

    PubMed

    De Senna, Andrea F Kroll; De Oliveira, Solange A; Velarde, Luis G C; Setúbal, Sérgio

    2014-12-01

    The objective of this cross-sectional study was to assess the nutritional status of HIV-positive patients in a hospital in the city of Niteroi, Rio de Janeiro, Brazil. We studied 235 patients (130 men and 105 women) from May 2009 to June 2010. The frequency of undernourishment among women was 7.6%; 26.7% of the women were overweight, and 16.2% were obese. Among men, the frequency of undernourishment was 3.8%; 25.4% of the men were overweight, and 6.9% were obese. A logistic regression was done to investigate the relationship between nutritional status and potential predisposing factors. Women were more frequently affected by obesity and undernourishment than men. However, only the difference in obesity was significant, and women had almost three times higher odds of being obese (OR 2.6; 95% CI 1.03-6.65). According to a nationwide survey done in Brazil during 2008-2009, 50.1% of the Brazilian healthy males were overweight, and 12.5% were obese; 48% of healthy females were overweight, and 16.9% were obese. Although the prevalence of undernourishment in HIV-positive patients is now lower than that observed in the beginning of the AIDS epidemic and excess weight is increasingly common among people living with HIV/AIDS, the proportion of excess weight was found lower and of undernourishment was higher in the present study than that found in the Brazilian population.

  4. Analysis of wear of polyethylene hip joint cup related to its positioning in patient's body.

    PubMed

    Rońda, Jacek; Wojnarowski, Paweł

    2013-01-01

    Polyethylene parts of endoprosthesis are the weakest parts of each medical implant. They can be worn out within several years. During this period, a patient can enjoy good physical efficiency until the wear of polyethylene part limits his/her mobility. Then the reoperation is necessary and positioning of all parts of endoprosthesis has an effect on future patient's mobility and durability of implant. Elements of endoprosthesis during exploitation are heavily loaded both by normal and tangential forces and moments. In this paper, the dependence of wear of polyethylene cup on its positioning in pelvis is the major problem. Wear of the cup is determined by two measures: the depth and volume of a material rubbed off from the contact surface. The sensitivity of the depth of rubbing off is evaluated relative to two angles of anteversion and abduction, and radii of the cup. Numerical results are obtained by using Abaqus FE system with data related to patient's activity identified on the basis of medical reports.

  5. The Reverse Thomas Position for Thoracolumbar Fracture Height Restoration: Relative Contribution of Patient Positioning in Percutaneous Balloon Kyphoplasty for Acute Vertebral Compressions

    PubMed Central

    Cawley, Derek T.; Beecher, Suzanne M.; Baker, Joseph F.; McCabe, John P.

    2016-01-01

    Background Standard positioning for percutaneous balloon kyphoplasty requires placing a patient prone with supports under the iliac crests and upper thorax. The authors believe that hip hyperextension maximises pelvic anteversion creating anterior longitudinal ligamentotaxis, thus facilitating restoration of vertebral height. Methods Radiographic imaging including pre-operative, post-positioning, post balloon tamp inflation and post-operative lateral radiographs were analysed for anterior and posterior column height, wedge angle of the affected vertebra and 3-level Cobb angle in patients with recent fractures of T11-L1. Fracture dimensions of the index vertebra were expressed as percentage of the analogous dimension of the referent vertebra. Results From a total of 149 patients, a full imaging sequence was available on 21 cases of vertebral compression fractures. The described positioning technique created a mean anterior column height increase from 68.3% to 75.3% with positioning (p = 0.15), increasing to 82.3% post balloon inflation. Average Cobb and wedge angle improvement of 4.7° (p = 0.004)and 3.6° (p = 0.002) from positioning along were also recorded. Conclusion The Reverse Thomas Position is a safe and effective technique for augmenting thoracolumbar fracture height restoration in percutaneous balloon kyphoplasty. PMID:27441179

  6. Plasmid Dynamics in KPC-Positive Klebsiella pneumoniae during Long-Term Patient Colonization

    PubMed Central

    Park, Morgan; Deming, Clayton; Thomas, Pamela J.; Young, Alice C.; Coleman, Holly; Sison, Christina; Weingarten, Rebecca A.; Lau, Anna F.; Dekker, John P.; Palmore, Tara N.; Frank, Karen M.

