Radiation Therapy and MK-3475 for Patients With Recurrent/Metastatic Head and Neck Cancer, Renal Cell Cancer, Melanoma, and Lung Cancer

ClinicalTrials.gov

2017-10-25

Head and Neck Squamous Cell Carcinoma; Metastatic Renal Cell Cancer; Recurrent Head and Neck Carcinoma; Recurrent Lung Carcinoma; Recurrent Renal Cell Carcinoma; Recurrent Skin Carcinoma; Stage III Renal Cell Cancer; Stage IV Lung Cancer; Stage IV Skin Melanoma

Hypertension Caused by Lenvatinib and Everolimus in the Treatment of Metastatic Renal Cell Carcinoma.

PubMed

Bendtsen, Mathias Alrø Fichtner; Grimm, Daniela; Bauer, Johann; Wehland, Markus; Wise, Petra; Magnusson, Nils E; Infanger, Manfred; Krüger, Marcus

2017-08-10

Multikinase inhibitors (MKI) and mammalian target of rapamycin (mTOR) inhibitors prolong progression-free (PFS) and overall survival (OS) in the treatment of metastatic renal cell carcinoma (mRCC) by reducing angiogenesis and tumor growth. In this regard, the MKI lenvatinib and the mTOR inhibitor everolimus proved effective when applied alone, but more effective when they were administered combined. Recently, both drugs were included in clinical trials, resulting in international clinical guidelines for the treatment of mRCC. In May 2016, lenvatinib was approved by the American Food and Drug Administration (FDA) for the use in combination with everolimus, as treatment of advanced renal cell carcinoma following one prior antiangiogenic therapy. A major problem of treating mRCC with lenvatinib and everolimus is the serious adverse event (AE) of arterial hypertension. During the treatment with everolimus and lenvatinib combined, 42% of the patients developed hypertension, while 10% of the patients treated with everolimus alone and 48% of the of the lenvatinib only treated patients developed hypertension. Lenvatinib carries warnings and precautions for hypertension, cardiac failure, and other adverse events. Therefore, careful monitoring of the patients is necessary.

Hypertension Caused by Lenvatinib and Everolimus in the Treatment of Metastatic Renal Cell Carcinoma

PubMed Central

Bendtsen, Mathias Alrø Fichtner; Grimm, Daniela; Bauer, Johann; Wehland, Markus; Wise, Petra; Magnusson, Nils E.; Infanger, Manfred; Krüger, Marcus

2017-01-01

Multikinase inhibitors (MKI) and mammalian target of rapamycin (mTOR) inhibitors prolong progression-free (PFS) and overall survival (OS) in the treatment of metastatic renal cell carcinoma (mRCC) by reducing angiogenesis and tumor growth. In this regard, the MKI lenvatinib and the mTOR inhibitor everolimus proved effective when applied alone, but more effective when they were administered combined. Recently, both drugs were included in clinical trials, resulting in international clinical guidelines for the treatment of mRCC. In May 2016, lenvatinib was approved by the American Food and Drug Administration (FDA) for the use in combination with everolimus, as treatment of advanced renal cell carcinoma following one prior antiangiogenic therapy. A major problem of treating mRCC with lenvatinib and everolimus is the serious adverse event (AE) of arterial hypertension. During the treatment with everolimus and lenvatinib combined, 42% of the patients developed hypertension, while 10% of the patients treated with everolimus alone and 48% of the of the lenvatinib only treated patients developed hypertension. Lenvatinib carries warnings and precautions for hypertension, cardiac failure, and other adverse events. Therefore, careful monitoring of the patients is necessary. PMID:28796163

Sequential therapy in metastatic clear cell renal carcinoma: TKI-TKI vs TKI-mTOR.

PubMed

Felici, Alessandra; Bria, Emilio; Tortora, Giampaolo; Cognetti, Francesco; Milella, Michele

2012-12-01

With seven targeted agents, directed against the VEGF/VEGF receptor (VEGFR) axis or the mTOR pathway, approved for the treatment of metastatic renal cell carcinoma and more active agents in advanced phase of clinical testing, questions have arisen with regard to their optimal use, either in combination or in sequence. One of the most compelling (and debated) issues is whether continued VEGF/VEGFR inhibition with agents hitting the same targets (TKI-TKI) affords better results than switching mechanisms of action by alternating VEGFR and mTOR inhibition (TKI-mTOR). In this article, the authors review the (little) available evidence coming from randomized Phase III clinical trials and try to fill in the (many) remaining gaps using evidence from small-size, single-arm Phase II studies and retrospective series, as well as reviewing preclinical evidence supporting either strategy.

Safety and clinical efficacy of everolimus in the treatment of advanced renal cell carcinoma (RCC)

PubMed Central

Shahani, Rohan; Kwan, Kevin G; Kapoor, Anil

2010-01-01

Renal cell carcinoma (RCC) is one of the most lethal genitourinary malignancies. Recently, there has been a paradigm shift in the management of advanced RCC. New targeted therapies including vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) inhibitors have been developed which have shown promising results in a patient population who otherwise had very few options for treatment. The first mTOR inhibitor, temsirolimus, an intravenous prodrug, has shown improved overall survival in poor prognosis patients. More recently, an oral mTOR inhibitor, everolimus (RAD 001), has been developed which has been shown to delay disease progression in patients with metastatic RCC who have progressed on other targeted therapies. Although a survival advantage in phase III trials is seen with everolimus, associated systemic toxicities, while generally well tolerated, are not insignificant. These include mucositis, hyperglycemia, hyperlipidemia, and pneumonitis. Despite the side effects, emerging evidence points to everolimus as the optimal second-line treatment for patients with advanced renal cell carcinoma. PMID:21701620

Trastuzumab in Treating Patients With Previously Treated, Locally Advanced, or Metastatic Cancer of the Urothelium

ClinicalTrials.gov

2013-05-01

Distal Urethral Cancer; Metastatic Transitional Cell Cancer of the Renal Pelvis and Ureter; Proximal Urethral Cancer; Recurrent Bladder Cancer; Recurrent Transitional Cell Cancer of the Renal Pelvis and Ureter; Recurrent Urethral Cancer; Stage IV Bladder Cancer; Transitional Cell Carcinoma of the Bladder; Urethral Cancer Associated With Invasive Bladder Cancer

A unique case of spontaneous regression of metastatic papillary renal cell carcinoma: a case report

PubMed Central

Lim, Rebecca; Tan, Puay Hoon; Cheng, Christopher; Agasthian, Thirugnanam; Tan, Hwei Ling; Teh, Bin Tean

2009-01-01

Spontaneous regression of cancer is a rare, but well documented, phenomenon. We present a unique case of an 82 year old Chinese male who experienced spontaneous regression of histologically-verified metastatic type II papillary renal cell carcinoma in the absence of intervening systemic therapy or surgery. This is the first reported case of spontaneous regression of papillary renal cell carcinoma. The mechanism of spontaneous regression remains unknown, and represents a challenge for existing oncology paradigms. PMID:19918481

A case of denosumab-induced hypocalcaemia in a patient with non-metastatic prostate cancer and renal impairment.

PubMed

Blackley, S; Anderson, K; Berg, J

2015-01-01

Denosumab is an emerging new treatment for osteoporosis in postmenopausal women and men with non-metastatic prostate cancer. It is largely used by specialists as an alternative treatment in patients with contraindications to traditional, more commonly used drugs such as bisphosphonates. One important side effect is hypocalcaemia, which may be life threatening. The risk of this is increased in renal impairment, mainly if eGFR < 30 ml/min/1.73m(2), and is exacerbated by vitamin D insufficiency. This is a case study of prolonged symptomatic hypocalcaemia after a single dose of denosumab in a patient with non-metastatic prostate cancer and moderate renal impairment (eGFR 40 ml/min/1.73m(2)). The patient presented with acute confusion, muscle cramps and myoclonic jerks 5 weeks after treatment. This case demonstrates the need to be aware of adverse effects of denosumab in mild-moderate renal impairment and the need to monitor calcium levels pre- and post-treatment.

Tumor Mutational Load and Immune Parameters across Metastatic Renal Cell Carcinoma Risk Groups.

PubMed

de Velasco, Guillermo; Miao, Diana; Voss, Martin H; Hakimi, A Ari; Hsieh, James J; Tannir, Nizar M; Tamboli, Pheroze; Appleman, Leonard J; Rathmell, W Kimryn; Van Allen, Eliezer M; Choueiri, Toni K

2016-10-01

Patients with metastatic renal cell carcinoma (mRCC) have better overall survival when treated with nivolumab, a cancer immunotherapy that targets the immune checkpoint inhibitor programmed cell death 1 (PD-1), rather than everolimus (a chemical inhibitor of mTOR and immunosuppressant). Poor-risk mRCC patients treated with nivolumab seemed to experience the greatest overall survival benefit, compared with patients with favorable or intermediate risk, in an analysis of the CheckMate-025 trial subgroup of the Memorial Sloan Kettering Cancer Center (MSKCC) prognostic risk groups. Here, we explore whether tumor mutational load and RNA expression of specific immune parameters could be segregated by prognostic MSKCC risk strata and explain the survival seen in the poor-risk group. We queried whole-exome transcriptome data in renal cell carcinoma patients (n = 54) included in The Cancer Genome Atlas who ultimately developed metastatic disease or were diagnosed with metastatic disease at presentation and did not receive immune checkpoint inhibitors. Nonsynonymous mutational load did not differ significantly by the MSKCC risk group, nor was the expression of cytolytic genes-granzyme A and perforin-or selected immune checkpoint molecules different across MSKCC risk groups. In conclusion, this analysis revealed that mutational load and expression of markers of an active tumor microenvironment did not correlate with MSKCC risk prognostic classification in mRCC. Cancer Immunol Res; 4(10); 820-2. ©2016 AACR. ©2016 American Association for Cancer Research.

Recommendations from the Spanish Oncology Genitourinary Group for the treatment of metastatic renal cancer.

PubMed

Bellmunt, Joaquim; Calvo, Emiliano; Castellano, Daniel; Climent, Miguel Angel; Esteban, Emilio; García del Muro, Xavier; González-Larriba, José Luis; Maroto, Pablo; Trigo, José Manuel

2009-03-01

For almost the last two decades, interleukin-2 and interferon-alpha have been the only systemic treatment options available for metastatic renal cell carcinoma. However, in recent years, five new targeted therapies namely sunitinib, sorafenib, temsirolimus, everolimus and bevacizumab have demonstrated clinical activity in these patients. With the availability of new targeted agents that are active in this disease, there is a need to continuously update the treatment algorithm of the disease. Due to the important advances obtained, the Spanish Oncology Genitourinary Group (SOGUG) has considered it would be useful to review the current status of the disease, including the genetic and molecular biology factors involved, the current predicting models for development of metastases as well as the role of surgery, radiotherapy and systemic therapies in the early- or late management of the disease. Based on this previous work, a treatment algorithm was developed.

Eribulin Mesylate in Treating Patients With Locally Advanced or Metastatic Cancer of the Urothelium and Kidney Dysfunction

ClinicalTrials.gov

2018-04-24

Metastatic Urothelial Carcinoma; Recurrent Bladder Urothelial Carcinoma; Recurrent Urethral Urothelial Carcinoma; Recurrent Urothelial Carcinoma of the Renal Pelvis and Ureter; Renal Failure; Stage III Bladder Urothelial Carcinoma AJCC v6 and v7; Stage IV Bladder Urothelial Carcinoma AJCC v7

Metastatic renal cell carcinoma complicated with diffuse alveolar hemorrhage: a rare adverse effect of sunitinib.

PubMed

Yamada, Tadaaki; Ohtsubo, Koushiro; Izumi, Kouji; Takeuchi, Shinji; Mouri, Hisatsugu; Yamashita, Kaname; Yasumoto, Kazuo; Ghenev, Peter; Kitagawa, Satoshi; Yano, Seiji

2010-12-01

We report the case of a 67-year-old man with metastatic papillary renal cell carcinoma (RCC) who developed bloody sputum after the administration of sunitinib. Chest computed tomography revealed diffuse ground-glass opacity lesions, and bloody bronchoalveolar lavage fluid was obtained by flexible bronchoscopy. The abnormal shadows promptly regressed after withdrawal of sunitinib. In four cycles of sunitinib treatment, he suffered from controllable diffuse alveolar hemorrhage. Finally, he died of respiratory failure 8 months after onset. This is the first case report of diffuse alveolar hemorrhage as an adverse effect of sunitinib in metastatic papillary RCC. Care should be taken with pulmonary hemorrhage in the use of anti-angiogenesis agents in not only squamous cell lung cancer, but also metastatic lung tumors.

Longitudinal Assessment of Vascular Function With Sunitinib in Patients With Metastatic Renal Cell Carcinoma.

PubMed

Catino, Anna B; Hubbard, Rebecca A; Chirinos, Julio A; Townsend, Ray; Keefe, Stephen; Haas, Naomi B; Puzanov, Igor; Fang, James C; Agarwal, Neeraj; Hyman, David; Smith, Amanda M; Gordon, Mary; Plappert, Theodore; Englefield, Virginia; Narayan, Vivek; Ewer, Steven; ElAmm, Chantal; Lenihan, Daniel; Ky, Bonnie

2018-03-01

Sunitinib, used widely in metastatic renal cell carcinoma, can result in hypertension, left ventricular dysfunction, and heart failure. However, the relationships between vascular function and cardiac dysfunction with sunitinib are poorly understood. In a multicenter prospective study of 84 metastatic renal cell carcinoma patients, echocardiography, arterial tonometry, and BNP (B-type natriuretic peptide) measures were performed at baseline and at 3.5, 15, and 33 weeks after sunitinib initiation, correlating with sunitinib cycles 1, 3, and 6. Mean change in vascular function parameters and 95% confidence intervals were calculated. Linear regression models were used to estimate associations between vascular function and left ventricular ejection fraction, longitudinal strain, diastolic function (E/e'), and BNP. After 3.5 weeks of sunitinib, mean systolic blood pressure increased by 9.5 mm Hg (95% confidence interval, 2.0-17.1; P =0.02) and diastolic blood pressure by 7.2 mm Hg (95% confidence interval, 4.3-10.0; P <0.001) across all participants. Sunitinib resulted in increases in large artery stiffness (carotid-femoral pulse wave velocity) and resistive load (total peripheral resistance and arterial elastance; all P <0.05) and changes in pulsatile load (total arterial compliance and wave reflection). There were no statistically significant associations between vascular function and systolic dysfunction (left ventricular ejection fraction and longitudinal strain). However, baseline total peripheral resistance, arterial elastance, and aortic impedance were associated with worsening diastolic function and filling pressures over time. In patients with metastatic renal cell carcinoma, sunitinib resulted in early, significant increases in blood pressure, arterial stiffness, and resistive and pulsatile load within 3.5 weeks of treatment. Baseline vascular function parameters were associated with worsening diastolic but not systolic function. © 2018 American Heart

Metastatic Renal Cell Carcinoma Masquerading as Jugular Foramen Paraganglioma: A Role for Novel Magnetic Resonance Imaging.

PubMed

Thomas, Andrew J; Wiggins, Richard H; Gurgel, Richard K

2017-08-01

To describe a case of metastatic renal cell carcinoma (RCC) masquerading as a jugular foramen paraganglioma (JP). To compare imaging findings between skull base metastatic RCC and histologically proven paraganglioma. A case of unexpected metastatic skull base RCC is reviewed. Computed tomography (CT) and magnetic resonance imaging (MRI) were compared between 3 confirmed cases of JP and our case of metastatic RCC. Diffusion-weighted MRI (DW-MRI) sequences and computed apparent diffusion coefficient (ADC) values were compared between these entities. A 55-year-old man presents with what appears clinically and radiographically to be JP. The tumor was resected, then discovered on postoperative pathology to be metastatic RCC. Imaging was retrospectively compared between 3 histologically confirmed cases of JP and our case of skull base RCC. The RCC metastasis was indistinguishable from JP on CT and traditional MRI but distinct by ADC values calculated from DW-MRI. Metastatic RCC at the skull base may mimic the clinical presentation and radiographic appearance of JP. The MRI finding of flow voids is seen in both paraganglioma and metastatic RCC. Diffusion-weighted MRI is able to distinguish these entities, highlighting its potential utility in distinguishing skull base lesions.

Third-line Targeted Therapy in Metastatic Renal Cell Carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium.

PubMed

Wells, J Connor; Stukalin, Igor; Norton, Craig; Srinivas, Sandy; Lee, Jae Lyun; Donskov, Frede; Bjarnason, Georg A; Yamamoto, Haru; Beuselinck, Benoit; Rini, Brian I; Knox, Jennifer J; Agarwal, Neeraj; Ernst, D Scott; Pal, Sumanta K; Wood, Lori A; Bamias, Aristotelis; Alva, Ajjai S; Kanesvaran, Ravindran; Choueiri, Toni K; Heng, Daniel Y C

2017-02-01

The use of third-line targeted therapy (TTT) in metastatic renal cell carcinoma (mRCC) is not well characterized and varies due to the lack of robust data to guide treatment decisions. This study examined the use of third-line therapy in a large international population. To evaluate the use and efficacy of targeted therapy in a third-line setting. Twenty-five international cancer centers provided consecutive data on 4824 mRCC patients who were treated with an approved targeted therapy. One thousand and twelve patients (21%) received TTT and were included in the analysis. Patients were analyzed for overall survival (OS) and progression-free survival using Kaplan-Meier curves, and were evaluated for overall response. Cox regression analyses were used to determine the statistical association between OS and the six factors included in the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic model. Subgroup analysis was performed on patients stratified by their IMDC prognostic risk status. Everolimus was the most prevalent third-line therapy (27.5%), but sunitinib, sorafenib, pazopanib, temsirolimus, and axitinib were all utilized in over ≥9% of patients. Patients receiving any TTT had an OS of 12.4 mo, a progression-free survival of 3.9 mo, and 61.1% of patients experienced an overall response of stable disease or better. Patients not receiving TTT had an OS of 2.1 mo. Patients with favorable- (7.2%) or intermediate-risk (65.3%) disease had the highest OS with TTT, 29.9 mo and 15.5 mo, respectively, while poor-risk (27.5%) patients survived 5.5 mo. Results are limited by the retrospective nature of the study. TTT remains highly heterogeneous. The IMDC prognostic criteria can be used to stratify third-line patients. TTT use in favorable- and intermediate-risk patients was associated with the greatest OS. Patients with favorable- and intermediate-prognostic criteria disease treated with third-line targeted therapy have an associated

Adjuvant therapy for advanced renal cell carcinoma.

PubMed

Meissner, Matthew A; McCormick, Barrett Z; Karam, Jose A; Wood, Christopher G

2018-07-01

Locally advanced, non-metastatic renal cell carcinoma (RCC) is conventionally managed with surgery. However, patients are at a high risk of RCC recurrence and have poor survival outcomes. An effective adjuvant systemic treatment is needed to improve on these outcomes. Targeted molecular and immune-based therapies have been investigated, or are under investigation, but their role in this setting remains unclear. Areas covered: A comprehensive search of PubMed and ClinicalTrials.gov was performed for relevant literature. The following topics pertinent to adjuvant therapy in RCC were evaluated: strategies for patient selection, cytokine-based immunotherapy, vaccine therapy, VEGF and non-VEGF targeted molecular agents, and immune checkpoint inhibitors. Expert commentary: Strong evidence for the incorporation of adjuvant therapy in high-risk RCC is lacking. Multiple targeted molecular therapies have been examined with only one approved for use. Genetic and molecular-based prognostic models are needed to determine who may benefit from adjuvant therapy. Developing adjuvant therapy strategies in the future depends on the results of important ongoing trials with immunotherapy and targeted agents.

A case of metastatic Xp11.2 translocation renal cell carcinoma successfully managed by cytoreductive nephrectomy followed by axitinib therapy.

PubMed

Nishimura, Koichi; Takagi, Toshio; Toda, Naohiro; Yamamoto, Tomoko; Kondo, Tsunenori; Ishida, Hideki; Nagashima, Yoji; Tanabe, Kazunari

2017-03-01

Targeted medications for metastatic adult Xp11.2 translocation renal cell carcinoma (RCC) remain to be identified. We herein report a case of metastatic Xp11.2 translocation RCC controlled with cytoreductive nephrectomy (CN) and axitinib therapy. A 57-year-old woman complained of fatigue and low back pain. Imaging studies revealed a right renal tumor, with multiple lung and mediastinal lymph node metastases. Although the patient received 10 mg axitinib therapy for 5 months at the hospital she was initially admitted to, the size of the primary and metastatic lesions was not reduced. Thus, she was referred to the Tokyo Women's Medical University Hospital (Tokyo, Japan) for further treatment, where she underwent CN. On macroscopic examination, almost the entire kidney was replaced by a yellowish brown tumor >80 mm in diameter. Immunohistochemical examination confirmed the diagnosis of Xp11.2 translocation RCC. One month after surgery, axitinib therapy was resumed and the size of the metastatic lesions gradually decreased. These findings suggest that axitinib therapy is effective for adult Xp11.2 translocation RCC.

A case of metastatic Xp11.2 translocation renal cell carcinoma successfully managed by cytoreductive nephrectomy followed by axitinib therapy

PubMed Central

Nishimura, Koichi; Takagi, Toshio; Toda, Naohiro; Yamamoto, Tomoko; Kondo, Tsunenori; Ishida, Hideki; Nagashima, Yoji; Tanabe, Kazunari

2017-01-01

Targeted medications for metastatic adult Xp11.2 translocation renal cell carcinoma (RCC) remain to be identified. We herein report a case of metastatic Xp11.2 translocation RCC controlled with cytoreductive nephrectomy (CN) and axitinib therapy. A 57-year-old woman complained of fatigue and low back pain. Imaging studies revealed a right renal tumor, with multiple lung and mediastinal lymph node metastases. Although the patient received 10 mg axitinib therapy for 5 months at the hospital she was initially admitted to, the size of the primary and metastatic lesions was not reduced. Thus, she was referred to the Tokyo Women's Medical University Hospital (Tokyo, Japan) for further treatment, where she underwent CN. On macroscopic examination, almost the entire kidney was replaced by a yellowish brown tumor >80 mm in diameter. Immunohistochemical examination confirmed the diagnosis of Xp11.2 translocation RCC. One month after surgery, axitinib therapy was resumed and the size of the metastatic lesions gradually decreased. These findings suggest that axitinib therapy is effective for adult Xp11.2 translocation RCC. PMID:28451413

Imaging and Management of Intrathoracic Renal Cell Carcinoma Metastases.

PubMed

Price, Melissa; Wu, Carol C; Genshaft, Scott; Sadow, Peter M; Xie, Ling; Shepard, Jo-Anne O; McDermott, Shaunagh

2018-06-01

Renal cell carcinoma (RCC) has a propensity to metastasize to the chest, with the lungs being the most common distant metastatic site. The histologic subtype of RCC has implications for prognosis. Significant advances have been made in the management of metastatic RCC, both in systemic and locoregional therapies. The aim of this article is to review appearances of intrathoracic metastases from RCC and to discuss treatment considerations.

VEGF Trap in Treating Patients With Recurrent, Locally Advanced, or Metastatic Cancer of the Urothelium

ClinicalTrials.gov

2014-10-10

Adenocarcinoma of the Bladder; Distal Urethral Cancer; Metastatic Transitional Cell Cancer of the Renal Pelvis and Ureter; Proximal Urethral Cancer; Recurrent Bladder Cancer; Recurrent Transitional Cell Cancer of the Renal Pelvis and Ureter; Recurrent Urethral Cancer; Squamous Cell Carcinoma of the Bladder; Stage III Bladder Cancer; Stage III Urethral Cancer; Stage IV Bladder Cancer; Transitional Cell Carcinoma of the Bladder; Urethral Cancer Associated With Invasive Bladder Cancer

Evaluation of renal function change during first-line tyrosine kinase inhibitor therapy for metastatic renal cell carcinoma.

PubMed

Ishihara, Hiroki; Kondo, Tsunenori; Fukuda, Hironori; Yoshida, Kazuhiko; Omae, Kenji; Takagi, Toshio; Iizuka, Junpei; Kobayashi, Hirohito; Tanabe, Kazunari

2017-12-01

The change in renal function induced by first-line tyrosine kinase inhibitor therapy for metastatic renal cell carcinoma remains unclear. One hundred and thirty-four patients were evaluated. Sunitinib (SU) and sorafenib (SO) were administered to 91 (67.9%) and 43 (32.1%) patients, respectively. The change in estimated glomerular filtration rate (ΔeGFR) was calculated as [(eGFR at each time point - pre-treatment eGFR)/pre-treatment eGFR] × 100. ΔeGFR was compared between SU- and SO users using a mixed-effects model for repeated measures data with two or greater. Additionally, predictors for ΔeGFR ≤ -10% at 6 months after therapy initiation were evaluated using multivariate logistic regression analysis. Throughout the 24 months after therapy initiation, ΔeGFR was negatively greater in SU users, compared with that in SO users (P < 0.0001). In SU users, renal dysfunction was observed regardless of pre-treatment chronic kidney disease (CKD) status, whereas the magnitude of renal dysfunction was milder in SO users. In SO users without pre-treatment CKD, renal function did not significantly deteriorate. Moreover, ΔeGFR ≤ -10% was more frequently observed in SU users after 3 months (P = 0.0121) and 6 months (P = 0.0009). Finally, SU usage was an independent predictor for ΔeGFR ≤ -10% at 6 months (odds ratio 8.87, P = 0.0053), along with pre-treatment hypertension (odds ratio 4.69, P = 00072). Deterioration of renal function was stronger with SU than SO. During SU therapy, renal function should be monitored and pre-treatment kidney function should be taken into consideration for therapy selection. © The Author 2017. Published by Oxford University Press.

IMA901, a multipeptide cancer vaccine, plus sunitinib versus sunitinib alone, as first-line therapy for advanced or metastatic renal cell carcinoma (IMPRINT): a multicentre, open-label, randomised, controlled, phase 3 trial.

PubMed

Rini, Brian I; Stenzl, Arnulf; Zdrojowy, Romauld; Kogan, Mikhail; Shkolnik, Mikhail; Oudard, Stephane; Weikert, Steffen; Bracarda, Sergio; Crabb, Simon J; Bedke, Jens; Ludwig, Joerg; Maurer, Dominik; Mendrzyk, Regina; Wagner, Claudia; Mahr, Andrea; Fritsche, Jens; Weinschenk, Toni; Walter, Steffen; Kirner, Alexandra; Singh-Jasuja, Harpreet; Reinhardt, Carsten; Eisen, Tim

2016-11-01

In a phase 2 study in patients with metastatic renal cell carcinoma, overall survival was associated with T-cell responses against IMA901, a vaccine consisting of ten tumour-associated peptides. In this phase 3 trial, we aimed to determine the clinical effect of adding IMA901 to sunitinib, the standard first-line treatment in metastatic renal cell carcinoma with postulated favourable immunomodulatory effects. The IMPRINT study is an open-label, randomised, controlled, phase 3 trial done at 124 clinical sites in 11 countries. HLA-A*02-positive patients (aged ≥18 years) with treatment-naive, histologically confirmed metastatic or locally advanced (or both) clear-cell renal cell carcinoma were randomly assigned (3:2) to receive sunitinib plus up to ten intradermal vaccinations of IMA901 (4·13 mg) and granulocyte macrophage colony-stimulating factor (75 μg), with one dose of cyclophosphamide (300 mg/m 2 ) 3 days before the first vaccination, or to receive sunitinib alone. Sunitinib (50 mg) was given orally once daily, with each cycle defined as 4 weeks on treatment followed by 2 weeks off treatment, until progression of disease as determined by the investigator, death, or withdrawal of consent. Block randomisation (block size five) was done centrally using an interactive web response system, stratified by prognostic risk, geographical region, and previous nephrectomy. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival from randomisation until death of any cause as determined by the investigator, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01265901. Between Dec 22, 2010, and Dec 15, 2012, we screened 1171 patients, of whom 339 were randomly assigned to receive sunitinib plus IMA901 (n=204) or sunitinib monotherapy (n=135). Patients had a median follow-up of 33·27 months (IQR 29·92-35·64). Median overall survival did not differ significantly between the

Dynamic Contrast-Enhanced Magnetic Resonance Imaging as a Pharmacodynamic Biomarker for Pazopanib in Metastatic Renal Carcinoma.

PubMed

Sweis, Randy F; Medved, Milica; Towey, Shannon; Karczmar, Gregory S; Oto, Aytekin; Szmulewitz, Russell Z; O'Donnell, Peter H; Fishkin, Paul; Karrison, Theodore; Stadler, Walter M

2017-04-01

Traditional imaging assessment criteria might not correlate well with clinical benefit from vascular endothelial growth factor pathway-directed therapy in metastatic renal cancer. Preclinical data suggest tumor growth is preceded by a rise in K trans level, a parameter derived from dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) that reflects vascular permeability. We thus hypothesized that K trans might be a predictive biomarker for pazopanib. Patients with metastatic renal cancer were treated with pazopanib at 800 mg oral daily until disease progression. MRI of the abdomen and pelvis with a DCE-MRI sequence was obtained at baseline and every 8 weeks. Seventy-three DCE-MRI scans were completed and 66 were technically assessable. Of the 17 patients with at least 1 DCE-MRI scan after the baseline scan, 16 (94%) had a decline in K trans level. Changes in K trans compared with baseline after 1, 8, 16, and 24 weeks were -49%, -65%, -63%, and -53%, respectively (P = .0052, repeated measures analysis of variance). The median K trans nadir occurred at 8 weeks. The median progression-free survival (PFS) was 32.1 weeks. PFS was longer in patients with higher baseline K trans values (P = .036, log rank). Baseline K trans did not reach significance in a Cox proportional hazard model including clinical prognostic index and previous treatments (P = .083). We show that K trans is a pharmacodynamic biomarker for pazopanib therapy in metastatic renal cancer. Because of the small sample size, the predictive capacity of K trans recovery could not be assessed, but baseline K trans correlated with PFS. Copyright © 2016 Elsevier Inc. All rights reserved.

EphA2 Is a Potential Player of Malignant Cellular Behavior in Non-Metastatic Renal Cell Carcinoma Cells but Not in Metastatic Renal Cell Carcinoma Cells.

PubMed

Cho, Min Chul; Cho, Sung Yong; Yoon, Cheol Yong; Lee, Seung Bae; Kwak, Cheol; Kim, Hyeon Hoe; Jeong, Hyeon

2015-01-01

To investigate the role of EphA2 in malignant cellular behavior in renal cell carcinoma (RCC) cells and whether FAK/RhoA signaling can act as downstream effectors of EphA2 on RCC cells. Expression of EphA2 protein in non-metastatic RCC (Caki-2 and A498), metastatic RCC cells (Caki-1 and ACHN), HEK-293 cells and prostate cancer cells (PC-3 and DU-145; positive controls of EphA2 expression) was evaluated by Western blot. Changes in mRNA or protein expression of EphA2, FAK or membrane-bound RhoA following EphA2, FAK or RhoA small interfering RNA (siRNA) transfection were determined by reverse transcription polymerase chain reaction or Western blot. The effect of siRNA treatment on cellular viability, apoptosis and invasion was analyzed by cell counting kit-8, Annexin-V and modified Matrigel-Boyden assays, respectively. In all RCC cell lines, the expression of EphA2 protein was detectable at variable levels; however, in HEK-293 cells, EphA2 expression was very low. Treatment with EphA2 siRNA significantly reduced the expression of EphA2 mRNA and protein in all RCC cell lines. For non-metastatic RCC cells (Caki-2 and A498) but not metastatic RCC cells (Caki-1 and ACHN), cellular viability, invasiveness, resistance to apoptosis, expression of membrane-bound RhoA protein and FAK phosphorylation were significantly decreased in EphA2 siRNA-treated cells compared to the control. In non-metastatic RCC cells, FAK siRNA significantly attenuated the invasiveness, resistance to apoptosis, as well as expression of membrane-bound RhoA protein without changing protein expression of EphA2. RhoA siRNA significantly decreased the malignant cellular behavior and expression of membrane-bound RhoA protein without changing EphA2 protein expression or FAK phosphorylation. Our data provide the first functional evidence that the EphA2/FAK/RhoA signaling pathway plays a critical role in the malignant cellular behavior of RCC and appears to be functional particularly in the early stage of

Changes in Renal Function of Patients with Metastatic Renal Cell Carcinoma During Treatment with Molecular-Targeted Agents.

PubMed

Miyake, Hideaki; Muramaki, Mototsugu; Imai, Satoshi; Harada, Ken-Ichi; Fujisawa, Masato

2016-06-01

Impairment of renal function is a serious issue that should be considered in patients undergoing treatment with molecular-targeted agents for metastatic renal cell carcinoma (mRCC). The objective of this study was to assess the impact of molecular-targeted therapy on changes in renal function among patients with mRCC. The study included 408 mRCC patients treated with sunitinib, sorafenib, axitinib, everolimus and/or temsirolimus. Among these, 185, 128 and 95 received molecular-targeted agents as first-line (group 1), second-line (group 2) and third-line (group 3) therapy, respectively. No significant differences between the estimated glomerular filtration rate (eGFR) at baseline and that at the end of molecular-targeted therapy were noted among the three groups of patients. In addition, there were no significant differences between eGFR prior to the introduction of molecular-targeted therapy and that at the end of therapy across agents and lines of targeted therapy, with the exception of patients treated with axitinib and everolimus in second-line and third-line therapy, respectively. In group 1, a reduction in eGFR of >10 % from baseline was independently associated with performance status, hypertension and treatment duration, while in groups 2 and 3, only treatment duration was independently related to a reduction in eGFR of >10 %. It appears that renal function in patients with mRCC is not markedly impaired by molecular-targeted therapies, irrespective of the specific agents introduced; however, it may be necessary to pay special attention to deterioration in renal function when molecular-targeted therapy is continued for longer periods.

Atezolizumab With or Without Eribulin Mesylate in Treating Patients With Recurrent Locally Advanced or Metastatic Urothelial Cancer

ClinicalTrials.gov

2018-06-05

Metastatic Urothelial Carcinoma; Recurrent Bladder Urothelial Carcinoma; Recurrent Urethral Urothelial Carcinoma; Recurrent Urothelial Carcinoma of the Renal Pelvis and Ureter; Renal Pelvis Urothelial Carcinoma; Stage III Bladder Urothelial Carcinoma AJCC v6 and v7; Stage III Renal Pelvis Cancer AJCC v7; Stage III Ureter Cancer AJCC v7; Stage III Urethral Cancer AJCC v7; Stage IV Bladder Urothelial Carcinoma AJCC v7; Stage IV Renal Pelvis Cancer AJCC v7; Stage IV Ureter Cancer AJCC v7; Stage IV Urethral Cancer AJCC v7; Ureter Urothelial Carcinoma

Phase 2 study of ABT-510 in patients with previously untreated advanced renal cell carcinoma.

PubMed

Ebbinghaus, Scot; Hussain, Maha; Tannir, Nizar; Gordon, Michael; Desai, Apurva A; Knight, Raymond A; Humerickhouse, Rod A; Qian, Jiang; Gordon, Gary B; Figlin, Robert

2007-11-15

Angiogenesis is a characteristic of renal cell carcinoma. ABT-510 is an angiogenesis inhibitor that mimics the antiangiogenic properties of thrombospondin-1. This study was designed to assess the safety and efficacy of ABT-510 in patients with advanced renal cell carcinoma. Patients with previously untreated metastatic or unresectable renal cell carcinoma were randomized to treatment with one of two doses of ABT-510, self-administered s.c. twice daily in 28-day treatment periods without intervening rest periods. End points were progression-free survival (PFS), objective response rate, overall survival, and toxicity. The objective response rate was 4% in the 10 mg twice daily group, and there were two unconfirmed PRs in the 100 mg twice daily group. Respective median PFS was 4.2 and 3.3 months, with a 6-month PFS of 39% and 32%. Median overall survival was 27.8 months (10 mg twice daily) and 26.1 months (100 mg twice daily). The most frequent adverse events were injection site reactions (84%), fatigue (50%), headache (20%), and nausea (19%). The incidence of treatment-related, grade 3/4 adverse events was low and included three bleeding episodes (gastrointestinal hemorrhage, intracranial hemorrhage, and hemoptysis) and one thrombotic event (deep vein thrombosis). No deaths were attributed to ABT-510. There was little evidence of clinical activity for ABT-510, and further evaluation as a single agent for treating advanced renal cell carcinoma is not warranted. The evidence of a favorable safety profile may justify further evaluation in combination therapy.

Secondary hemophagocytic lymphohistiocytosis in the setting of metastatic renal cell carcinoma: a case report.

PubMed

El-Masry, Monica; Eisenbud, Lauren; Tran, Minh-Ha

2017-03-02

Hemophagocytic lymphohistiocytosis is a disease process characterized by unregulated hyperactivation of the immune system associated with multiorgan involvement and high mortality rates. Early recognition is crucial and a recently validated diagnostic schema, the H-Score, may facilitate diagnosis particularly in secondary hemophagocytic lymphohistiocytosis cases. We present a patient with secondary hemophagocytic lymphohistiocytosis in association with metastatic renal cell carcinoma in whom high-dose steroid therapy induced a remarkable response. A 35-year-old Vietnamese man with quiescent systemic lupus erythematosus was diagnosed 5 months prior to admission with left-sided renal cell carcinoma metastatic to the pancreas and spine. Ten days prior to admission, a febrile illness (temperatures to 39 °C) associated with flu-like symptoms unresponsive to levofloxacin developed. He took only two doses of pazopanib prior to admission. High fevers unresponsive to antimicrobial therapy, cytopenias, disseminated intravascular coagulation, and progressive multiorgan failure led to intubation and intensive care unit stay. Extensive infectious disease workup showed only negative results, but elevation of interleukin-2 receptor, exceedingly high ferritin levels and other features earned an H-Score of 302, consistent with >99% diagnostic probability for secondary hemophagocytic lymphohistiocytosis. High-dose steroid therapy produced a rapid clinical and biochemical response. Hemophagocytic lymphohistiocytosis is a life-threatening disorder which is likely to be under-recognized. Increased awareness of this disease entity and its diagnosis is crucial toward early recognition and treatment. To our knowledge, our patient is only the second reported with secondary hemophagocytic lymphohistiocytosis occurring in the setting of renal cell carcinoma.

[Non-metastatic clear cell renal cancer: dependence of the tumour stage on clinico-anatomic and morphologic factors; prognostic value of macro- and karyometric characteristics].

PubMed

Iurin, A G

2010-01-01

Non-metastatic clear-cell renal cancer: dependence of the tumour stage on clinico-anatomic and morphologic factors; prognostic value of macro- and karyometric characteristics Sankt Peterburg Pathology Bureau, Sankt Peterburg It was shown based on multivariate regression analysis that pT1a3bN0MO stages of non-metastatic clear-cell renal cancer significantly correlate not only with the tumor size and invasion into the fatty tissue and/or renal vein but also with the invasion into the renal capsule and with the mean maximum diameter and mean nucleus area of tumor cells. There was no correlation of clear-cell renal cancer stages with tumor proliferative activity, gene p53 mutation, oncosuppressor gene PTEN expression, fraction of tumour clear-cell component, and such clinical characteristics as patients' sex, age, and body mass index. Taking into account statistically significant differences between the patients' survival rates, the regression equations developed in this work may be used for the prediction of disease outcome.

Prognostic impact of the pretreatment aspartate transaminase/alanine transaminase ratio in patients treated with first-line systemic tyrosine kinase inhibitor therapy for metastatic renal cell carcinoma.

PubMed

Kang, Minyong; Yu, Jiwoong; Sung, Hyun Hwan; Jeon, Hwang Gyun; Jeong, Byong Chang; Park, Se Hoon; Jeon, Seong Soo; Lee, Hyun Moo; Choi, Han Yong; Seo, Seong Il

2018-05-13

To examine the prognostic role of the pretreatment aspartate transaminase/alanine transaminase or De Ritis ratio in patients with metastatic renal cell carcinoma receiving first-line systemic tyrosine kinase inhibitor therapy. We retrospectively searched the medical records of 579 patients with metastatic renal cell carcinoma who visited Samsung Medical Center, Seoul, Korea, from January 2001 through August 2016. After excluding 210 patients, we analyzed 360 patients who received first-line tyrosine kinase inhibitor therapy. Cancer-specific survival and overall survival were defined as the primary and secondary end-points, respectively. A multivariate Cox proportional hazards regression model was used to identify independent prognosticators of survival outcomes. The overall population was divided into two groups according to the pretreatment De Ritis ratio as an optimal cut-off value of 1.2, which was determined by a time-dependent receiver operating characteristic curve analysis. Patients with a higher pretreatment De Ritis ratio (≥1.2) had worse cancer-specific survival and overall survival outcomes, compared with those with a lower De Ritis ratio (<1.2). Notably, a higher De Ritis ratio (≥1.2) was found to be an independent predictor of both cancer-specific survival (hazard ratio 1.61, 95% confidence interval 1.13-2.30) and overall survival outcomes (hazard ratio 1.69, 95% confidence interval 1.19-2.39), along with male sex, multiple metastasis (≥2), non-clear cell histology, advanced pT stage (≥3), previous metastasectomy and the Memorial Sloan Kettering Cancer Center risk classification. Our findings show that the pretreatment De Ritis ratio can provide valuable information about the survival outcomes of metastatic renal cell carcinoma patients receiving first-line tyrosine kinase inhibitor therapy. © 2018 The Japanese Urological Association.

Cytoreductive Nephrectomy in Elderly Patients with Metastatic Renal Cell Carcinoma in the Targeted Therapy Era.

PubMed

Uprety, Dipesh; Bista, Amir; Smith, Angela L; Vallatharasu, Yazhini; Marinier, David E

2018-05-01

The role of cytoreductive nephrectomy (CN) for metastatic renal cell cancer (mRCC) is not clearly understood after the approval of targeted therapies, particularly in the elderly population. The aim of this study was to compare survivals between patients who did and did not receive CN. The SEER-18 database was utilized in order to identify elderly patients with mRCC to compare overall survival (OS) and cancer-specific survival (CSS) between patients who did or did not receive CN between February 2006 and 2012. Kaplan-Meier curve and log rank test were used to compare OS and CSS between these two arms. Cox proportional hazard model was used for multivariate analysis and statistical significance was defined as p≤0.05. There was a significant survival benefit for those who received CN compared to those who did not receive CN (median OS: 18 months vs. 4 months, p<0.001; median CSS: 21 months vs. 5 months, p<0.001). CN offered significant survival benefit, even in elderly patients with metastatic renal cell cancer. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Validation of the International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) prognostic model for first-line pazopanib in metastatic renal carcinoma: the Spanish Oncologic Genitourinary Group (SOGUG) SPAZO study.