    2016-01-01

    ABSTRACT Carbapenem-resistant Klebsiella pneumoniae strains are formidable hospital pathogens that pose a serious threat to patients around the globe due to a rising incidence in health care facilities, high mortality rates associated with infection, and potential to spread antibiotic resistance to other bacterial species, such as Escherichia coli. Over 6 months in 2011, 17 patients at the National Institutes of Health (NIH) Clinical Center became colonized with a highly virulent, transmissible carbapenem-resistant strain of K. pneumoniae. Our real-time genomic sequencing tracked patient-to-patient routes of transmission and informed epidemiologists’ actions to monitor and control this outbreak. Two of these patients remained colonized with carbapenemase-producing organisms for at least 2 to 4 years, providing the opportunity to undertake a focused genomic study of long-term colonization with antibiotic-resistant bacteria. Whole-genome sequencing studies shed light on the underlying complex microbial colonization, including mixed or evolving bacterial populations and gain or loss of plasmids. Isolates from NIH patient 15 showed complex plasmid rearrangements, leaving the chromosome and the blaKPC-carrying plasmid intact but rearranging the two other plasmids of this outbreak strain. NIH patient 16 has shown continuous colonization with blaKPC-positive organisms across multiple time points spanning 2011 to 2015. Genomic studies defined a complex pattern of succession and plasmid transmission across two different K. pneumoniae sequence types and an E. coli isolate. These findings demonstrate the utility of genomic methods for understanding strain succession, genome plasticity, and long-term carriage of antibiotic-resistant organisms. PMID:27353756

  7. Multidrug resistance in hydrocarbon-tolerant Gram-positive and Gram-negative bacteria.

    PubMed

    Stancu, Mihaela Marilena; Grifoll, Magdalena

    2011-01-01

    New Gram-positive and Gram-negative bacteria were isolated from Poeni oily sludge, using enrichment procedures. The six Gram-positive strains belong to Bacillus, Lysinibacillus and Rhodococcus genera. The eight Gram-negative strains belong to Shewanella, Aeromonas, Pseudomonas and Klebsiella genera. Isolated bacterial strains were tolerant to saturated (i.e., n-hexane, n-heptane, n-decane, n-pentadecane, n-hexadecane, cyclohexane), monoaromatic (i.e., benzene, toluene, styrene, xylene isomers, ethylbenzene, propylbenzene) and polyaromatic (i.e., naphthalene, 2-methylnaphthalene, fluorene) hydrocarbons, and also resistant to different antimicrobial agents (i.e., ampicillin, kanamycin, rhodamine 6G, crystal violet, malachite green, sodium dodecyl sulfate). The presence of hydrophilic antibiotics like ampicillin or kanamycin in liquid LB-Mg medium has no effects on Gram-positive and Gram-negative bacteria resistance to toxic compounds. The results indicated that Gram-negative bacteria are less sensitive to toxic compounds than Gram-positive bacteria, except one bacteria belonging to Lysinibacillus genus. There were observed cellular and molecular modifications induced by ampicillin or kanamycin to isolated bacterial strains. Gram-negative bacteria possessed between two and four catabolic genes (alkB, alkM, alkB/alkB1, todC1, xylM, PAH dioxygenase, catechol 2,3-dioxygenase), compared with Gram-positive bacteria (except one bacteria belonging to Bacillus genus) which possessed one catabolic gene (alkB/alkB1). Transporter genes (HAE1, acrAB) were detected only in Gram-negative bacteria.

  8. Biofortification of