PubMed

Pérez-Valderrama, B; Arranz Arija, J A; Rodríguez Sánchez, A; Pinto Marín, A; Borrega García, P; Castellano Gaunas, D E; Rubio Romero, G; Maximiano Alonso, C; Villa Guzmán, J C; Puertas Álvarez, J L; Chirivella González, I; Méndez Vidal, M J; Juan Fita, M J; León-Mateos, L; Lázaro Quintela, M; García Domínguez, R; Jurado García, J M; Vélez de Mendizábal, E; Lambea Sorrosal, J J; García Carbonero, I; González del Alba, A; Suárez Rodríguez, C; Jiménez Gallego, P; Meana García, J A; García Marrero, R D; Gajate Borau, P; Santander Lobera, C; Molins Palau, C; López Brea, M; Fernández Parra, E M; Reig Torras, O; Basterretxea Badiola, L; Vázquez Estévez, S; González Larriba, J L

2016-04-01

Patients with metastatic renal carcinoma (mRCC) treated with first-line pazopanib were not included in the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic model. SPAZO (NCT02282579) was a nation-wide retrospective observational study designed to assess the effectiveness and validate the IMDC prognostic model in patients treated with first-line pazopanib in clinical practice. Data of 278 patients, treated with first-line pazopanib for mRCC in 34 centres in Spain, were locally recorded and externally validated. Mean age was 66 years, there were 68.3% male, 93.5% clear-cell type, 74.8% nephrectomized, and 81.3% had ECOG 0-1. Metastatic sites were: lung 70.9%, lymph node 43.9%, bone 26.3%, soft tissue/skin 20.1%, liver 15.1%, CNS 7.2%, adrenal gland 6.5%, pleura/peritoneum 5.8%, pancreas 5%, and kidney 2.2%. After median follow-up of 23 months, 76.4% had discontinued pazopanib (57.2% due to progression), 47.9% had received second-line targeted therapy, and 48.9% had died. According to IMDC prognostic model, 19.4% had favourable risk (FR), 57.2% intermediate risk (IR), and 23.4% poor risk (PR). No unexpected toxicities were recorded. Response rate was 30.3% (FR: 44%, IR: 30% PR: 17.3%). Median progression-free survival (whole population) was 11 months (32 in FR, 11 in IR, 4 in PR). Median and 2-year overall survival (whole population) were 22 months and 48.1%, respectively (FR: not reached and 81.6%, IR: 22 and 48.7%, PR: 7 and 18.8%). These estimations and their 95% confidence intervals are fully consistent with the outcomes predicted by the IMDC prognostic model. Our results validate the IMDC model for first-line pazopanib in mRCC and confirm the effectiveness and safety of this treatment. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

The development and piloting of the REnal specific Advanced Communication Training (REACT) programme to improve Advance Care Planning for renal patients.

PubMed

Bristowe, Katherine; Shepherd, Kate; Bryan, Liz; Brown, Heather; Carey, Irene; Matthews, Beverley; O'Donoghue, Donal; Vinen, Katie; Murtagh, Fliss E M

2014-04-01

In recent years, the End-Stage Kidney Disease population has increased and is ever more frail, elderly and co-morbid. A care-focused approach needs to be incorporated alongside the disease focus, to identify those who are deteriorating and improve communication about preferences and future care. Yet many renal professionals feel unprepared for such discussions. To develop and pilot a REnal specific Advanced Communication Training (REACT) programme to address the needs of End-Stage Kidney Disease patients and renal professionals. Two-part study: (1) development of the REnal specific Advanced Communication Training programme informed by multi-professional focus group and patient survey and (2) piloting of the programme. The REnal specific Advanced Communication Training programme was piloted with 16 participants (9 renal nurses/health-care assistants and 7 renal consultants) in two UK teaching hospitals. The focus group identified the need for better information about end-of-life phase, improved awareness of patient perspectives, skills to manage challenging discussions, 'hands on' practice in a safe environment and follow-up to discuss experiences. The patient survey demonstrated a need to improve communication about concerns, treatment plans and decisions. The developed REnal specific Advanced Communication Training programme was acceptable and feasible and was associated with a non-significant increase in confidence in communicating about end-of-life issues (pre-training: 6.6/10, 95% confidence interval: 5.7-7.4; post-training: 6.9/10, 95% confidence interval: 6.1-7.7, unpaired t-test - p = 0.56), maintained at 3 months. There is a need to improve end-of-life care for End-Stage Kidney Disease patients, to enable them to make informed decisions about future care. Challenges include prioritising communication training among service providers.

Diabetes mellitus with obesity is a predictor of recurrence in patients with non-metastatic renal cell carcinoma.

PubMed

Fukushima, Hiroshi; Masuda, Hitoshi; Yokoyama, Minato; Tatokoro, Manabu; Yoshida, Soichiro; Ishioka, Junichiro; Matsuoka, Yoh; Numao, Noboru; Koga, Fumitaka; Saito, Kazutaka; Fujii, Yasuhisa; Kihara, Kazunori

2013-07-01

To investigate the associations of diabetes mellitus with recurrence and prognosis after surgery for non-metastatic renal cell carcinoma and the effect modification of obesity on the above relationships. We retrospectively evaluated 543 patients with non-metastatic renal cell carcinoma (pT1-4N0M0) who underwent radical or partial nephrectomy. The association of diabetes mellitus with recurrence was analyzed using the Kaplan-Meier method and the Cox regression model. We also examined whether the above relationships were modified by obesity using subgroup analysis and tests of interaction. For subgroup analysis, the body mass index was categorized as non-obese (<25 kg/m(2)) and obese (≥25 kg/m(2)). Eighty-two patients (15.1%) had a history of diabetes mellitus. During the mean follow-up of 66.7 months, 68 patients (12.5%) developed recurrence. Although the body mass index was not associated with recurrence, diabetes mellitus was an independent predictor of recurrence in multivariate analysis (hazard ratio 2.43, P = 0.003), along with tumor diameter, grade and pathological T stage. In further subgroup analysis, the same relationship between diabetes mellitus and recurrence was clearly shown in the obese group (hazard ratio 4.07, P = 0.010), but not in the non-obese group (hazard ratio 1.95, P = 0.125). At the same time, obesity modified the effect of diabetes mellitus on recurrence with a trend (P-interaction = 0.086). In the obese group, 5-year recurrence-free survival rates were 75.3 and 91.9% for diabetes mellitus and non-diabetes mellitus patients, respectively (P < 0.001). Restricting analyses to patients with clear cell type histology did not materially change these results. Diabetes mellitus is a predictor of recurrence following surgery for non-metastatic renal cell carcinoma, especially in obese patients.

Validation of a short questionnaire to measure symptoms and functional limitations associated with hand-foot syndrome and mucositis in patients with metastatic renal cell carcinoma.

PubMed

Lai, Jin-Shei; Beaumont, Jennifer L; Diaz, Jose; Khan, Sadya; Cella, David

2016-01-15

Hand-foot syndrome and mucositis/stomatitis are frequent adverse events (AEs) of treatment with tyrosine kinase inhibitors in cancer therapy. Quality-of-life instruments that measure the functional consequences of these AEs are needed to assess the impact of therapeutic interventions and to guide patient care. The Hand-Foot and Mucositis Symptom and Impact Questionnaire (HAMSIQ [formerly the Supplementary Quality of Life Questionnaire]) was used in the COMPARZ trial (Pazopanib vs Sunitinib in the Treatment of Locally Advanced and/or Metastatic Renal Cell Carcinoma [national clinical trial no. NCT00720941]) and the PISCES study (Patient Preference Study of Pazopanib vs Sunitinib in Advanced or Metastatic Kidney Cancer [clinicaltrials.gov NCT01064310]) to assess mouth/throat and hand/foot soreness symptoms and subsequent limitations in patients receiving pazopanib or sunitinib for metastatic renal cell carcinoma. The objective of the current analysis was to validate the HAMSIQ using data from the PISCES study. The HAMSIQ was administered in the PISCES study at baseline and every 2 weeks over two 10-week periods to patients who were receiving pazopanib or sunitinib. Data from the first 10-week period were used to assess the feasibility, validity, and responsiveness of the HAMSIQ. In total, ≥85% of 169 patients completed the HAMSIQ (excluding the item concerning days off work). Correlations among items within the same limitation subscale generally were high (Cronbach α ≥ .80). HAMSIQ limitation scores differentiated patients according to their baseline performance status and severity of soreness. Small-to-moderate correlations were observed for the symptoms/limitation scores and for changes from baseline scores between the HAMSIQ and the Functional Assessment of Chronic Illness Therapy fatigue survey. The HAMSIQ demonstrated responsiveness to changes in clinical status and the development of hand-foot syndrome AEs over time. The HAMSIQ is a feasible, valid

Rapid Progressive Disease After Nivolumab Therapy in Three Patients with Metastatic Renal Cell Carcinoma

PubMed Central

KOBARI, YUKI; KONDO, TSUNENORI; TAKAGI, TOSHIO; OMAE, KENJI; NAKAZAWA, HAYAKAZU; TANABE, KAZUNARI

2017-01-01

Background/Aim: Rapid progressive disease (RPD), accelerated tumour growth immediate after the initiation of immune checkpoint inhibitor therapy, has been reported in melanoma and lung cancer. Herein, we describe 3 cases of RPD during the initial phase of nivolumab treatment for metastatic renal cell carcinoma. Patients and Methods: The first and second patients received nivolumab in the fourth-line setting. The third patient received nivolumab therapy as third-line treatment. Results: The first patient developed severe respiratory failure due to carcinomatous lymphangiosis 14 days after initiation of nivolumab therapy. The second patient developed leg paraplegia due to rapid growth of the metastatic tumour at the sixth thoracic vertebrae 5 days later. The third patient developed grade 4 hypercalcemia due to RPD on day 3. Conclusion: Clinicians should be aware of RPD during the initial phase of nivolumab therapy, especially in patients with critical lesions in the late-line setting. PMID:28652455

Dose escalation can maximize therapeutic potential of sunitinib in patients with metastatic renal cell carcinoma.

PubMed

Maráz, Anikó; Cserháti, Adrienn; Uhercsák, Gabriella; Szilágyi, Éva; Varga, Zoltán; Révész, János; Kószó, Renáta; Varga, Linda; Kahán, Zsuzsanna

2018-03-15

In patients with metastatic renal cell cancer, based on limited evidence, increased sunitinib exposure is associated with better outcome. The survival and toxicity data of patients receiving individualized dose escalated sunitinib therapy as compared to standard management were analyzed in this study. From July 2013, the data of metastatic renal cell cancer patients with slight progression but still a stable disease according to RECIST 1.1 criteria treated with an escalated dose of sunitinib (first level: 62.5 mg/day in 4/2 or 2 × 2/1 scheme, second level: 75 mg/day in 4/2 or 2 × 2/1 scheme) were collected prospectively. Regarding characteristics, outcome, and toxicity data, an explorative retrospective analysis of the register was carried out, comparing treatments after and before July 1, 2013 in the study (selected patients for escalated dose) and control (standard dose) groups, respectively. The study involved 103 patients receiving sunitinib therapy with a median overall and progression free survival of 25.36 ± 2.62 and 14.2 ± 3.22 months, respectively. Slight progression was detected in 48.5% of them. First and second-level dose escalation were indicated in 18.2% and 4.1% of patients, respectively. The dosing scheme was modified in 22.2%. The median progression free survival (39.7 ± 5.1 vs 14.2 ± 1.3 months (p = 0.037)) and the overall survival (57.5 ± 10.7 vs 27.9 ± 2.5 months (p = 0.044)) were significantly better in the study group (with dose escalation) than in the control group. Patients with nephrectomy and lower Memorial Sloan Kettering Cancer Center (MSKCC) scores showed more favorable outcomes. After dose escalation, the most common adverse events were worsening or development of fatigue, hypertension, stomatitis, and weight loss of over 10%. Escalation of sunitinib dosing in selected patients with metastatic renal cell cancer, especially in case of slight progression, based on tolerable toxicity is

New advances in renal amyloidosis.

PubMed

Nishi, Shinichi; Alchi, Bassam; Imai, Nofumi; Gejyo, Fumitake

2008-04-01

Renal amyloidosis is a rare and intractable disease that accounts for 0.2% of the original kidney diseases of dialysis patients in Japan. However, the number of patients with renal amyloidosis seems to be increasing in recent years. There have been some new concepts focusing on the mechanism of amyloidogenesis, such as molecular chaperones, seeding mechanism, and genetic polymorphisms of precursor protein. Clinical and histological features of renal amyloidosis vary according to the type. Significantly higher levels of urinary protein excretion are seen in the AL type, whereas microscopic haematuria is more prominent in the AA type. Histologically, amyloid deposition of AL type has stronger predilection for GBM than mesangium, and spicule formation is more frequently observed. In contrast, AA type has a higher affinity to TBM and interstitial area. For the histological diagnosis of renal amyloidosis, plural staining methods including Congo-red, Daylon and thioflavin-T stains are available. Combinations of these staining methods are necessary for establishing the precise diagnosis. The more recent and intensive treatments for renal amyloidosis are expected to improve patient outcome. For AL amyloidosis, high-dose melphalan plus high-dose dexamethasone or VAD, in conjunction with bone marrow stem cells transplantation, have shown a definitive effect on reducing urinary protein excretion. The biological agent, tumor necrosis factor (TNF alpha) blocker, improves the renal function in AA-type renal amyloidosis, as well as suppresses the inflammatory reactions in patients with rheumatoid arthritis. Clinical advances have been made in various aspects of renal amyloidosis.

Management of locally advanced and metastatic colon cancer in elderly patients.

PubMed

Kurniali, Peter C; Hrinczenko, Borys; Al-Janadi, Anas

2014-02-28

Colon cancer is the second leading cause of cancer mortality in the United States with a median age at diagnosis of 69 years. Sixty percent are diagnosed over the age of 65 years and 36% are 75 years or older. At diagnosis, approximately 58% of patients will have locally advanced and metastatic disease, for which systemic chemotherapy has been shown to improve survival. Treatment of cancer in elderly patients is more challenging due to multiple factors, including disabling co-morbidities as well as a decline in organ function. Cancer treatment of elderly patients is often associated with more toxicities that may lead to frequent hospitalizations. In locally advanced disease, fewer older patients receive adjuvant chemotherapy despite survival benefit and similar toxicity when compared to their younger counterparts. A survival benefit is also observed in the palliative chemotherapy setting for elderly patients with metastatic disease. When treating elderly patients with colon cancer, one has to consider drug pharmacokinetics and pharmacodynamics. Since chronological age is a poor marker of a patient's functional status, several methods of functional assessment including performance status and activities of daily living (ADL) or instrumental ADL, or even a comprehensive geriatric assessment, may be used. There is no ideal chemotherapy regimen that fits all elderly patients and so a regimen needs to be tailored for each individual. Important considerations when treating elderly patients include convenience and tolerability. This review will discuss approaches to the management of elderly patients with locally advanced and metastatic colon cancer.

Clinical Benefit of Everolimus as Second-Line Therapy in Metastatic Renal Cell Carcinoma: The French Retrospective SECTOR Study.

PubMed

Oudard, Stéphane; Joly, Florence; Geoffrois, Lionnel; Laguerre, Brigitte; Houede, Nadine; Barthelemy, Philippe; Gross-Goupil, Marine; Vano, Yann; Lucidarme, Oliver; Bidault, Francois; Kelkouli, Nadia; Slimane, Khemaies; Escudier, Bernard

2016-12-01

Real-world data of everolimus after vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitor (TKI) therapy in metastatic renal cell carcinoma (mRCC) are limited. The retrospective, noninterventional SECTOR (SECond line with afiniTOR) study (N = 165) assessed outcomes of second-line everolimus after initial VEGFR-TKI (TKI-everolimus, n = 144) and of third-line VEGFR-TKI after everolimus (TKI-everolimus-TKI, n = 59) in patients with mRCC. The primary end point was duration of everolimus therapy for both populations. Median duration was 4.0 months (range, 0.0-33.0 months) for second-line everolimus and 18.0 months (range, 2-78 months) for sequential VEGFR-TKI and everolimus. Median overall survival (OS) for this sequence was 36.0 months (95% confidence interval [CI], 27.0-56.0 months) and was longer for patients who received a first-line TKI for ≥ 9 months (not reached) than for < 9 months (28.0 months; P < .001). During second-line everolimus treatment, commonly reported adverse events (all grades) were fatigue (n = 66, 40.7%), anemia (n = 58, 35.8%), and stomatitis (n = 41, 25.3%). Median duration from initiation of first-line TKI to the end of the third-line TKI was 24.0 months (95% CI, 19.0-29.0 months). Median OS for this sequence was 41.0 months (95% CI, 25.0-57.0 months) and was significantly longer for patients who received the first-line TKI for ≥ 9 months (37.5 months) than for < 9 months (19.0 months; P < .0001). These results reflect clinical use of sequential TKI-everolimus and TKI-everolimus-TKI and provide additional evidence that everolimus could be an option in second-line therapy in mRCC. Results of the CheckMate-025 (Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma) and METEOR (Metastatic RCC Phase 3 Study Evaluating Cabozantinib versus Everolimus) studies might change the treatment landscape. Copyright © 2016 Elsevier Inc. All rights reserved.

Determination of glomerular function in advanced renal failure.

PubMed Central

Manz, F; Alatas, H; Kochen, W; Lutz, P; Rebien, W; Schärer, K

1977-01-01

In 15 children with advanced chronic renal failure, glomerular filtration rate was determined by different methods. Inulin clearance correlated well with the mean of creatinine and urea clearance, and also with 51-chromium edetic acid (EDTA) clearance measured over 24 hours. The absolute values of creatinine clearance and of 51Cr-EDTA clearance measured up to 8 hours were higher than inulin clearance. In advanced renal failure both the 51Cr-EDTA clearance measured over 24 hours, and the mean of creatinine and urea clearance, provide acceptable estimates of true glomerular filtration rate. PMID:411426

Final results from the large sunitinib global expanded-access trial in metastatic renal cell carcinoma.

PubMed

Gore, M E; Szczylik, C; Porta, C; Bracarda, S; Bjarnason, G A; Oudard, S; Lee, S-H; Haanen, J; Castellano, D; Vrdoljak, E; Schöffski, P; Mainwaring, P; Hawkins, R E; Crinò, L; Kim, T M; Carteni, G; Eberhardt, W E E; Zhang, K; Fly, K; Matczak, E; Lechuga, M J; Hariharan, S; Bukowski, R

2015-06-30

We report final results with extended follow-up from a global, expanded-access trial that pre-regulatory approval provided sunitinib to metastatic renal cell carcinoma (mRCC) patients, ineligible for registration-directed trials. Patients ⩾18 years received oral sunitinib 50 mg per day on a 4-weeks-on-2-weeks-off schedule. Safety was assessed regularly. Tumour measurements were scheduled per local practice. A total of 4543 patients received sunitinib. Median treatment duration and follow-up were 7.5 and 13.6 months. Objective response rate was 16% (95% confidence interval (CI): 15-17). Median progression-free survival (PFS) and overall survival (OS) were 9.4 months (95% CI: 8.8-10.0) and 18.7 months (95% CI: 17.5-19.5). Median PFS in subgroups of interest: aged ⩾65 years (33%), 10.1 months; Eastern Cooperative Oncology Group performance status ⩾2 (14%), 3.5 months; non-clear cell histology (12%), 6.0 months; and brain metastases (7%), 5.3 months. OS was strongly associated with the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model (n=4065). The most common grade 3/4 treatment-related adverse events were thrombocytopenia (10%), fatigue (9%), and asthenia, neutropenia, and hand-foot syndrome (each 7%). Final analysis of the sunitinib expanded-access trial provided a good opportunity to evaluate the long-term side effects of a tyrosine kinase inhibitor used worldwide in mRCC. Efficacy and safety findings were consistent with previous results.

Using Interferon Alfa Before Tyrosine Kinase Inhibitors May Increase Survival in Patients With Metastatic Renal Cell Carcinoma: A Turkish Oncology Group (TOG) Study.

PubMed

Artaç, Mehmet; Çoşkun, Hasan Şenol; Korkmaz, Levent; Koçer, Murat; Turhal, Nazım Serdar; Engin, Hüseyin; Dede, İsa; Paydaş, Semra; Öksüzoğlu, Berna; Bozcuk, Hakan; Demirkazık, Ahmet

2016-08-01

We aimed to investigate the outcomes of interferon alfa and sequencing tyrosine kinase inhibitors (TKIs) in patients with metastatic renal cell carcinoma. This multicenter study assessing the efficacy of TKIs after interferon alfa therapy in the first-line setting in patients with metastatic renal cell carcinoma. Patients (n = 104) from 8 centers in Turkey, who had been treated with interferon alfa in the first-line setting, were included in the study. Prognostic factors were evaluated for progression-free survival (PFS). The median age of the patients was 57 years. The median PFS of the patients treated with interferon alfa in the first-line was 3.6 months. A total of 61 patients received TKIs (sunitinib, n = 58; sorafenib, n = 3) after progression while on interferon alfa. The median PFS among the TKI-treated patients was 13.2 months. In the univariate analysis for interferon alfa treatment, neutrophil and hemoglobin level, platelet count, and Karnofsky performance status were the significant factors associated with PFS. In the univariate analysis for TKI treatment, neutrophil and hemoglobin levels were the significant factors for PFS. The median total PFS of the patients who had been treated with first-line interferon alfa and second-line TKIs was 24.9 months. This study showed that first-line interferon alfa treatment before TKIs may improve the total PFS in patients with metastatic renal cell carcinoma. Copyright © 2016 Elsevier Inc. All rights reserved.

Phase I trial on sms-D70 somatostatin analogue in advanced prostate and renal cell cancer.

PubMed

Joensuu, T K; Nilsson, S; Holmberg, A R; Márquez, M; Tenhunen, M; Saarto, T; Joensuu, H

2004-12-01

Plasma concentrations and tolerability of a novel somatostatin analogue sms-D70 were studied in patients with metastatic hormone-resistant prostate cancer (HRPC) or metastatic renal cell cancer. To overcome the limitations of the octapeptides having affinity only to somatostatin receptor subtypes 2 and 5, HRPC expressing mainly somatostatin receptors 1 and 4, a somatostatin derivative based on the natural somatostatin having affinity to all five somatostatin receptor subtypes, was developed. The in vivo stability of this dextran-conjugated derivative, somatostatin-D70, was confirmed previously in animal studies, and the nanomolar "panaffinity" has been shown in in vitro receptor binding studies on cell lines transfected with the somatostatin receptor genes. Sms-D70 was given with subcutaneous injection once a week at dose levels of 5, 10, 20, 35, and 50 mg. For pharmacokinetic studies, sms-D70 was labeled with 131I. Fourteen patients were treated, of whom 10 had prostate and 4 renal cell cancer. The kinetic data revealed high stability with a long half-life in the blood. The drug was well tolerated, and no grade 4 (WHO) toxicity was observed. The maximal tolerated dose could not be established due to the lack of dose-limiting toxicities. Objective PSA responses were not recorded in these heavily treated patients, but subjective stabilization of pain was observed and urinary symptoms were alleviated in four patients. Three patients with metastatic HRPC received 5-10-mg intravenous injections of sms-D70 once weekly for 4-14 months on a compassionate use basis. In all cases, serum PSA values decreased more than 50% from the pretreatment level, but these results are difficult to interpret due to concomitant treatments given to these patients. In conclusion, sms-D70 was well tolerated in the treatment of metastatic prostate and renal cell cancer, but no responses were found in these heavily treated patients.

High fidelity of driver chromosomal alterations among primary and metastatic renal cell carcinomas: implications for tumor clonal evolution and treatment.

PubMed

Kouba, Eril J; Eble, John N; Simper, Novae; Grignon, David J; Wang, Mingsheng; Zhang, Shaobo; Wang, Lisha; Martignoni, Guido; Williamson, Sean R; Brunelli, Matteo; Luchini, Claudio; Calió, Anna; Cheng, Liang

2016-11-01

Recent studies have demonstrated considerable genomic heterogeneity in both primary and metastatic renal cell carcinoma (RCC). This mutational diversity has serious implications for the development and implementation of targeted molecular therapies. We evaluated 39 cases of primary RCC tumors with their matched metastatic tumors to determine if the hallmark chromosomal anomalies of these tumors are preserved over the course of disease progression. Thirty-nine matched pairs of primary and metastatic RCCs (20 clear cell RCC, 16 papillary RCC, and 3 chromophobe RCC) were analyzed. All clear cell RCC and papillary RCC tumors were evaluated for chromosome 3p deletion, trisomy 7 and 17 using fluorescence in situ hybridization. Chromophobe RCC tumors were evaluated for genetic alterations in chromosomes 1, 2, 6, 10, and 17. Of the 20 clear cell RCC tumors, 18 primary tumors (90%) showed a deletion of chromosome 3p and were disomic for chromosomes 7 and 17. All molecular aberrations were conserved within the matched metastatic tumor. Of the 16 papillary RCC tumors, 10 primary tumors (62%) showed trisomy for both chromosomes 7 and 17 without 3p deletion. These molecular aberrations and others were conserved in the paired metastatic tumors. Of the three chromophobe RCC tumors, multiple genetic anomalies were identified in chromosomes 1, 2, 6, 10, and 17. These chromosomal aberrations were conserved in the matched metastatic tumors. Our results demonstrated genomic fidelity among the primary and metastatic lesions in RCCs. These findings may have important clinical and diagnostic implications.

Patterns of interstitial lung disease during everolimus treatment in patients with metastatic renal cell carcinoma.

PubMed

Mizuno, Ryuichi; Asano, Koichiro; Mikami, Shuji; Nagata, Hirohiko; Kaneko, Gou; Oya, Mototsugu

2012-05-01

To elucidate the patterns of interstitial lung disease during everolimus treatment in patients with metastatic renal cell carcinoma, we reviewed seven cases of everolimus-induced interstitial lung disease. Seven patients with metastatic renal cell carcinoma, which continued to progress despite treatment with sunitinib or sorafenib, developed interstitial lung disease after treatment with everolimus. Chest X-ray demonstrated diffuse infiltrates in lung fields, and chest computed tomography showed bilateral reticular and ground-glass opacities. Serum levels of lactate dehydrogenase (7/7), C-reactive protein (6/7), pulmonary surfactant associated protein D (1/7) and Krebs von den Lungen 6 (5/7) were elevated. The bronchoalveolar lavage fluid obtained from four patients with Grade 3 interstitial lung disease showed lymphocytosis. The transbronchial lung biopsy specimens showed interstitial lymphocytic infiltration and septal thickening of alveolar walls. In two cases with mild interstitial lung disease, the everolimus therapy was successfully continued. In four cases with Grade 3 interstitial lung disease, the drug was discontinued and steroid therapy was initiated. Pulmonary symptoms and radiological abnormalities resolved within 2 months. Serum Krebs von den Lungen 6 was elevated compared with baseline in all cases with interstitial lung disease. Some patients who developed mild interstitial lung disease during everolimus treatment could continue to receive the treatment. Even when severe interstitial lung disease developed, withdrawal of the drug and short-term use of high-dose steroids resulted in rapid recovery. Prompt recognition of interstitial lung disease exacerbation as well as exclusion of progressive disease or infection is of primary importance.

Advanced Renal Cell Carcinoma: Role of the Radiologist in the Era of Precision Medicine.

PubMed

Shinagare, Atul B; Krajewski, Katherine M; Braschi-Amirfarzan, Marta; Ramaiya, Nikhil H

2017-08-01

For the past decade, advanced renal cell carcinoma (RCC) has been at the forefront of oncologic innovation. Our rapidly evolving understanding of the molecular and genetic basis of RCC has revolutionized the management of advanced RCC; 10 novel molecular targeted agents and immune checkpoint inhibitor have received U.S. Food and Drug Administration approval for treatment of advanced RCC in a little over a decade. Amid this progress, imaging has assumed a central role in metastatic surveillance and follow-up of advanced RCC. State-of-the-art knowledge of the molecular basis of RCC and its treatment and imaging will help ensure that the radiology community remains relevant and central in the care of patients with advanced RCC. This article will review developments in management of advanced RCC from a radiologist's perspective to highlight our clinical role. It will describe how the underlying molecular mechanisms of RCC provide specific targets for novel anticancer agents. The relationship between the mechanisms of action of these novel anticancer agents and the imaging appearance of tumor response will be discussed, along with the available tumor response criteria and their strengths and weaknesses, thus assisting radiologists in response assessment in the setting of clinical trials or routine practice. The class- and drug-specific toxicities and complications associated with the novel anticancer agents will be summarized, since these are frequently missed or misinterpreted and require the radiologist's input in prompt detection and management. The potential role of radiogenomics and texture analysis in the management of advanced RCC will also be discussed. © RSNA, 2017.

Tumor mutational load and immune parameters across metastatic Renal Cell Carcinoma (mRCC) risk groups

PubMed Central

de Velasco, Guillermo; Miao, Diana; Voss, Martin H.; Hakimi, A. Ari; Hsieh, James J.; Tannir, Nizar M.; Tamboli, Pheroze; Appleman, Leonard J.; Rathmell, W. Kimryn; Van Allen, Eliezer M.; Choueiri, Toni K.

2016-01-01

Patients with metastatic renal cell carcinoma (mRCC) have better overall survival when treated with nivolumab, a cancer immunotherapy that targets the immune checkpoint inhibitor programmed cell death 1 (PD-1), rather than everolimus (a chemical inhibitor of mTOR and immunosuppressant). Poor-risk mRCC patients treated with nivolumab seemed to experience the greatest overall survival benefit, compared to patients with favorable or intermediate-risk, in an analysis of the CheckMate-025 trial subgroup of the Memorial Sloan Kettering Cancer Center (MSKCC) prognostic risk groups. Here we explore whether tumor mutational load and RNA expression of specific immune parameters could be segregated by prognostic MSKCC risk strata and explain the survival seen in the poor-risk group. We queried whole exome transcriptome data in RCC patients (n = 54) included in The Cancer Genome Atlas that ultimately developed metastatic disease or were diagnosed with metastatic disease at presentation and did not receive immune checkpoint inhibitors. Nonsynonymous mutational load did not differ significantly by MSKCC risk group, nor was the expression of cytolytic genes –granzyme A and perforin – or selected immune checkpoint molecules different across MSKCC risk groups. In conclusion, this analysis found that mutational load and expression of markers of an active tumor microenvironment did not correlate with MSKCC risk prognostic classification in mRCC. PMID:27538576

End-Stage Renal Disease From Cast Nephropathy in a Teenager With Neuroendocrine Carcinoma.

PubMed

Butani, Lavjay; Ducore, Jonathan

2016-07-01

Cast nephropathy is the most common manifestation of renal injury in patients with multiple myeloma but is rarely reported in other conditions. We are reporting our experience in caring for a teenager with a metastatic neuroendocrine carcinoma who developed rapidly progressive kidney injury that advanced to end-stage renal disease. On renal biopsy extensive tubular necrosis and intratubular eosinophilic casts were noted. This previously unreported finding should prompt oncologists to closely monitor for such a complication in patients with secretory tumors. Whether early plasmapheresis could be of benefit, as has been tried in multiple myeloma, remains to be determined.

Collecting and Studying Blood and Tissue Samples From Patients With Locally Recurrent or Metastatic Prostate or Bladder/Urothelial Cancer

ClinicalTrials.gov

2017-12-04

Healthy Control; Localized Urothelial Carcinoma of the Renal Pelvis and Ureter; Metastatic Malignant Neoplasm in the Bone; Metastatic Malignant Neoplasm in the Soft Tissues; Metastatic Urothelial Carcinoma of the Renal Pelvis and Ureter; Recurrent Bladder Carcinoma; Recurrent Prostate Carcinoma; Recurrent Urothelial Carcinoma of the Renal Pelvis and Ureter; Stage IV Bladder Cancer; Stage IV Bladder Urothelial Carcinoma; Stage IV Prostate Cancer

[Molecular biology of renal cancer: bases for genetic directed therapy in advanced disease].

PubMed

Maroto Rey, José Pablo; Cillán Narvaez, Elena

2013-06-01

There has been expansion of therapeutic options in the management of metastatic renal cell carcinoma due to a better knowledge of the molecular biology of kidney cancers. There are different tumors grouped under the term renal cell carcinoma, being clear cell cancer the most frequent and accounting for 80% of kidney tumors. Mutations in the Von Hippel-Lindau gene can be identified in up to 80% of sporadic clear cell cancer, linking a genetically inheritable disease where vascular tumors are frequent, with renal cell cancer. Other histologic types present specific alterations in molecular pathways, like c-MET in papillary type I tumors, and Fumarase Hydratase in papillary type II tumors. Identification of the molecular alteration for a specific tumor may offer an opportunity for treatment selection based on biomarkers, and, in the future, for developing an engineering designed genetic treatment.

Cytoreductive nephrectomy vs medical therapy as initial treatment: a rational approach to the sequence question in metastatic renal cell carcinoma.

PubMed

Spiess, Philippe E; Fishman, Mayer N

2010-10-01

Renal cell carcinoma (RCC) can be considered as two distinct entities: localized and metastatic disease. We conducted a review of the scientific literature published within the past decade pertaining to cytoreductive nephrectomy for metastatic RCC. Retrospective data and historical prospective series have demonstrated the survival benefit of debulking nephrectomy in well-selected RCC patients. New medical therapies, including vascular endothelial growth factor and mTOR pathway blocking drugs, are active biological agents, with survival improvement and potential regression of metastatic and primary tumors. Our current therapeutic challenge is the optimal integration of multimodal therapy consisting of systemic therapy and surgery including cytoreductive nephrectomy, debulking, and metastasectomy. Empiric data to guide this decision are limited. The decision concerning whether medical or surgical therapy should be the primary treatment approach selected must be made on an individual basis, taking into account patient performance status, clinical parameters, and physician expertise and recommendations, thus making each case a unique therapeutic challenge.

Weekly 24-hour continuous infusion interleukin-2 for metastatic melanoma and renal cell carcinoma: a phase I study.

PubMed

Perez, E A; Scudder, S A; Meyers, F A; Tanaka, M S; Paradise, C; Gandara, D R

1991-02-01

Twenty-nine patients with biopsy-confirmed metastatic melanoma (17) or metastatic renal cell carcinoma (12) were treated with escalating doses or recombinant human interleukin-2 (IL-2) administered as weekly 24-h intravenous infusions. Patients received from 3 to 12 x 10(6) C.U./m2 (18-72 x 10(6) I.U./m2) weekly over a treatment period of 1 to 16 weeks, with a median of eight weekly cycles administered. Patients in all treatment groups experienced non-life-threatening systemic side effects consisting of fever, nausea, vomiting, fluid retention, and diarrhea. Grade III hypotension was seen in four of six patients (67%) at 12 x 10(6) C.U./m2, and represented the dose-limiting toxicity. Grade IV hypotension occurred in 1 of 14 patients at 6 x 10(6) C.U./m2; no other grade IV toxicities were observed. Grade III fever occurred in 3 of 11 patients (27%) treated at 3 x 10(6) C.U./m2, 3 of 14 patients (21%) at 6 x 10(6) C.U./m2, and 3 of 6 patients (50%) at 9 x 10(6) C.U./m2. An objective response was observed in 3 of 28 evaluable patients (10%): 1 complete response and 1 partial response in renal cell cancer, and 1 partial response in a melanoma patient. We conclude that for future studies, the recommended dose of IL-2 given as a weekly 24-h infusion is 9 x 10(6) C.U./m2 and that a low rate of objective tumor response can be obtained in patients with melanoma and renal cell carcinoma using this regimen.

A medical oncologist's approach to immunotherapy for advanced renal tumors: is nephrectomy indicated?

PubMed

Cooney, Matthew M; Remick, Scot C; Vogelzang, Nicholas J

2004-02-01

Metastatic renal cell carcinoma is highly resistant to systemic therapy. Although interleukin-2 and interferon remain the most active agents for this disease, long-term survival rates remain poor. Two phase 3 trials, European Organization Research and Treatment of Cancer 30947 and Southwest Oncology Group 8949, have demonstrated a survival benefit of nephrectomy followed by interferon versus interferon alone in patients having an excellent performance status (PS 0 and 1). Removal of the primary tumor followed by interferon is not recommended for patients with a moderate or poor PS (PS 2-4). Even with this aggressive approach, most patients eventually will die from their kidney cancer; therefore, every patient with metastatic disease should be considered for enrollment into clinical trials.

[Sarcomatoid renal cell carcinoma].

PubMed

Arnoux, V; Lechevallier, E; Pamela, A; Long, J-A; Rambeaud, J-J

2013-06-01

The objective was to perform a systematic review of literature concerning epidemiology, clinical and biological data, prognosis and therapy of sarcomatoid renal cell carcinomas. Data on sarcomatoid renal cell carcinomas have been sought by querying the server Medline with MeSH terms following or combination of them: "renal carcinoma", "renal cell carcinoma," "renal cancer", "sarcomatoid" "sarcomatoid transformation" and "sarcomatoid differentiation." The articles obtained were selected according to their methodology, the language in English or French, the relevance and the date of publication. Twenty papers were selected. According to the literature, a sarcomatoid contingent can be observed in all subtypes of renal cell carcinomas, with a frequency of 1 to 15% of cases. The median age at diagnosis was 60 years with a majority of symptomatic patients (90%), mainly with abdominal pain and hematuria. These tumors were often found in patients with locally advanced or metastatic (45-77%). The imaging was not specific for the diagnosis and biopsy had a low sensitivity for identifying a sarcomatoid contingent. The treatment was based on a combination of maximal surgical resection whenever possible and systemic therapy for metastastic disease. Pathological data often showed large tumors, Furhman 4 grades, combined biphasic carcinomatous contingent (clear cell carcinoma in most cases) and sarcomatoid. Genetically, there was no specific abnormality but a complex association of chromosomal additions and deletions. The prognosis was pejorative with a specific median survival of 5 to 19 months without any impact of the sarcomatoid contingent rate. Sarcomatoid renal cell carcinoma is a form not to ignore despite its rarity. Mainly symptomatic and discovered at an advanced stage, it has a poor prognosis, requiring multidisciplinary management quickly and correctly. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Whole-Exome Sequencing in Two Extreme Phenotypes of Response to VEGF-Targeted Therapies in Patients With Metastatic Clear Cell Renal Cell Carcinoma.

PubMed

Fay, Andre P; de Velasco, Guillermo; Ho, Thai H; Van Allen, Eliezer M; Murray, Bradley; Albiges, Laurence; Signoretti, Sabina; Hakimi, A Ari; Stanton, Melissa L; Bellmunt, Joaquim; McDermott, David F; Atkins, Michael B; Garraway, Levi A; Kwiatkowski, David J; Choueiri, Toni K

2016-07-01

Advances in next-generation sequencing have provided a unique opportunity to understand the biology of disease and mechanisms of sensitivity or resistance to specific agents. Renal cell carcinoma (RCC) is a heterogeneous disease and highly variable clinical responses have been observed with vascular endothelial growth factor (VEGF)-targeted therapy (VEGF-TT). We hypothesized that whole-exome sequencing analysis might identify genotypes associated with extreme response or resistance to VEGF-TT in metastatic (mRCC). Patients with mRCC who had received first-line sunitinib or pazopanib and were in 2 extreme phenotypes of response were identified. Extreme responders (ERs) were defined as those with partial response or complete response for 3 or more years (n=13) and primary refractory patients (PRPs) were defined as those with progressive disease within the first 3 months of therapy (n=14). International Metastatic RCC Database Consortium prognostic scores were not significantly different between the groups (P=.67). Considering the genes known to be mutated in RCC at significant frequency, PBRM1 mutations were identified in 7 ERs (54%) versus 1 PRP (7%) (P=.01). In addition, mutations in TP53 (n=4) were found only in PRPs (P=.09). Our data suggest that mutations in some genes in RCC may impact response to VEGF-TT. Copyright © 2016 by the National Comprehensive Cancer Network.

Chyle fistula in advanced and metastatic thyroid cancer.

PubMed

Duque, Carlos S; Sánchez, Juan Guillermo; Dionigi, Gianlorenzo

2017-10-01

Chyle fistula (CF) is a rare but challenging condition for the surgeon and the patient's health. A retrospective review of single surgeon's case load in a 12-year period is presented, reviewing the case of those patients presenting with a CF. Three patients were found during this study period from more than 1,050 surgeries performed due to thyroid cancer. Patients underwent extensive lymph node dissection for advanced, metastatic and infiltrative disease. In all patients, a long hospital stay and surgical re-interventions were required. A description of the management of CF is presented along with a review of current Literature.

Presentation of renal cell carcinoma as cervical polyp metastasis.

PubMed

Godfrey, Gwendolyn J; Moore, Grace; Alatassi, Houda

2010-10-01

Secondary cervical adenocarcinomas are most commonly seen owing to the extension of a primary endometrial adenocarcinoma. Metastatic tumors from other sites are rather uncommon and, when seen, are most frequently from the ovaries, gastrointestinal tract, or breast. We report a case of metastatic renal cell carcinoma, clear cell variant, to the cervix, which presented as a cervical polyp in a postmenopausal female. To our knowledge, this is the fourth reported case of renal cell carcinoma metastatic to the cervix. This case is only the third in which the cervical metastasis was the presenting sign of renal cell carcinoma and the first in which the clinical presentation was as a cervical polyp.

NF-κB-Dependent Lymphoid Enhancer Co-option Promotes Renal Carcinoma Metastasis.

PubMed

Rodrigues, Paulo; Patel, Saroor A; Harewood, Louise; Olan, Ioana; Vojtasova, Erika; Syafruddin, Saiful E; Zaini, M Nazhif; Richardson, Emma K; Burge, Johanna; Warren, Anne Y; Stewart, Grant D; Saeb-Parsy, Kourosh; Samarajiwa, Shamith A; Vanharanta, Sakari

2018-06-06

Metastases, the spread of cancer cells to distant organs, cause the majority of cancer-related deaths. Few metastasis-specific driver mutations have been identified, suggesting aberrant gene regulation as a source of metastatic traits. However, how metastatic gene expression programs arise is poorly understood. Here, using human-derived metastasis models of renal cancer, we identify transcriptional enhancers that promote metastatic carcinoma progression. Specific enhancers and enhancer clusters are activated in metastatic cancer cell populations, and the associated gene expression patterns are predictive of poor patient outcome in clinical samples. We find that the renal cancer metastasis-associated enhancer complement consists of multiple coactivated tissue-specific enhancer modules. Specifically, we identify and functionally characterize a coregulatory enhancer cluster, activated by the renal cancer driver HIF2A and an NF-κB-driven lymphoid element, as a mediator of metastasis in vivo We conclude that oncogenic pathways can acquire metastatic phenotypes through cross-lineage co-option of physiologic epigenetic enhancer states. SIGNIFICANCE: Renal cancer is associated with significant mortality due to metastasis. We show that in metastatic renal cancer, functionally important metastasis genes are activated via co-option of gene regulatory enhancer modules from distant developmental lineages, thus providing clues to the origins of metastatic cancer. Cancer Discov; 8(7); 1-16. ©2018 AACR. ©2018 American Association for Cancer Research.

The role of fluorine-18-fluorodeoxyglucose positron emission tomography in evaluating the response to tyrosine-kinase inhibitors in patients with metastatic primary renal cell carcinoma.

PubMed

Caldarella, Carmelo; Muoio, Barbara; Isgrò, Maria Antonietta; Porfiri, Emilio; Treglia, Giorgio; Giovanella, Luca

2014-09-01

Positron emission tomography-computed tomography (PET-CT) using fluorodeoxyglucose (FDG) is increasingly used in the evaluation of patients with advanced renal cell carcinoma (RCC), primarily for staging purposes. The aim of this paper is to perform a systematic review about the usefulness of PET-CT using FDG in response assessment after treatment with tyrosine-kinase inhibitors (TKIs) in patients with advanced RCC. The scientific literature about the role of PET-CT using FDG in the assessment of response to treatment with TKIs in patients affected by advanced RCC was systematically reviewed. Seven studies about the role of PET-CT using FDG in the response assessment after treatment with TKIs (essentially sunitinib and sorafenib) in advanced RCC were retrieved in full-text and analysed, to determine the predictive role of this morpho-functional imaging method on patient outcome. To date, the role of PET-CT using FDG in evaluating the response to TKIs in metastatic RCC patients is still not well defined, partly due to heterogeneity of available studies; however, PET-CT reveals potential role for the selection of patients undergoing therapy with TKIs. The use of contrast-enhanced PET-CT appears to be promising for a "multi-dimensional" evaluation of treatment response in these patients.

Establishment and characterization of clear cell renal cell carcinoma cell lines with different metastatic potential from Chinese patients.

PubMed

Tan, Xiaojie; He, Songqin; Han, Yifang; Yu, Yongwei; Xiao, Jianru; Xu, Danfeng; Wang, Guoping; Du, Yan; Chang, Wenjun; Yin, Jianhua; Su, Tong; Hou, Jianguo; Cao, Guangwen

2013-02-26

Clear cell renal cell carcinoma (ccRCC) cell lines with distinct metastatic potential are essential to study the mechanism of ccRCC metastasis. However, none of them originated from Chinese. Primary cell cultures were performed using a primary tumor of a 49-year-old male ccRCC patient and a metastatic tumor of a 62-year-old male patient who had received nephrectomy to excise primary ccRCC 10 years ago. Cell growth, microstructure, cytogenetics, cytometry, expression of metastasis-associated molecules, tumorigenesis and metastasis were subsequently characterized. Two successive cell lines named NRCC from the primary ccRCC and MRCC from the metastatic ccRCC were established, respectively. Compared to NRCC, MRCC exhibited stronger anchorage-independent growth and invasion potentials and contained more glycogen granules in the cytoplasm. Gains of chromosomes and some translocations were the major chromosomal aberrations in both cell strains. CD24 expression was more frequent in MRCC than in NRCC and the same was true for CD56. The transcriptional levels of TNFα, IL-6, VEGF, HIF2α, MMP2, and RhoC were significantly higher in MRCC than in NRCC. Cytosolic IκBα protein was more degraded in MRCC than in NRCC following TNFα treatment. Both cell lines had strong tumorigenicity in athymic nude mice. However, MRCC had strong potential in generating metastasis to lung and hemorrhagic ascites than NRCC following orthotopic transplantations. Cancer cells isolated from metastatic ccRCC have more malignant and metastatic potential than those from the primary tumor from the patients who shared the similar race background. Establishment of MRCC and NRCC may provide suitable models with which to investigate molecular mechanisms of ccRCC metastasis.

High-dose interleukin 2 in patients with metastatic renal cell carcinoma with sarcomatoid features.

PubMed

Achkar, Tala; Arjunan, Ananth; Wang, Hong; Saul, Melissa; Davar, Diwakar; Appleman, Leonard J; Friedland, David; Parikh, Rahul A

2017-01-01

High-dose interleukin-2 (HD IL-2) is used in the treatment of metastatic renal cell carcinoma (mRCC) and has an overall response rate (ORR) of 12-20% and a complete response rate (CR) of 8% in unselected populations with predominantly clear cell type renal cell carcinoma. Nearly 10-15% of patients with renal cell carcinoma exhibit sarcomatoid differentiation, a feature which correlates with a median overall survival (OS) of 9 months and overall poor prognosis. We report a single institution experience with 21 patients with mRCC with sarcomatoid features post-nephrectomy who were treated with HD IL-2. Twenty one patients with mRCC with sarcomatoid features post-nephrectomy who underwent therapy with HD IL-2 were identified at the University of Pittsburgh Medical Center from 2004 to 2016. Baseline patient characteristics, HD IL-2 cycles, time to progression, and subsequent therapies were evaluated. OS and progression-free survival (PFS) in the cohort were calculated using the Kaplan-Meier method. Disease characteristics were evaluated for significance using the Fischer's exact test and Wilcoxon rank sum test. Patients were predominantly Caucasian males with a median age of 54 years. A majority, 86% of these patients, had metastatic disease at time of initial presentation, primarily with lung and lymph node involvement. The ORR and CR with HD IL-2 was 10% and 5%, respectively. Initial localized disease presentation is the only variable that was significantly associated with response to HD IL-2 (p = 0.0158). Number of HD IL-2 doses did not correlate with response with a mean of 16.5 and 15.0 total doses in responders and non-responders, respectively (p = 0.53). Median PFS with HD IL-2 was 7.9 months (95% CI, 5.0-21.3). Median OS was 30.5 months (95% CI 13.3-57.66). Within the subset of patients who had progression on IL-2, median OS was 19.4 months (95% CI, 13.3-35.3). In patients who received second-line therapy, median PFS was 7.9 months (95% CI 2.4-10.2). In

A Review of Immune Checkpoint Inhibitors for the Management of Locally Advanced or Metastatic Urothelial Carcinoma.

PubMed

Hanna, Kirollos S

2017-11-01

Urothelial carcinoma (UC) is the second most common malignancy of the genitourinary system and the sixth most common cancer in the United States. The overall incidence of UC appears to be on the decline, but death rates have remained stable. Stage IV metastatic disease is associated with only a 5% survival rate at 5 years. Gemcitabine and cisplatin combinations or dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin are the preferred regimens for individuals with advance, metastatic disease and a good performance status and organ function. Second-line therapies in this setting are limited. During the course of 1 year, five immune checkpoint inhibitors were approved for treatment of cancers in the locally advanced or metastatic setting: atezolizumab, nivolumab, durvalumab, avelumab, and pembrolizumab. Immunotherapies have played a significant role in the treatment of various cancers and have continued to expand. It is of utmost importance that practitioners include checkpoint inhibitors as treatment options for UC. Based on the limited data, pembrolizumab and atezolizumab may be the drugs of choice, as they are supported by the most influential data to date; however, further research is warranted. Ongoing clinical trials will further assess the benefits of inducing cellular immunity in the treatment of UC. These therapies mark a new landscape in the treatment of UC. In this article, the available data on immune checkpoint inhibitors for the treatment of locally advanced or metastatic UC and their place in therapy are reviewed. © 2017 Pharmacotherapy Publications, Inc.

Renin-angiotensin system (RAS) blockade attenuates growth and metastatic potential of renal cell carcinoma in mice.

PubMed

Araújo, Wedson F; Naves, Marcelo A; Ravanini, Juliana N; Schor, Nestor; Teixeira, Vicente P C

2015-09-01

Renal cell carcinoma (RCC) is the most frequent type of cancer among renal neoplasms in adults and responds poorly to radiotherapy and chemotherapy. There is evidence that blockade of the renin-angiotensin system (RAS) might have antineoplastic effects. The aim of this study was to investigate the effects of RAS blockade on RCC in a murine model. Murine renal cancer cells (Renca) were injected (1 × 10(5)) into the subcapsular space of the left kidney of BALB/c mice (8 wk of age). The animals were divided into 4 groups: a control group (no treatment), angiotensin-receptor blockers group (losartan 100mg/kg/d), angiotensin-converting enzyme inhibitor group (captopril 10mg/kg/d), and angiotensin-receptor blockers +angiotensin-converting enzyme inhibitor group (losartan 100mg/kg/d +captopril 10mg/kg/d). The animals received the drugs by gavage for 21 days after inoculation, beginning 2 days before tumor induction, and were then euthanized. After killing the animals, the kidneys and lungs were removed, weighed, and processed for histopathological and immunohistochemical analyses. Angiogenesis and vascular microvessels were assessed with the antibodies anti-vascular endothelial growth factor and anti-CD34. Angiotensin II-inoculated animals developed renal tumors. Treated animals presented smaller tumors, regardless of the therapeutic regimen, and far fewer lung metastases in both quantity and dimension compared with the controls. The expression of vascular endothelial growth factor and CD34 were significantly decreased in renal tumors of treated animals compared with the controls. Our findings suggest that blockade of RAS decreases tumor proliferation and metastatic capacity of RCC in this experimental model. Copyright © 2015 Elsevier Inc. All rights reserved.

Chyle fistula in advanced and metastatic thyroid cancer

PubMed Central

Sánchez, Juan Guillermo; Dionigi, Gianlorenzo

2017-01-01

Background Chyle fistula (CF) is a rare but challenging condition for the surgeon and the patient’s health. Methods A retrospective review of single surgeon’s case load in a 12-year period is presented, reviewing the case of those patients presenting with a CF. Results Three patients were found during this study period from more than 1,050 surgeries performed due to thyroid cancer. Patients underwent extensive lymph node dissection for advanced, metastatic and infiltrative disease. In all patients, a long hospital stay and surgical re-interventions were required. Conclusions A description of the management of CF is presented along with a review of current Literature. PMID:29142832

Successes and limitations of targeted therapies in renal cell carcinoma.

PubMed

Pracht, Marc; Berthold, Dominik

2014-01-01

Until recently, the standard treatment for metastatic renal cell carcinoma (RCC) was nonspecific immunotherapy based on interleukin-2 or interferon-α. This was associated with a modest survival benefit and with significant clinical toxicities. The understanding of numerous molecular pathways in RCC, including HIF, VEGF, mTOR, and the consecutive use of targeted therapies since the beginning of 2005 have significantly improved outcomes for patients with metastatic RCC with an overall survival greater than 2 years. At present, at least 7 targeted agents are approved for first and consecutive lines of treatment of clear cell metastatic RCC. Long-term benefit and extended survival may be achieved through the optimal use of targeted therapies: optimal dosing, adverse event management and treatment duration and compliance. Advances in the finding of prognostic factors highlight the potential for personalizing treatment for patients with metastatic RCC. Data regarding the best sequencing of targeted therapies, predictive biomarkers, best timing of surgery, patient risk profiles, understanding of resistance mechanisms and safety of targeted therapies are growing and will provide a further step ahead in the management of advanced RCC. In parallel, a new class of therapeutics is emerging in RCC: immunotherapy; in particular check-point blockade antibodies are showing very promising results. © 2014 S. Karger AG, Basel.

The effect of apatinib in the treatment of metastatic renal cell carcinoma: a case report and review of the literature.

PubMed

Bi, Jinling; Liu, Haiyuan; Huang, Yong

2017-01-01

The aim of this study was to explore the effect of apatinib in the treatment of metastatic renal cell carcinoma (mRCC) and related adverse events. A case of mRCC was reported which recurred after surgery and roferon treatment. The patient was treated with apatinib at a dose of 500 mg orally, twice daily, 28 days/cycle. The metastatic lesions improved based on computed tomography after apatinib administration in the fourth and eighth month. The progression-free survival of the patient had increased almost to 8 months. The patient showed a good tolerance with only an adverse effect of mild-to-moderate hand-foot syndrome which was managed well. Apatinib is an option for mRCC after previous treatment. However, more and larger trials are still needed.

Advances in the Treatment of Metastatic Melanoma: Adoptive T Cell Therapy

PubMed Central

Bernatchez, Chantale; Radvanyi, Laszlo G.; Hwu, Patrick

2012-01-01

Metastatic melanoma is notoriously resistant to chemotherapy and radiotherapy regimens. The prospect for newly diagnosed metastatic melanoma patients is grim with a median survival of less than a year. Currently, the only therapies resulting in long term disease free intervals, high dose Interleukin-2 (IL-2) and more recently anti-CTLA-41, work through activation of the immune system. However, with both therapies the response rate is low. Advances in our knowledge of how the immune system interacts with cancer have led to a number of strategies to manipulate anti-tumor immune responses through immunotherapy. This review will focus on one avenue of immunotherapy using the transfer of T cells referred to as “Adoptive Cell Therapy” (ACT), which involves the ex vivo expansion of autologous tumor-specific T cells to large numbers that are ultimately transferred back to the patient to boost anti-tumor immunity. This approach has been shown to be effective in the treatment of virally induced cancers, as well as metastatic melanoma. Recent successes with ACT hold promise and further emphasize the tremendous potential benefit of harnessing the immune system in the fight against cancer. PMID:22484193

Oncological outcomes after cytoreductive nephrectomy for patients with metastatic renal cell carcinoma with inferior vena caval tumor thrombus.

PubMed

Miyake, Hideaki; Sugiyama, Takayuki; Aki, Ryota; Matsushita, Yuto; Tamura, Keita; Motoyama, Daisuke; Ito, Toshiki; Otsuka, Atsushi

2018-06-01

To evaluate the oncological outcomes of patients with metastatic renal cell carcinoma (mRCC) involving the inferior vena cava (IVC) who received cytoreductive nephrectomy. This study included 75 consecutive metastatis renal cell carcinoma (mRCC) patients with inferior vena cava (IVC) tumor thrombus undergoing cytoreductive nephrectomy and tumor thrombectomy followed by systemic therapy. Of the 75 patients, 11, 33, 24 and 7 had level I, II, III and IV IVC thrombus, respectively. Following surgical treatment, 25 (group A), 27 (group B) and 23 (group C) received cytokine therapy alone, molecular-targeted therapy alone and both therapies, respectively, as management for metastatic diseases. The median overall survival (OS) of the 75 patients was 16.2 months. No significant differences in OS were noted according to the level of the IVC tumor thrombus. There were no significant differences in OS among groups A, B and C; however, OS in groups B and C was significantly superior to that in group A. Furthermore, multivariate analysis of several parameters identified the following independent predictors of poor OS-elevated C-reactive protein, liver metastasis and postoperative treatment with cytokine therapy alone. The prognosis of mRCC patients with IVC thrombus undergoing cytoreductive nephrectomy may be significantly affected by the type of postoperative systemic therapy rather than the level of the IVC tumor thrombus. Accordingly, cytoreductive nephrectomy should be considered as a major therapeutic option for patients with mRCC involving the IVC, particularly in the era of targeted therapy.

[Systemic Treatment of Metastatic Renal Cell Cancer--Back to the Future?].

PubMed

Ivanyi, P; Grünwald, V

2015-11-01

A variety of therapeutic agents are currently available for the systemic treatment of metastatic renal cell carcinoma (mRCC). It was only when targeted treatment was developed in the past decade that a significant improvement was achieved in tumour therapy. This also led to the development of sequential treatment for mRCC.7 molecular targeted agents are available today (axitinib, bevacizumab/ IFNα, everolimus, pazopanib, sorafenib, sunitinib, and temsirolimus). Due to the individualisation of treatment it remains a challenge to choose the most appropriate drug in a given setting, with the choice being based on the knowledge of the relevant clinical data as well as individual patient parameters.During the recent past, efforts have been made to test different inhibitors or combinations without a major breakthrough. Instead, the development of novel specific immunotherapeutic approaches now heralds the next level of treatment in mRCC. The first significant trial results will be expected this year, and further trials for optimisation of treatment are warranted. © Georg Thieme Verlag KG Stuttgart · New York.

Apatinib treatment in extensive metastatic advanced thymic carcinoma.

PubMed

He, Y; Liu, S; E, M; Wang, C; Shi, M; Liu, G; Abiyasi, N

2018-01-01

Apatinib is a novel oral, anti-tumor, angiogenic-targeting drug that can selectively target vascular endothelial growth factor receptor-2 (VEGFR-2). In clinical trials, this new tyrosine kinase inhibitor (TKI) has been shown to be an effective and safe treatment for a variety of malignancies. Currently, there is a lack of studies of patients with thymic carcinoma; therefore, we present a case of advanced thymic carcinoma treated with apatinib after chemotherapy failure with multiple lung metastases. This patient has been taking a dose of 500 mg of apatinib per day, and his efficacy has achieved partial response (PR), according to the RECIST 1.1 standard, and progression-free survival (PFS) is 6.3 months at this point. Apatinib will continue as his maintenance treatment. During the treatment, drug-related toxicity and side effects were tolerable. Thus, apatinib may be a meaningful option for the treatment of advanced metastatic thymic carcinoma after chemotherapy failure.

Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma: a randomised double-blind phase 2 trial

PubMed Central

Rini, Brian I; Melichar, Bohuslav; Ueda, Takeshi; GrÜnwald, Viktor; Fishman, Mayer N; Arranz, José A; Bair, Angel H; Pithavala, Yazdi K; Andrews, Glen I; Pavlov, Dmitri; Kim, Sinil; Jonasch, Eric

2014-01-01

Summary Background Population pharmacokinetic data suggest axitinib plasma exposure correlates with efficacy in metastatic renal-cell carcinoma. Axitinib dose titration might optimise exposure and improve outcomes. We prospectively assessed the efficacy and safety of axitinib dose titration in previously untreated patients with metastatic renal-cell carcinoma. Methods In this randomised, double-blind, multicentre, phase 2 study, patients were enrolled from 49 hospitals and outpatient clinics in the Czech Republic, Germany, Japan, Russia, Spain, and USA. Patients with treatment-naive metastatic renal-cell carcinoma received axitinib 5 mg twice daily during a 4 week lead-in period. Those patients with blood pressure 150/90 mm Hg or lower, no grade 3 or 4 treatment-related toxic effects, no dose reductions, and no more than two antihypertensive drugs for 2 consecutive weeks were stratified by Eastern Cooperative Oncology Group performance status (0 vs 1), and then randomly assigned (1:1) to either masked titration with axitinib to total twice daily doses of 7 mg, and then 10 mg, if tolerated, or placebo titration. Patients who did not meet these criteria continued without titration. The primary objective was comparison of the proportion of patients achieving an objective response between randomised groups. Safety analyses were based on all patients who received at least one dose of axitinib. This ongoing trial is registered with ClinicalTrials.gov, number NCT00835978. Findings Between Sept 2, 2009, and Feb 28, 2011, we enrolled 213 patients, of whom 112 were randomly assigned to either the axitinib titration group (56 patients) or the placebo titration group (56 patients). 91 were not eligible for titration, and ten withdrew during the lead-in period. 30 patients (54%, 95% CI 40–67) in the axitinib titration group had an objective response, as did 19 patients (34%, 22–48]) in the placebo titration group (one-sided p=0·019). 54 (59%, 95% CI 49–70) of non

Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma: a randomised double-blind phase 2 trial.

PubMed

Rini, Brian I; Melichar, Bohuslav; Ueda, Takeshi; Grünwald, Viktor; Fishman, Mayer N; Arranz, José A; Bair, Angel H; Pithavala, Yazdi K; Andrews, Glen I; Pavlov, Dmitri; Kim, Sinil; Jonasch, Eric

2013-11-01

Population pharmacokinetic data suggest axitinib plasma exposure correlates with efficacy in metastatic renal-cell carcinoma. Axitinib dose titration might optimise exposure and improve outcomes. We prospectively assessed the efficacy and safety of axitinib dose titration in previously untreated patients with metastatic renal-cell carcinoma. In this randomised, double-blind, multicentre, phase 2 study, patients were enrolled from 49 hospitals and outpatient clinics in the Czech Republic, Germany, Japan, Russia, Spain, and USA. Patients with treatment-naive metastatic renal-cell carcinoma received axitinib 5 mg twice daily during a 4 week lead-in period. Those patients with blood pressure 150/90 mm Hg or lower, no grade 3 or 4 treatment-related toxic effects, no dose reductions, and no more than two antihypertensive drugs for 2 consecutive weeks were stratified by Eastern Cooperative Oncology Group performance status (0 vs 1), and then randomly assigned (1:1) to either masked titration with axitinib to total twice daily doses of 7 mg, and then 10 mg, if tolerated, or placebo titration. Patients who did not meet these criteria continued without titration. The primary objective was comparison of the proportion of patients achieving an objective response between randomised groups. Safety analyses were based on all patients who received at least one dose of axitinib. Between Sept 2, 2009, and Feb 28, 2011, we enrolled 213 patients, of whom 112 were randomly assigned to either the axitinib titration group (56 patients) or the placebo titration group (56 patients). 91 were not eligible for titration, and ten withdrew during the lead-in period. 30 patients (54%, 95% CI 40-67) in the axitinib titration group had an objective response, as did 19 patients (34%, 22-48]) in the placebo titration group (one-sided p=0·019). 54 (59%, 95% CI 49-70) of non-randomised patients achieved an objective response. Common grade 3 or worse, all-causality adverse events in treated patients

Results of a Phase 1/2 Study in Metastatic Renal Cell Carcinoma Patients Treated with a Patient-specific Adjuvant Multi-peptide Vaccine after Resection of Metastases.

PubMed

Rausch, Steffen; Gouttefangeas, Cécile; Hennenlotter, Jörg; Laske, Karoline; Walter, Kerstin; Feyerabend, Susan; Chandran, Premachandran Anoop; Kruck, Stephan; Singh-Jasuja, Harpreet; Frick, Annemarie; Kröger, Nils; Stevanović, Stefan; Stenzl, Arnulf; Rammensee, Hans-Georg; Bedke, Jens

2017-10-04

Treatment of metastatic renal cell carcinoma comprises metastasectomy±systemic medical treatment. Specific immunotherapy after metastasectomy could be a complementary option. In this phase 1/2 study, safety and tolerability of an adjuvant multi-peptide vaccine (UroRCC) after metastasectomy was evaluated together with immune response and efficacy, compared with a contemporary cohort of patients (n=44) treated with metastasectomy only. Nineteen metastatic renal cell carcinoma patients received UroRCC via intradermal or subcutaneous application randomized to immunoadjuvants (granulocyte-macrophage colony-stimulating factor or Montanide). Adverse events of UroRCC were mainly grade I and II; frequency of immune response was higher for major histocompatibility complex class II peptides (17/19, 89.5%) than for major histocompatibility complex class I peptides (8/19, 42.1%). Median overall survival was not reached in the UroRCC group (mean: 112.6 mo, 95% confidence interval [CI]: 92.1-133.1) and 58.0 mo (95% CI: 32.7-83.2) in the control cohort (p=0.015). UroRCC was an independent prognosticator of overall survival (hazard ratio=0.19, 95% CI: 0.05-0.69, p=0.012). Adjuvant UroRCC multi-peptide vaccine after metastasectomy was well tolerated, immunogenic, and indicates potential clinical benefit when compared with a contemporary control cohort (NCT02429440). The application of a patient-specific peptide vaccine after complete resection of metastases in metastatic renal cell carcinoma patients resulted in favorable tolerability and outcome. Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Nine-year prostate cancer survival differences between aggressive versus conservative therapy in men with advanced and metastatic prostate cancer.

PubMed

Dall'Era, Marc A; Lo, Mary J; Chen, Jaclyn; Cress, Rosemary; Hamilton, Ann S

2018-05-01

To the authors' knowledge, the survival benefit of local therapy in the setting of advanced prostate cancer remains unknown. The authors investigated whether prostate-directed treatment with either surgery or radiotherapy versus conservative treatment in the setting of locally advanced or metastatic disease was associated with improved survival within a cohort of men from the Centers for Disease Control and Prevention's (CDC) Breast and Prostate Cancer Data Quality and Patterns of Care Study (CDC POC-BP). Men diagnosed with locally advanced (cT3-T4 or N+ and M0) or metastatic prostate cancer were identified. The authors compared survival by treatment type, categorized as conservative (androgen deprivation therapy only) versus aggressive (radical prostatectomy or any type of radiotherapy). Nine-year overall survival and prostate cancer-specific survival were estimated using the Kaplan-Meier method. The Cox proportional hazards model was used to determine factors independently associated with 9-year prostate cancer-specific survival. For men with advanced, nonmetastatic prostate cancer, conservative treatment alone was associated with a 4 times higher likelihood of prostate cancer mortality compared with men treated with surgery (hazard ratio, 4.18; 95% confidence interval, 1.44-12.14). In contrast, no difference was found between conservative versus aggressive treatment after adjusting for covariates for men with metastatic disease. The 9-year prostate cancer-specific survival rate was 27% for those receiving aggressive treatment versus 24% for men undergoing conservative treatment. The authors did not observe a survival advantage with local therapy in addition to standard androgen deprivation therapy for men with metastatic prostate cancer. However, the results of the current study did affirm advantages in the setting of locally advanced disease. Aggressive local therapy in the setting of metastatic disease needs to be studied carefully before clinical adoption

Extracellular vesicles for personalized therapy decision support in advanced metastatic cancers and its potential impact for prostate cancer.

PubMed

Soekmadji, Carolina; Corcoran, Niall M; Oleinikova, Irina; Jovanovic, Lidija; Ramm, Grant A; Nelson, Colleen C; Jenster, Guido; Russell, Pamela J

2017-10-01

The use of circulating tumor cells (CTCs) and circulating extracellular vesicles (EVs), such as exosomes, as liquid biopsy-derived biomarkers for cancers have been investigated. CTC enumeration using the CellSearch based platform provides an accurate insight on overall survival where higher CTC counts indicate poor prognosis for patients with advanced metastatic cancer. EVs provide information based on their lipid, protein, and nucleic acid content and can be isolated from biofluids and analyzed from a relatively small volume, providing a routine and non-invasive modality to monitor disease progression. Our pilot experiment by assessing the level of two subpopulations of small EVs, the CD9 positive and CD63 positive EVs, showed that the CD9 positive EV level is higher in plasma from patients with advanced metastatic prostate cancer with detectable CTCs. These data show the potential utility of a particular EV subpopulation to serve as biomarkers for advanced metastatic prostate cancer. EVs can potentially be utilized as biomarkers to provide accurate genotypic and phenotypic information for advanced prostate cancer, where new strategies to design a more personalized therapy is currently the focus of considerable investigation. © 2017 Wiley Periodicals, Inc.

Vorinostat in Treating Patients With Locally Recurrent or Metastatic Cancer of the Urothelium

ClinicalTrials.gov

2015-01-28

Localized Transitional Cell Cancer of the Renal Pelvis and Ureter; Metastatic Transitional Cell Cancer of the Renal Pelvis and Ureter; Recurrent Transitional Cell Cancer of the Renal Pelvis and Ureter; Regional Transitional Cell Cancer of the Renal Pelvis and Ureter; Transitional Cell Carcinoma of the Bladder

Molecular Markers and Targeted Therapeutics in Metastatic Tumors of the Spine: Changing the Treatment Paradigms.

PubMed

Goodwin, C Rory; Abu-Bonsrah, Nancy; Rhines, Laurence D; Verlaan, Jorrit-Jan; Bilsky, Mark H; Laufer, Ilya; Boriani, Stefano; Sciubba, Daniel M; Bettegowda, Chetan

2016-10-15

A review of the literature. The aim of this study was to discuss the evolution of molecular signatures and the history and development of targeted therapeutics in metastatic tumor types affecting the spinal column. Molecular characterization of metastatic spine tumors is expected to usher in a revolution in diagnostic and treatment paradigms. Molecular characterization will provide critical information that can be used for initial diagnosis, prognosticating the ideal treatment strategy, assessment of treatment efficacy, surveillance and monitoring recurrence, and predicting complications, clinical outcome, and overall survival in patients diagnosed with metastatic cancers to the spinal column. A review of the literature was performed focusing on illustrative examples of the role that molecular-based therapeutics have played in clinical outcomes for patients diagnosed with metastatic tumor types affecting the spinal column. The impact of molecular therapeutics including receptor tyrosine kinases and immune checkpoint inhibitors and the ability of molecular signatures to provide prognostic information are discussed in metastatic breast cancer, lung cancer, prostate cancer, melanoma, and renal cell cancer affecting the spinal column. For the providers who will ultimately counsel patients diagnosed with metastases to the spinal column, molecular advancements will radically alter the management/surgical paradigms utilized. Ultimately, the translation of these molecular advancements into routine clinical care will greatly improve the quality and quantity of life for patients diagnosed with spinal malignancies and provide better overall outcomes and counseling for treating physicians. N/A.

Transforming Growth Factor-β1 as a Novel Marker of Response to Therapy for Renal Cell Carcinoma.

PubMed

Adler, H L

2001-01-01

Renal cell carcinoma is expected to account for 30,000 new cancer cases and 11,900 cancer deaths in the United States in 1999 (1). At the time of initial presentation, up to one-third of patients with renal cell carcinoma (RCC) have metastatic disease; furthermore, almost half of the patients resected for cure will relapse (2). Due to the poor results of cytotoxic chemotherapy in the management of metastatic RCC (3), physicians have explored the use of new therapies including immunotherapy and gene therapy. Some of these therapies are discussed in other chapters of this textbook. The use of these new therapies allows for the identification and utilization of new tumor markers that may allow investigators to identify patients at risk for advanced disease as well as establish new definitions of tumor response.

Differential expression of c-Met between primary and metastatic sites in clear-cell renal cell carcinoma and its association with PD-L1 expression.

PubMed

Lalani, Aly-Khan A; Gray, Kathryn P; Albiges, Laurence; Callea, Marcella; Pignon, Jean-Christophe; Pal, Soumitro; Gupta, Mamta; Bhatt, Rupal S; McDermott, David F; Atkins, Michael B; Woude, G F Vande; Harshman, Lauren C; Choueiri, Toni K; Signoretti, Sabina

2017-11-28

In preclinical models, c-Met promotes survival of renal cancer cells through the regulation of programmed death-ligand 1 (PD-L1). However, this relationship in human clear cell renal cell carcinoma (ccRCC) is not well characterized. We evaluated c-Met expression in ccRCC patients using paired primary and metastatic samples and assessed the association with PD-L1 expression and other clinical features. Areas with predominant and highest Fuhrman nuclear grade (FNG) were selected. c-Met expression was evaluated by IHC using an anti-Met monoclonal antibody (MET4 Ab) and calculated by a combined score (CS, 0-300): intensity of c-Met staining (0-3) x % of positive cells (0-100). PD-L1 expression in tumor cells was previously assessed by IHC and PD-L1+ was defined as PD-L1 > 0% positive cells. Our cohort consisted of 45 pairs of primary and metastatic ccRCC samples. Overall, c-Met expression was higher in metastatic sites compared to primary sites (average c-Met CS: 55 vs. 28, p = 0.0003). Higher c-Met expression was associated with higher FNG (4 vs. 3) in primary tumors (average c-Met CS: 52 vs. 20, p = 0.04). c-Met expression was numerically greater in PD-L1+ vs. PD-L1- tumors. Higher c-Met expression in metastatic sites compared to primary tumors suggests that testing for biomarkers of response to c-Met inhibitors should be conducted in metastases. While higher c-Met expression in PD-L1+ tumors requires further investigation, it supports exploring these targets in combination clinical trials.

A renal transplantation advanced pharmacy practice experience.

PubMed

Chisholm, Marie A

2006-02-15

To establish and evaluate an ambulatory care renal transplantation clinic advanced pharmacy practice experience (APPE). Students spend 5 weeks performing pharmaceutical care activities for renal transplant patients, presenting health-related topics, and conducting research. A paired t test was used to determine differences between students' pre- and post-APPE test scores. Standardized evaluations completed by the preceptor and the students were used to evaluate learning and the APPE. Posttest scores were significantly higher than pretest scores (n = 17; 88.2 +/- 7.3 vs 55.9 +/- 22.4; p < 0.001). Overall, students found this APPE enjoyable and believed that it increased their knowledge concerning transplant medicine and patient care. With the recommendation that all transplant programs have clinical pharmacy services, it is imperative to train students to care for transplant patients. Information in this manuscript can be used as a guide for utilizing the combined resources from schools of pharmacy and transplantation centers to implement a renal transplant ambulatory care APPE.

Recent Advances in Renal Ammonia Metabolism and Transport

PubMed Central

Weiner, I. David; Verlander, Jill W.

2016-01-01

Purpose of review The purpose of this review is to provide a succinct description of recent findings that advance our understanding of the fundamental renal process of ammonia metabolism and transport in conditions relevant to the clinician. Recent findings Recent studies advance our understanding of renal ammonia metabolism. Mechanisms through which chronic kidney disease and altered dietary protein intake alter ammonia excretion have been identified. Lithium, although it can acutely cause distal RTA, was shown with long-term use to increase urinary ammonia excretion, and this appeared to be mediated, at least in part, by increased Rhcg expression. Gene deletion studies showed that the ammonia recycling enzyme, glutamine synthetase, has a critical role in normal and acidosis-stimulated ammonia metabolism and that the proximal tubule basolateral bicarbonate transporter, NBCe1, is necessary for normal ammonia metabolism. Finally, our understanding of the molecular ammonia species, NH3 versus NH4+, transported by Rh glycoproteins continues to be advanced. Summary Fundamental studies have been recently published that advance our understanding of the regulation of ammonia metabolism in clinically important circumstances and our understanding of the mechanisms and regulation of proximal tubule ammonia generation and the mechanisms through which Rh glycoproteins contribute to ammonia secretion. PMID:27367914

CREATE: Cross-tumoral Phase 2 With Crizotinib

ClinicalTrials.gov

2018-01-18

Locally Advanced and/or Metastatic Anaplastic Large Cell Lymphoma; Locally Advanced and/or Metastatic Inflammatory Myofibroblastic Tumor; Locally Advanced and/or Metastatic Papillary Renal Cell Carcinoma Type 1; Locally Advanced and/or Metastatic Alveolar Soft Part Sarcoma; Locally Advanced and/or Metastatic Clear Cell Sarcoma; Locally Advanced and/or Metastatic Alveolar Rhabdomyosarcoma

Renal Tumors

PubMed Central

Tan, Puay Hoon; Cheng, Liang; Rioux-Leclercq, Nathalie; Merino, Maria J.; Netto, George; Reuter, Victor E.; Shen, Steven S.; Grignon, David J.; Montironi, Rodolfo; Egevad, Lars; Srigley, John R.; Delahunt, Brett; Moch, Holger

2016-01-01

The International Society of Urological Pathology convened a consensus conference on renal cancer, preceded by an online survey, to address issues relating to the diagnosis and reporting of renal neoplasia. In this report, the role of biomarkers in the diagnosis and assessment of prognosis of renal tumors is addressed. In particular we focused upon the use of immunohistochemical markers and the approach to specific differential diagnostic scenarios. We enquired whether cytogenetic and molecular tools were applied in practice and asked for views on the perceived prognostic role of biomarkers. Both the survey and conference voting results demonstrated a high degree of consensus in participants’ responses regarding prognostic/predictive markers and molecular techniques, whereas it was apparent that biomarkers for these purposes remained outside the diagnostic realm pending clinical validation. Although no individual antibody or panel of antibodies reached consensus for classifying renal tumors, or for confirming renal metastatic disease, it was noted from the online survey that 87% of respondents used immunohistochemistry to subtype renal tumors sometimes or occasionally, and a majority (87%) used immunohistochemical markers (Pax 2 or Pax 8, renal cell carcinoma [RCC] marker, panel of pan-CK, CK7, vimentin, and CD10) in confirming the diagnosis of metastatic RCC. There was consensus that immunohistochemistry should be used for histologic subtyping and applied before reaching a diagnosis of unclassified RCC. At the conference, there was consensus that TFE3 and TFEB analysis ought to be requested when RCC was diagnosed in a young patient or when histologic appearances were suggestive of the translocation subtype; whereas Pax 2 and/or Pax 8 were considered to be the most useful markers in the diagnosis of a renal primary. PMID:24025522

High-dose interleukin 2 in patients with metastatic renal cell carcinoma with sarcomatoid features

PubMed Central

Arjunan, Ananth; Wang, Hong; Saul, Melissa; Davar, Diwakar; Appleman, Leonard J.; Friedland, David; Parikh, Rahul A.

2017-01-01

Background High-dose interleukin-2 (HD IL-2) is used in the treatment of metastatic renal cell carcinoma (mRCC) and has an overall response rate (ORR) of 12–20% and a complete response rate (CR) of 8% in unselected populations with predominantly clear cell type renal cell carcinoma. Nearly 10–15% of patients with renal cell carcinoma exhibit sarcomatoid differentiation, a feature which correlates with a median overall survival (OS) of 9 months and overall poor prognosis. We report a single institution experience with 21 patients with mRCC with sarcomatoid features post-nephrectomy who were treated with HD IL-2. Methods Twenty one patients with mRCC with sarcomatoid features post-nephrectomy who underwent therapy with HD IL-2 were identified at the University of Pittsburgh Medical Center from 2004 to 2016. Baseline patient characteristics, HD IL-2 cycles, time to progression, and subsequent therapies were evaluated. OS and progression-free survival (PFS) in the cohort were calculated using the Kaplan-Meier method. Disease characteristics were evaluated for significance using the Fischer′s exact test and Wilcoxon rank sum test. Results Patients were predominantly Caucasian males with a median age of 54 years. A majority, 86% of these patients, had metastatic disease at time of initial presentation, primarily with lung and lymph node involvement. The ORR and CR with HD IL-2 was 10% and 5%, respectively. Initial localized disease presentation is the only variable that was significantly associated with response to HD IL-2 (p = 0.0158). Number of HD IL-2 doses did not correlate with response with a mean of 16.5 and 15.0 total doses in responders and non-responders, respectively (p = 0.53). Median PFS with HD IL-2 was 7.9 months (95% CI, 5.0–21.3). Median OS was 30.5 months (95% CI 13.3–57.66). Within the subset of patients who had progression on IL-2, median OS was 19.4 months (95% CI, 13.3–35.3). In patients who received second-line therapy, median PFS was 7

Trigriluzole With Nivolumab and Pembrolizumab in Treating Patients With Metastatic or Unresectable Solid Malignancies or Lymphoma

ClinicalTrials.gov

2018-05-23

Lymphoma; Metastatic Malignant Solid Neoplasm; Metastatic Melanoma; Metastatic Renal Cell Cancer; Recurrent Bladder Carcinoma; Recurrent Classical Hodgkin Lymphoma; Recurrent Head and Neck Squamous Cell Carcinoma; Recurrent Lymphoma; Recurrent Malignant Solid Neoplasm; Recurrent Renal Cell Carcinoma; Stage III Bladder Cancer; Stage III Lymphoma; Stage III Non-Small Cell Lung Cancer AJCC v7; Stage III Renal Cell Cancer; Stage III Skin Melanoma; Stage IIIA Non-Small Cell Lung Cancer AJCC v7; Stage IIIA Skin Melanoma; Stage IIIB Non-Small Cell Lung Cancer AJCC v7; Stage IIIB Skin Melanoma; Stage IIIC Skin Melanoma; Stage IV Bladder Cancer; Stage IV Lymphoma; Stage IV Non-Small Cell Lung Cancer AJCC v7; Stage IV Renal Cell Cancer; Stage IV Skin Melanoma; Stage IVA Bladder Cancer; Stage IVB Bladder Cancer; Unresectable Head and Neck Squamous Cell Carcinoma; Unresectable Solid Neoplasm

Current advances in targeted therapies for metastatic gastric cancer: improving patient care.

PubMed

Aguiar, Pedro Nazareth; Muniz, Thiago Pimentel; Miranda, Raelson Rodrigues; Tadokoro, Hakaru; Forones, Nora Manoukian; Monteiro, Ines-de-Paula; Castelo-Branco, Pedro; Janjigian, Yelena Y; De Mello, Ramon Andrade

2016-03-01

In this article, we review the literature on the current advances in targeted therapies for metastatic gastric cancer aimed at improving patient care. We conclude that the key to guiding targeted therapy is individual biomarkers, which are not completely elucidated. HER2 overexpression is the only predictive biomarker currently in use. Furthermore, it is necessary to understand that gastric tumors are heterogeneous; therefore, is impossible to evaluate a novel biological compound without evaluating personal biomarkers. The selection of patients who are able to receive each treatment is paramount for improving advanced gastric cancer survival and reducing unnecessary costs.

[Advanced and Metastatic Lung Cancer – What is new in the Diagnosis and Therapy?].

PubMed

Rothschild, Sacha I

2015-07-01

Lung cancer is one of the most common types of malignancies worldwide. The majority of patients are diagnosed with an incurable advanced/metastatic stage disease. Palliative treatment approaches improve the survival and the quality of life of these patients. Lung cancer is subdivided according to histology and molecular biology. The most important classification separates small cell from non-small cell lung cancer. In the subgroup of non-small cell lung cancer novel treatment approaches coming along with an improved prognosis have been established during the last decade. The current manuscript provides an overview on current treatment options for metastatic lung cancer. Furthermore, an outlook on promising future treatment options is provided.

MLN0264 in Previously Treated Asian Participants With Advanced Gastrointestinal Carcinoma or Metastatic or Recurrent Gastric or Gastroesophageal Junction Adenocarcinoma Expressing Guanylyl Cyclase C

ClinicalTrials.gov

2017-02-08

Advanced Gastrointestinal Carcinoma; Gastroesophageal Junction Adenocarcinoma; Recurrent Gastric Adenocarcinoma; Recurrent Gastroesophageal Junction Adenocarcinoma; Metastatic Gastric Adenocarcinoma; Metastatic Gastroesophageal Junction Adenocarcinoma; Recurrent Gastrointestinal Carcinoma

Autophagy induction by silibinin positively contributes to its anti-metastatic capacity via AMPK/mTOR pathway in renal cell carcinoma.

PubMed

Li, Feng; Ma, Zhenkun; Guan, Zhenfeng; Chen, Yule; Wu, Kaijie; Guo, Peng; Wang, Xinyang; He, Dalin; Zeng, Jin

2015-04-15

Silibinin, a dietary cancer chemopreventive flavonoid from the seeds of milk thistle, has been reported to exhibit anti-metastatic effects on renal cell carcinoma (RCC), but the mechanism underlying this phenomenon is not fully understood. The present study aimed at examining the potential role of autophagy in regulating silibinin-induced anti-metastatic effects on RCC cells. Using RCC ACHN and 786-O cells as a model system in vitro, we found that silibinin treatment increased the expression of LC3-II, resulted in the formation of autophagolysosome vacuoles, and caused a punctate fluorescence pattern with the monomeric red fluorescence protein-enhanced green fluorescence protein-LC3 (mRFP-EGFP-LC3) protein, which all are markers for cellular autophagy. Autophagy flux was induced by silibinin in RCC cells, as determined by LC3 turnover assay. Mechanically, the adenosine 5'-monophosphate activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway was identified as involved in regulation of silibinin-induced autophagy. Furthermore, autophagy induction was demonstrated to positively contribute to silibinin-induced anti-metastatic effects on RCC cells in vitro. Activation of autophagy enhanced silibinin-induced inhibition of migration and invasion of RCC cells, while inhibition of autophagy attenuated it. These findings thus provide new information about the potential link between autophagy and metastasis inhibition induced by silibinin, and the induction of autophagy may shed some light into future treatment strategies for metastatic RCC.

Autophagy Induction by Silibinin Positively Contributes to Its Anti-Metastatic Capacity via AMPK/mTOR Pathway in Renal Cell Carcinoma

PubMed Central

Li, Feng; Ma, Zhenkun; Guan, Zhenfeng; Chen, Yule; Wu, Kaijie; Guo, Peng; Wang, Xinyang; He, Dalin; Zeng, Jin

2015-01-01

Silibinin, a dietary cancer chemopreventive flavonoid from the seeds of milk thistle, has been reported to exhibit anti-metastatic effects on renal cell carcinoma (RCC), but the mechanism underlying this phenomenon is not fully understood. The present study aimed at examining the potential role of autophagy in regulating silibinin-induced anti-metastatic effects on RCC cells. Using RCC ACHN and 786-O cells as a model system in vitro, we found that silibinin treatment increased the expression of LC3-II, resulted in the formation of autophagolysosome vacuoles, and caused a punctate fluorescence pattern with the monomeric red fluorescence protein-enhanced green fluorescence protein-LC3 (mRFP-EGFP-LC3) protein, which all are markers for cellular autophagy. Autophagy flux was induced by silibinin in RCC cells, as determined by LC3 turnover assay. Mechanically, the adenosine 5'-monophosphate activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway was identified as involved in regulation of silibinin-induced autophagy. Furthermore, autophagy induction was demonstrated to positively contribute to silibinin-induced anti-metastatic effects on RCC cells in vitro. Activation of autophagy enhanced silibinin-induced inhibition of migration and invasion of RCC cells, while inhibition of autophagy attenuated it. These findings thus provide new information about the potential link between autophagy and metastasis inhibition induced by silibinin, and the induction of autophagy may shed some light into future treatment strategies for metastatic RCC. PMID:25884331

Systemic therapy for metastatic renal cell carcinoma in treatment naïve patients: a risk-based approach.

PubMed

Bukowski, Ronald M

2010-10-01

Kidney cancer is the ninth most common cancer in the USA, with an annual incidence of approximately 55,000 cases per year. Over 13,000 patients are estimated to die from this disease annually. Cloning of the VHL gene, recognition of the associated abnormalities in sporadic clear-cell carcinoma, and its role as a regulator of the hypoxic response, were important milestones in our understanding of renal-cell carcinoma (RCC) biology and the recognition of the vascular endothelial growth factor (VEGF) dependency of RCC. A variety of clinical features, including histologic features, prognostic factors, and patient history of comorbid illness, provide the framework in which the results of recent clinical trials and regulatory approvals of these agents are utilized to develop treatment recommendations for the largest metastatic patient RCC group, the therapy naïve individual. The rationale for use of VEGF-targeted therapy in advanced RCC patients and the recently developed treatment options for these individuals are reviewed. Regulatory approval of sorafenib for the treatment of metastatic RCC (mRCC), was followed by the approval of sunitinib, temsirolimus, bevacizumab plus interferon (IFNα), everolimus, and--most recently--pazopanib. These licences were granted from late 2005 through late 2009, a very short span of 4 years. In treatment-naïve mRCC patients, sunitinib, sorafenib, pazopanib, bevacizumab + IFNα, and temsirolimus were approved by the Food and Drug Administration (FDA) and/or the European Medicines Agency (EMEA). The clinical trials and data supporting these approvals are reviewed. This review examines these developments and provides the reader an overview and understanding of available current systemic therapy options for treatment-naïve mRCC patients. As multiple treatment options are now available for treatment-naïve mRCC patients, an understanding of how to utilize this group of agents is required. The use of various clinical features allows a

Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma.

PubMed

Choueiri, Toni K; Escudier, Bernard; Powles, Thomas; Mainwaring, Paul N; Rini, Brian I; Donskov, Frede; Hammers, Hans; Hutson, Thomas E; Lee, Jae-Lyun; Peltola, Katriina; Roth, Bruce J; Bjarnason, Georg A; Géczi, Lajos; Keam, Bhumsuk; Maroto, Pablo; Heng, Daniel Y C; Schmidinger, Manuela; Kantoff, Philip W; Borgman-Hagey, Anne; Hessel, Colin; Scheffold, Christian; Schwab, Gisela M; Tannir, Nizar M; Motzer, Robert J

2015-11-05

Cabozantinib is an oral, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) as well as MET and AXL, each of which has been implicated in the pathobiology of metastatic renal-cell carcinoma or in the development of resistance to antiangiogenic drugs. This randomized, open-label, phase 3 trial evaluated the efficacy of cabozantinib, as compared with everolimus, in patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy. We randomly assigned 658 patients to receive cabozantinib at a dose of 60 mg daily or everolimus at a dose of 10 mg daily. The primary end point was progression-free survival. Secondary efficacy end points were overall survival and objective response rate. Median progression-free survival was 7.4 months with cabozantinib and 3.8 months with everolimus. The rate of progression or death was 42% lower with cabozantinib than with everolimus (hazard ratio, 0.58; 95% confidence interval [CI] 0.45 to 0.75; P<0.001). The objective response rate was 21% with cabozantinib and 5% with everolimus (P<0.001). A planned interim analysis showed that overall survival was longer with cabozantinib than with everolimus (hazard ratio for death, 0.67; 95% CI, 0.51 to 0.89; P=0.005) but did not cross the significance boundary for the interim analysis. Adverse events were managed with dose reductions; doses were reduced in 60% of the patients who received cabozantinib and in 25% of those who received everolimus. Discontinuation of study treatment owing to adverse events occurred in 9% of the patients who received cabozantinib and in 10% of those who received everolimus. Progression-free survival was longer with cabozantinib than with everolimus among patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy. (Funded by Exelixis; METEOR ClinicalTrials.gov number, NCT01865747.).

Study of CB-103 in Adult Patients With Advanced or Metastatic Solid Tumours and Haematological Malignancies

ClinicalTrials.gov

2018-01-30

Advanced or Metastatic Solid Tumours; Breast Cancer; Colorectal Cancer; Gastric Cancer; Cholangiocellular Carcinoma; Ovarian Cancer; Cervical Cancer; Prostate Cancer; Melanoma; Sarcoma; NSCLC; Desmoid Tumour; Adenoid Cystic Carcinoma; Glioblastoma Multiforme; Hodgkin Lymphoma; Non-hodgkin Lymphoma; Multiple Myeloma

Advanced chronic kidney disease in non-valvular atrial fibrillation: extending the utility of R2CHADS2 to patients with advanced renal failure.

PubMed

Bautista, Josef; Bella, Archie; Chaudhari, Ashok; Pekler, Gerald; Sapra, Katherine J; Carbajal, Roger; Baumstein, Donald

2015-04-01

The R2CHADS2 is a new prediction rule for stroke risk in atrial fibrillation (AF) patients wherein R stands for renal risk. However, it was created from a cohort that excluded patients with advanced renal failure (defined as glomerular filtration rate of <30 mL/min). Our study extends the use of R2CHADS2 to patients with advanced renal failure and aims to compare its predictive power against the currently used CHADS and CHA2DS2VaSc. This retrospective cohort study analyzed the 1-year risk for stroke of the 524 patients with AF at Metropolitan Hospital Center. AUC and C statistics were calculated using three groups: (i) the entire cohort including patients with advanced renal failure, (ii) a cohort excluding patients with advanced renal failure and (iii) all patients with GFR < 30 mL/min only. R2CHADS2, as a predictor for stroke risk, consistently performs better than CHADS2 and CHA2DS2VsC in groups 1 and 2. The C-statistic was highest in R2CHADS compared with CHADS or CHADSVASC in group 1 (0.718 versus 0.605 versus 0.602) and in group 2 (0.724 versus 0.584 versus 0.579). However, there was no statistically significant difference in group 3 (0.631 versus 0.629 versus 0.623). Our study supports the utility of R2CHADS2 as a clinical prediction rule for stroke risk in patients with advanced renal failure.

Examining the bleeding incidences associated with targeted therapies used in metastatic renal cell carcinoma.

PubMed

Crist, MacKenzie; Hansen, Elizabeth; Chablani, Lipika; Guancial, Elizabeth

2017-12-01

A systematic review was conducted to illustrate the bleeding risks associated with targeted therapies used in the treatment of metastatic renal cell carcinoma (mRCC). Eligible studies included phase II, III, or IV clinical trials using pazopanib, sunitinib, cabozantinib, lenvatinib, everolimus, temsirolimus, bevacizumab, axitinib, and/or sorafenib in the setting of mRCC. Types of bleeding event(s), bleeding event frequency, and incidence of thrombocytopenia were collected from the relevant articles. ClinicalTrials.gov was also searched for incidence of "Serious bleeding adverse effects" reported in these trials. The incidences of bleeding events ranged from 1 to 36%, and incidences of thrombocytopenia ranged from 2 to 78%. Available serious bleeding adverse events ranged from 1 to 7%. The highest percentage of bleeding incidences were seen with bevacizumab, while the lowest percentage of bleeding incidences were seen with axitinib. All of the included trials were of high quality per Jadad scoring. Copyright © 2017 Elsevier B.V. All rights reserved.

A Continuation Study Using Sunitinib Malate For Patients Leaving Treatment On A Previous Sunitinib Study.

ClinicalTrials.gov

2015-10-07

Metastatic Breast Cancer [F]; Advanced Breast Cancer; Metastatic Castration Resistant Prostate Cancer; Metastatic Renal Cell Cancer; Non-Small Cell Lung Cancer; Thyroid Cancer; Advanced/Metastatic Non-Small Cell Lung Cancer; Advanced Gastric Cancer; Gastrointestinal Stromal Tumor; Hepatocellular Carcinoma; Pancreatic Islet Cell Carcinoma; Pancreatic Neuroendocrine Tumor

Metastatic Organotropism: An Intrinsic Property of Breast Cancer Molecular Subtypes.

PubMed

Wei, Shi; Siegal, Gene P

2017-03-01

It has long been known that some cancers have the propensity to metastasize to certain organs thus creating a nonrandom distribution of sites for distant relapse, a phenomenon known as "metastatic organotropism." Some of these examples include ovary primary to abdominal cavity, prostate primary to bone, and pancreas primary to liver. In contrast, other tumor types, such as mammary and renal cell carcinoma, can relapse in multiple organs although approximately half of advanced breast cancers metastasize to bone. On the other hand gene expression profiling studies have identified various breast cancer classes with prognostic significance. Recent studies have revealed that breast cancer subtypes differ not only in primary tumor characteristics but also in their metastatic behavior. In particular, the luminal tumors are remarkable for their significant bone-seeking phenotype; the HER2 subtype demonstrates a significant liver-homing characteristic; whereas so-called triple-negative breast cancers predispose to lung metastases. These findings suggest that this knowledge could potentially be utilized in the development of effective disease surveillance strategies in the pursuit of precision medicine, thus necessitating further investigation.

Pathologic Predictors of Survival During Lymph Node Dissection for Metastatic Renal-Cell Carcinoma: Results From a Multicenter Collaboration.

PubMed

Chipollini, Juan; Abel, E Jason; Peyton, Charles C; Boulware, David C; Karam, Jose A; Margulis, Vitaly; Master, Viraj A; Zargar-Shoshtari, Kamran; Matin, Surena F; Sexton, Wade J; Raman, Jay D; Wood, Christopher G; Spiess, Philippe E

2018-04-01

To determine the therapeutic value of lymph node dissection (LND) during cytoreductive nephrectomy (CN) and assess predictors of cancer-specific survival (CSS) in metastatic renal-cell carcinoma. We identified 293 consecutive patients treated with CN at 4 academic institutions from March 2000 to May 2015. LND was performed in 187 patients (63.8%). CSS was estimated by the Kaplan-Meier method for the entire cohort and for a propensity score-matched cohort. Cox proportional hazards regression was used to evaluate CSS in a multivariate model and in an inverse probability weighting-adjusted model for patients who underwent dissection. Median follow-up was 12.6 months (interquartile range, 4.47, 30.3), and median survival was 15.9 months. Of the 293 patients, 187 (63.8%) underwent LND. One hundred six patients had nodal involvement (pN+) with a median CSS of 11.3 months (95% confidence interval [CI], 6.6, 15.9) versus 24.2 months (95% confidence interval, 14.1, 34.3) for pN- patients (log-rank P = .002). The hazard ratio for LND was 1.325 (95% CI, 1.002, 1.75) for the whole cohort and 1.024 (95% CI, 0.682, 1.537) in the propensity score-matched cohort. Multivariate analysis revealed that number of positive lymph nodes (P < .001) was a significant predictor of worse CSS. For patients with metastatic renal-cell carcinoma undergoing CN with lymphadenectomy, the number of nodes positive was predictive of survival at short-term follow-up. However, nonstandardized lymphadenectomy only provided prognostic information without therapeutic benefit. Prospective studies with standardized templates are required to further ascertain the therapeutic value of LND. Copyright © 2017 Elsevier Inc. All rights reserved.

Optimal management of metastatic renal cell carcinoma: current status.

PubMed

Escudier, Bernard; Albiges, Laurence; Sonpavde, Guru

2013-04-01

The armamentarium for the systemic therapy of advanced renal cell carcinoma (RCC) has undergone dramatic changes over the past 6 years. While high-dose interleukin (IL)-2 remains an option for highly selected good and intermediate risk patients with clear-cell histology because of durable complete responses in a small fraction of patients, cytokine-based therapy including interferon (IFN) has been supplanted by vascular-endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) inhibitors. Treatment decision is initially based on prognostication of the disease. As metastatic RCC (mRCC) is commonly an indolent disease, a period of observation should always been considered. For good and intermediate risk disease, pazopanib, sunitinib or the combination of bevacizumab plus IFN are considered. Notably, recent data suggest non-inferiority for the efficacy of pazopanib compared to sunitinib coupled with a better toxicity profile. A novel VEGF receptor inhibitor, tivozanib, is expected to be approved based on improvement in PFS when compared to sorafenib in the first-line setting. The use of temsirolimus for poor risk disease is supported by a phase III trial dedicated to this group of patients. The role of cytoreductive nephrectomy in the context of VEGF and mTOR inhibitors is being studied in randomized trials. Selected patients with solitary or oligometastatic disease may be eligible for metastatectomy. Following first-line VEGF inhibitors, second-line therapy with everolimus and axitinib have demonstrated benefits in progression-free survival (PFS). One phase III trial comparing sorafenib and temsirolimus in the post-sunitinib setting showed no difference in PFS, the primary endpoint, but did show a superior overall survival for sorafenib. Sorafenib, pazopanib and axitinib have all demonstrated clinical benefit following cytokines. Therapy following first-line mTOR inhibitors remains undefined, although VEGF inhibitors have demonstrated activity in

Phase II Study of Two Weeks on, One Week off Sunitinib Scheduling in Patients With Metastatic Renal Cell Carcinoma.

PubMed

Jonasch, Eric; Slack, Rebecca S; Geynisman, Daniel M; Hasanov, Elshad; Milowsky, Matthew I; Rathmell, W Kimryn; Stovall, Summer; Juarez, Donna; Gilchrist, Troy R; Pruitt, Lisa; Ornstein, Moshe C; Plimack, Elizabeth R; Tannir, Nizar M; Rini, Brian I

2018-06-01

Purpose Standard frontline treatment of patients with metastatic renal cell carcinoma currently includes sunitinib. A barrier to long-term treatment with sunitinib includes the development of significant adverse effects, including diarrhea, hand-foot syndrome (HFS), and fatigue. This trial assessed the effect of an alternate 2 weeks on, 1 week off (2/1) schedule of sunitinib on toxicity and efficacy in previously untreated patients with metastatic renal cell carcinoma. Methods Patients started with oral administration of 50 mg sunitinib on a 2/1 schedule and underwent schedule and dose alterations if toxicity developed. The primary end point was < 15% grade ≥ 3 fatigue, diarrhea, or HFS. With 60 patients, the upper bound of the CI would fall below the published 4/2 schedule grade ≥ 3 toxicity rate of 25% to 30%. Results Fifty-nine patients were treated between August 2014 and March 2016. Seventy-seven percent were intermediate or poor risk per Memorial Sloan Kettering Cancer Center criteria. With a median follow-up of 17 months, 25% of patients experienced grade 3 fatigue, HFS, or diarrhea; 37% required a dose reduction, and 10% discontinued because of toxicity. The overall response rate was 57%, median progression-free survival was 13.7 months, and median overall survival was not reached. At 12 weeks, Functional Assessment of Cancer Therapy-General scores dropped between 0% and 10% from baseline, with less reduction in patients who continued treatment longer. Conclusion The primary end point of decreased grade 3 toxicity was not met; however, treatment with a 2/1 sunitinib schedule is associated with a lack of grade 4 toxicity, a low patient discontinuation rate, and high efficacy.

Store-Operated Ca2+ Entry Does Not Control Proliferation in Primary Cultures of Human Metastatic Renal Cellular Carcinoma

PubMed Central

Turin, Ilaria; Potenza, Duilio Michele; Bottino, Cinzia; Glasnov, Toma N.; Ferulli, Federica; Mosca, Alessandra; Guerra, Germano; Rosti, Vittorio; Luinetti, Ombretta; Porta, Camillo; Pedrazzoli, Paolo

2014-01-01

Store-operated Ca2+ entry (SOCE) is activated following depletion of the inositol-1,4,5-trisphosphate (InsP3)-sensitive Ca2+ pool to regulate proliferation in immortalized cell lines established from either primary or metastatic lesions. The molecular nature of SOCE may involve both Stim1, which senses Ca2+ levels within the endoplasmic reticulum (ER) Ca2+ reservoir, and a number of a Ca2+-permeable channels on the plasma membrane, including Orai1, Orai3, and members of the canonical transient receptor (TRPC1–7) family of ion channels. The present study was undertaken to assess whether SOCE is expressed and controls proliferation in primary cultures isolated from secondary lesions of heavily pretreated metastatic renal cell carcinoma (mRCC) patients. SOCE was induced following pharmacological depletion of the ER Ca2+ store, but not by InsP3-dependent Ca2+ release. Metastatic RCC cells express Stim1-2, Orai1–3, and TRPC1–7 transcripts and proteins. In these cells, SOCE was insensitive to BTP-2, 10 µM Gd3+ and Pyr6, while it was inhibited by 100 µM Gd3+, 2-APB, and carboxyamidotriazole (CAI). Neither Gd3+ nor 2-APB or CAI impaired mRCC cell proliferation. Consistently, no detectable Ca2+ signal was elicited by growth factor stimulation. Therefore, a functional SOCE is expressed but does not control proliferation of mRCC cells isolated from patients resistant to multikinase inhibitors. PMID:25126575

[Small renal mass].

PubMed

Prokofiev, D; Kreutzer, N; Kress, A; Wissing, F; Pfeifer, H; Stolzenburg, J-U; Dietel, A; Schwalenberg, T; Do, M; Truß, M C

2012-10-01

The frequent application of ultrasound and radiological imaging for non-urological indications in recent years has resulted in an increase in the diagnosis of small renal masses. The treatment options for patients with a small renal mass include active surveillance, surgery (both open and minimally invasive) as well as ablative techniques. As there is a risk for metastatic spread even in small renal masses surgical extirpation remains the treatment of choice in most patients. Ablative procedures, such as cryoablation and radiofrequency ablation are appropriate for old and multi-morbid patients who require active treatment of a small renal mass. Active surveillance is an alternative for high-risk patients. Meticulous patient selection by the urologist and patient preference will determine the choice of treatment option in the future.

The Evolving Treatment Landscape of Advanced Renal Cell Carcinoma in Patients Progressing after VEGF Inhibition

PubMed Central

Barata, Pedro C.; Ornstein, Moshe C.

2017-01-01

Despite significant changes in the therapeutic landscape of renal cell carcinoma, the majority of patients with metastatic disease eventually progress after first-line treatment with vascular endothelial growth factor receptors (VEGFR) tyrosine kinase inhibitor (TKI) therapy. Understanding existing data on subsequent therapies is crucial to define an optimal treatment sequence following first-line failure. This review examines the data supporting currently approved agents in this setting and provides a framework for decision-making regarding treatment sequencing beyond first-line therapy with VEGFR TKIs. PMID:28725539

How to manage intravenous vinflunine in cancer patients with renal impairment: results of a pharmacokinetic and tolerability phase I study

PubMed Central

Isambert, Nicolas; Delord, Jean Pierre; Tourani, Jean Marc; Fumoleau, Pierre; Ravaud, Alain; Pinel, Marie Claire; Petain, Aurelie; Nguyen, Thierry; Nguyen, Laurent

2014-01-01

Aims Vinflunine (VFL) ditartrate, a novel tubulin-targeted inhibitor, is registered for the treatment of patients with advanced or metastatic urothelial transitional cell carcinoma. This phase I study assessed the effect of renal impairment on the pharmacokinetics and tolerability of VFL. Methods VFL was infused in patients with advanced/metastatic solid tumours once every 3 weeks with anticipated dose reduction on the first cycle stratified according to the creatinine clearance (CLcr) values. Pharmacokinetic data were collected on the first two cycles in renally impaired patients (CLcr ≤ 60 ml min−1) and were compared with a control cohort of patients (CLcr > 60 ml min−1). Results Thirty-three patients (46–86 years) were treated, 13 in group 1 (40 ml min−1 ≤ CLcr ≤ 60 ml min−1) and 20 in group 2 (20 ml min−1 ≤ CLcr < 40 ml min−1). The renal dysfunction induced a mean decrease in VFL clearance of 12% in group 1 and 28% in group 2, compared with the control group. The anticipated dose reduction given in renally impaired patients (i.e. 280 mg m−2 and 250 mg m−2 in groups 1 and 2, respectively) yielded similar drug exposure to control patients. The tolerance profile of VFL in patients with renal dysfunction was similar to that observed in patients with CLcr > 60 ml min−1. Conclusion In conclusion, the recommended doses of intravenous VFL administered once every 3 weeks in cancer patients with renal impairment are 280 mg m−2 when CLcr is between 40 and 60 ml min−1 and 250 mg m−2 when CLcr is between 20 and <40 ml min−1. PMID:24283925

Algorithms in the First-Line Treatment of Metastatic Clear Cell Renal Cell Carcinoma--Analysis Using Diagnostic Nodes.

PubMed

Rothermundt, Christian; Bailey, Alexandra; Cerbone, Linda; Eisen, Tim; Escudier, Bernard; Gillessen, Silke; Grünwald, Viktor; Larkin, James; McDermott, David; Oldenburg, Jan; Porta, Camillo; Rini, Brian; Schmidinger, Manuela; Sternberg, Cora; Putora, Paul M

2015-09-01

With the advent of targeted therapies, many treatment options in the first-line setting of metastatic clear cell renal cell carcinoma (mccRCC) have emerged. Guidelines and randomized trial reports usually do not elucidate the decision criteria for the different treatment options. In order to extract the decision criteria for the optimal therapy for patients, we performed an analysis of treatment algorithms from experts in the field. Treatment algorithms for the treatment of mccRCC from experts of 11 institutions were obtained, and decision trees were deduced. Treatment options were identified and a list of unified decision criteria determined. The final decision trees were analyzed with a methodology based on diagnostic nodes, which allows for an automated cross-comparison of decision trees. The most common treatment recommendations were determined, and areas of discordance were identified. The analysis revealed heterogeneity in most clinical scenarios. The recommendations selected for first-line treatment of mccRCC included sunitinib, pazopanib, temsirolimus, interferon-α combined with bevacizumab, high-dose interleukin-2, sorafenib, axitinib, everolimus, and best supportive care. The criteria relevant for treatment decisions were performance status, Memorial Sloan Kettering Cancer Center risk group, only or mainly lung metastases, cardiac insufficiency, hepatic insufficiency, age, and "zugzwang" (composite of multiple, related criteria). In the present study, we used diagnostic nodes to compare treatment algorithms in the first-line treatment of mccRCC. The results illustrate the heterogeneity of the decision criteria and treatment strategies for mccRCC and how available data are interpreted and implemented differently among experts. The data provided in the present report should not be considered to serve as treatment recommendations for the management of treatment-naïve patients with multiple metastases from metastatic clear cell renal cell carcinoma outside

Tyrosine-Kinase Inhibitors Therapies with Mainly Anti-Angiogenic Activity in Advanced Renal Cell Carcinoma: Value of PET/CT in Response Evaluation

PubMed Central

Ranieri, Girolamo; Marech, Ilaria; Niccoli Asabella, Artor; Di Palo, Alessandra; Porcelli, Mariangela; Lavelli, Valentina; Rubini, Giuseppe; Ferrari, Cristina; Gadaleta, Cosmo Damiano

2017-01-01

Renal cell carcinoma (RCC) is the most frequent renal tumor and the majority of patients are diagnosed with advanced disease. Tumor angiogenesis plays a crucial role in the development and progression of RCC together with hypoxia and glucose metabolism. These three pathways are strictly connected to the cell growth and proliferation, like a loop that is self-feeding. Over the last few years, the ever-deeper knowledge of its contribution in metastatic RCC led to the discovery of numerous tyrosine kinase inhibitors (TKIs) targeting pro-angiogenic receptors at different levels such as sunitinib, sorafenib, pazopanib, axitinib, tivozanib, and dovitinib. As anti-angiogenic agents, TKIs interfere the loop, being able to inhibit tumor proliferation. TKIs are now available treatments for advanced RCC, which demonstrated to improve overall survival and/or progression free survival. Their effects can be detectable early on Positron Emission Tomography/Computed Tomography (PET/CT) by change in 18F-fluoro-2-deoxy-2-d-glucose (18F-FDG) uptake, the main radiotracer used to date, as a strong indicator of biological response. 18F-FDG PET/CT demonstrated an ability to predict and monitor disease progression, allowing an early and reliable identification of responders, and could be used for image-guided optimization and “personalization” of anti-angiogenic regimens. New radiotracers for biometabolic imaging are currently under investigation, which exploit the other pathways involved in the cancer process, including cellular proliferation, aerobic metabolism, cell membrane synthesis, hypoxia and amino acid transport, as well as the angiogenic process, but they require further studies. PMID:28891933

Pattern of Care Study in Metastatic Renal-Cell Carcinoma in the Preimmunotherapy Era in Switzerland.

PubMed

Sandmeier, Nadja; Rothschild, Sacha I; Rothermundt, Christian; Cathomas, Richard; Schardt, Julian; Berthold, Dominik; von Burg, Philippe; Müller, Beat; Beyer, Jörg; Vogt, Deborah R; Stenner, Frank

2018-02-02

In metastatic renal-cell carcinoma (mRCC), physicians have a plethora of therapeutic choices, with the latest addition of checkpoint inhibitors. However, many questions regarding the best use of the respective drugs remain unanswered. Therefore, it is important to examine and summarize the outcome of real-world experiences to understand the practical value of the various drugs in daily use and foster optimal treatment algorithms for patients with renal-cell carcinoma. We sought to describe the pattern of care in mRCC under circumstances with access to all therapeutic options for patients. We examined the outcome of patients with mRCC who were treated at 8 major centers in Switzerland, mainly with vascular endothelial growth factor-targeted therapy and mammalian target of rapamycin inhibitors. Data from 110 patients with mRCC who had undergone more than one systemic therapy were collected and analyzed. We assessed the pattern of care for patients with mRCC in an unrestricted health care system and outcomes with regard to the respective treatment sequences. We also studied the compliance of individual therapies with published guidelines and correlated the adherence to outcome. Finally, immediate versus deferred treatment and the number of received therapeutic drug lines were analyzed. Median survival of patients treated with targeted agents for mRCC was 2.0 years. Exposure to more than 2 lines of systemic drugs did not improve outcome of patients with mRCC. Copyright © 2018 Elsevier Inc. All rights reserved.

Contemporary experience with high-dose interleukin-2 therapy and impact on survival in patients with metastatic melanoma and metastatic renal cell carcinoma.

PubMed

Alva, Ajjai; Daniels, Gregory A; Wong, Michael K K; Kaufman, Howard L; Morse, Michael A; McDermott, David F; Clark, Joseph I; Agarwala, Sanjiv S; Miletello, Gerald; Logan, Theodore F; Hauke, Ralph J; Curti, Brendan; Kirkwood, John M; Gonzalez, Rene; Amin, Asim; Fishman, Mayer; Agarwal, Neeraj; Lowder, James N; Hua, Hong; Aung, Sandra; Dutcher, Janice P

2016-12-01

High-dose interleukin-2 (HD IL-2) was approved for treatment of metastatic renal cell carcinoma (mRCC) in 1992 and for metastatic melanoma (mM) in 1998, in an era predating targeted therapies and immune checkpoint inhibitors. The PROCLAIM SM registry was established to collect and analyze data for patients treated with HD IL-2 in the current era. This analysis includes 170 patients with mM and 192 patients with mRCC treated between 2005 and 2012 with survival data current as of July 27, 2015. For patients with mM, complete response (CR) was observed in 5 %, partial response (PR) in 10 %, stable disease (SD) in 22 %, and 63 % had progressive disease (PD). The median overall survival (mOS) for these patients was 19.6 months, with a median follow-up of 43.1 months. The mOS was not reached for patients achieving CR or PR, and was 33.4 months for patients with SD. For patients with mRCC, 6 % achieved CR, 9 % had PR, 22 % had SD, and 62 % had PD. The mOS was 41 months, with a median follow-up of 46.6 months. The mOS for patients who had CR and PR was not reached and was 49.6 months for patients with SD. There were no treatment-related deaths among 362 patients. The duration of mOS for patients with mM and mRCC is longer than historically reported. These data support a continued role for IL-2 in the treatment of eligible patients with mM or mRCC and warrant further evaluation of HD IL-2 in combination or sequence with other therapeutic agents.

Pembrolizumab and Ziv-aflibercept in Treating Patients With Advanced Solid Tumors

ClinicalTrials.gov

2018-03-08

Adult Solid Neoplasm; Metastatic Melanoma; Metastatic Renal Cell Cancer; Recurrent Colorectal Carcinoma; Recurrent Melanoma; Recurrent Ovarian Carcinoma; Recurrent Renal Cell Carcinoma; Stage IV Ovarian Cancer AJCC v6 and v7; Stage IVA Colorectal Cancer AJCC v7; Stage IVB Colorectal Cancer AJCC v7

Whole Blood mRNA Expression-Based Prognosis of Metastatic Renal Cell Carcinoma.

PubMed

Giridhar, Karthik V; Sosa, Carlos P; Hillman, David W; Sanhueza, Cristobal; Dalpiaz, Candace L; Costello, Brian A; Quevedo, Fernando J; Pitot, Henry C; Dronca, Roxana S; Ertz, Donna; Cheville, John C; Donkena, Krishna Vanaja; Kohli, Manish

2017-11-03

The Memorial Sloan Kettering Cancer Center (MSKCC) prognostic score is based on clinical parameters. We analyzed whole blood mRNA expression in metastatic clear cell renal cell carcinoma (mCCRCC) patients and compared it to the MSKCC score for predicting overall survival. In a discovery set of 19 patients with mRCC, we performed whole transcriptome RNA sequencing and selected eighteen candidate genes for further evaluation based on associations with overall survival and statistical significance. In an independent validation of set of 47 patients with mCCRCC, transcript expression of the 18 candidate genes were quantified using a customized NanoString probeset. Cox regression multivariate analysis confirmed that two of the candidate genes were significantly associated with overall survival. Higher expression of BAG1 [hazard ratio (HR) of 0.14, p < 0.0001, 95% confidence interval (CI) 0.04-0.36] and NOP56 (HR 0.13, p < 0.0001, 95% CI 0.05-0.34) were associated with better prognosis. A prognostic model incorporating expression of BAG1 and NOP56 into the MSKCC score improved prognostication significantly over a model using the MSKCC prognostic score only ( p < 0.0001). Prognostic value of using whole blood mRNA gene profiling in mCCRCC is feasible and should be prospectively confirmed in larger studies.

A simple prognostic model for overall survival in metastatic renal cell carcinoma.

PubMed

Assi, Hazem I; Patenaude, Francois; Toumishey, Ethan; Ross, Laura; Abdelsalam, Mahmoud; Reiman, Tony

2016-01-01

The primary purpose of this study was to develop a simpler prognostic model to predict overall survival for patients treated for metastatic renal cell carcinoma (mRCC) by examining variables shown in the literature to be associated with survival. We conducted a retrospective analysis of patients treated for mRCC at two Canadian centres. All patients who started first-line treatment were included in the analysis. A multivariate Cox proportional hazards regression model was constructed using a stepwise procedure. Patients were assigned to risk groups depending on how many of the three risk factors from the final multivariate model they had. There were three risk factors in the final multivariate model: hemoglobin, prior nephrectomy, and time from diagnosis to treatment. Patients in the high-risk group (two or three risk factors) had a median survival of 5.9 months, while those in the intermediate-risk group (one risk factor) had a median survival of 16.2 months, and those in the low-risk group (no risk factors) had a median survival of 50.6 months. In multivariate analysis, shorter survival times were associated with hemoglobin below the lower limit of normal, absence of prior nephrectomy, and initiation of treatment within one year of diagnosis.

A simple prognostic model for overall survival in metastatic renal cell carcinoma

PubMed Central

Assi, Hazem I.; Patenaude, Francois; Toumishey, Ethan; Ross, Laura; Abdelsalam, Mahmoud; Reiman, Tony

2016-01-01

Introduction: The primary purpose of this study was to develop a simpler prognostic model to predict overall survival for patients treated for metastatic renal cell carcinoma (mRCC) by examining variables shown in the literature to be associated with survival. Methods: We conducted a retrospective analysis of patients treated for mRCC at two Canadian centres. All patients who started first-line treatment were included in the analysis. A multivariate Cox proportional hazards regression model was constructed using a stepwise procedure. Patients were assigned to risk groups depending on how many of the three risk factors from the final multivariate model they had. Results: There were three risk factors in the final multivariate model: hemoglobin, prior nephrectomy, and time from diagnosis to treatment. Patients in the high-risk group (two or three risk factors) had a median survival of 5.9 months, while those in the intermediate-risk group (one risk factor) had a median survival of 16.2 months, and those in the low-risk group (no risk factors) had a median survival of 50.6 months. Conclusions: In multivariate analysis, shorter survival times were associated with hemoglobin below the lower limit of normal, absence of prior nephrectomy, and initiation of treatment within one year of diagnosis. PMID:27217858

Sorafenib in Treating Patients With Regional or Metastatic Cancer of the Urothelium

ClinicalTrials.gov

2014-05-20

Adenocarcinoma of the Bladder; Distal Urethral Cancer; Metastatic Transitional Cell Cancer of the Renal Pelvis and Ureter; Proximal Urethral Cancer; Recurrent Bladder Cancer; Recurrent Transitional Cell Cancer of the Renal Pelvis and Ureter; Recurrent Urethral Cancer; Regional Transitional Cell Cancer of the Renal Pelvis and Ureter; Squamous Cell Carcinoma of the Bladder; Stage III Bladder Cancer; Stage IV Bladder Cancer; Transitional Cell Carcinoma of the Bladder; Urethral Cancer Associated With Invasive Bladder Cancer

Emerging Therapies in Metastatic Prostate Cancer.

PubMed

Sonnenburg, Daniel W; Morgans, Alicia K

2018-04-11

In the last decade, there have been multiple landmark therapeutic advances for the treatment of metastatic prostate cancer, both in the castration-resistant and hormone-sensitive setting. In this review, we highlight recent progress and ongoing trials for metastatic prostate cancer, including advances in chemotherapy, androgen receptor-directed therapy, targeted therapies, and immunotherapy. Several landmark studies for men with metastatic hormone-sensitive prostate cancer demonstrated improvement in overall survival with the addition of docetaxel chemotherapy or abiraterone acetate to standard androgen deprivation therapy. A single-arm phase 2 study of the PARP inhibitor olaparib demonstrated high response rates and more favorable progression-free and overall survival for men with metastatic castration-resistant prostate cancer and DNA repair defects treated with olaparib compared with men without DNA repair defects. Multiple ongoing clinical trials are investigating novel hormonal therapies and combinations of chemotherapy, targeted small molecules, immunotherapy, and radiopharmaceuticals. Progress continues to be made in the treatment of metastatic prostate cancer, and ongoing clinical trials continue to investigate novel agents and approaches to treatment.

Role of RPLND and Metastasectomy in the Management of Oligometastatic Renal Cell Carcinoma.

PubMed

Nagaraja, H; Srivatsa, N; Hemalatha, S; Shweta, S; Raghunath, S K

2018-03-01

Although lymphadenectomy is currently accepted as most accurate and reliable staging procedure for lymph node metastases, its therapeutic benefit in renal cell carcinoma (RCC) still remains controversial. Although the new, targeted therapy paradigms have changed the treatment of patients with advanced RCC and offer prolonged survival, cure is extremely uncommon in the absence of surgical resections. In this paper, the current role of metastasectomy is reviewed. Review the available literature concerning the role of retroperitoneal lymph node dissection and metastasectomy in outcome of oligometastatic RCC. A PubMed search was conducted to identify original articles, review articles, and editorials addressing the role of retroperitoneal lymph node dissection and metastasectomy in outcome of oligometastatic RCC. Keywords included renal tumors, renal cell cancer, kidney cancer, lymphadenectomy, metastasectomy, and oligometastases. While there is no randomized study available, recent large observational studies have better defined the prognosis of patients with metastatic RCC with or without metastasectomy and RPLND. To date, the available evidence suggests that RPLND and metastasectomy may be beneficial when technically feasible in patients with locally advanced (unfavorable clinical and pathologic characteristics) and oligometastatic disease. A proportion of patients will achieve long-term survival with aggressive surgical resection.

Sorafenib in Japanese Patients with Locally Advanced or Metastatic Medullary Thyroid Carcinoma and Anaplastic Thyroid Carcinoma.

PubMed

Ito, Yasuhiro; Onoda, Naoyoshi; Ito, Ken-Ichi; Sugitani, Iwao; Takahashi, Shunji; Yamaguchi, Iku; Kabu, Koki; Tsukada, Katsuya

2017-09-01

Therapeutic options for treating advanced or metastatic medullary thyroid carcinoma (MTC) and anaplastic thyroid carcinoma (ATC) are still limited in Japan, even though vandetanib for MTC and lenvatinib for MTC and ATC have been approved. Sorafenib is an oral multikinase inhibitor approved for the treatment of patients with radioactive iodine-refractory differentiated thyroid cancer (DTC). An uncontrolled, open-label, multicenter, single-arm, Phase 2 clinical study was conducted to evaluate the safety and efficacy of sorafenib in Japanese patients with MTC and ATC. Japanese patients with histologically confirmed ATC and locally advanced or metastatic MTC were enrolled from April to September 2014. The primary endpoint was to evaluate the safety of sorafenib. Treatment efficacy variables including progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and maximum reduction in tumor size were evaluated as secondary endpoints. Patients received sorafenib 400 mg orally twice daily on a continuous basis and then continued treatment until the occurrence of disease progression, unacceptable toxicity, or withdrawal of consent. A total of 20 patients were screened, and 18 (8 with MTC and 10 with ATC) were enrolled. The most common drug-related adverse events were palmar-plantar erythrodysesthesia (72%), alopecia (56%), hypertension (56%), and diarrhea (44%). In the ATC patients, median PFS was 2.8 months [confidence interval 0.7-5.6], and median OS was 5.0 months [confidence interval 0.7-5.7]; ORR and DCR were 0% and 40%, respectively. In the MTC population, neither median PFS nor OS had been reached at the time of this analysis; ORR was 25% and DCR was 75%. The toxicities reported in this study were consistent with the known safety profile of sorafenib. Sorafenib seems to be effective in the treatment of advanced MTC but not ATC, and could be a new treatment option for locally advanced or metastatic MTC and

Veliparib, Cisplatin, and Gemcitabine Hydrochloride in Treating Patients With Advanced Biliary, Pancreatic, Urothelial, or Non-Small Cell Lung Cancer

ClinicalTrials.gov

2013-07-01

Advanced Adult Primary Liver Cancer; Localized Unresectable Adult Primary Liver Cancer; Metastatic Transitional Cell Cancer of the Renal Pelvis and Ureter; Regional Transitional Cell Cancer of the Renal Pelvis and Ureter; Stage III Bladder Cancer; Stage III Pancreatic Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Bladder Cancer; Stage IV Non-small Cell Lung Cancer; Stage IV Pancreatic Cancer; Transitional Cell Carcinoma of the Bladder; Unresectable Extrahepatic Bile Duct Cancer; Unresectable Gallbladder Cancer

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

PubMed

Kim, Esther S; Scott, Lesley J

2017-06-01

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

[Atezolizumab (Tecentriq®): Activity, indication and modality of use in advanced or metastatic urinary bladder carcinoma].

PubMed

Bernard-Tessier, Alice; Bonnet, Clément; Lavaud, Pernelle; Gizzi, Marco; Loriot, Yohann; Massard, Christophe

2018-02-01

Treatments for patients with metastatic or advanced urothelial carcinomas on progression after first line chemotherapy or unfit for cisplatin are currently limited. Atezolizumab (Tecentriq ® ) is a monoclonal antibody targeting PD-L1. The first of IMVIGOR 210 phase II trial (NCT02951767) investigated atezolizumab as front line treatment among 119 patients with metastatic urothelial cancer unfit for cisplatin. Response rate was 23% and median overall survival 15.9 months. The second cohort (NCT02108652) included 310 patients whose tumors were progressing after first line platinum-based chemotherapy. Response rate was 15% and median overall survival 7.9 months. Among patients with high PD-L1 expression on infiltrating immune cells (ICs), response rate was 26% and median overall survival 11 months. Atezolizumab was well-tolerated in both cohorts with 66% of treatment-related toxicities including 12% (cohort 1) and 7% (cohort 2) of grade 3-4 adverse events. These results led to an approval by the FDA in United States and the EMA in Europe. In France, atezolizumab was available through an early access agreement by the French National Agency for Medicines and Health Products (ANSM) for patients with metastatic or advanced urothelial carcinomas on progression after first line chemotherapy or unfit for cisplatin. So far, its avaibility in France within the EMA approval is pending its pricing. Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

Immunotherapy in urothelial cancer, part 1: T-cell checkpoint inhibition in advanced or metastatic disease.

PubMed

Yu, Steven S; Dorff, Tanya B; Ballas, Leslie K; Sadeghi, Sarmad; Skinner, Eila C; Quinn, David I

2017-06-01

Cancer of the urothelium is the sixth most common cancer in the United States and is seen predominantly in men. Most cases of this disease present as non-muscle-invasive bladder cancer (NMIBC), with cancer recurrence or progression to muscle-invasive cancer in more than 50% of patients after initial therapy. NMIBC is an immune-responsive disease, as indicated by the use of intravesical bacillus Calmette-Guérin as treatment for more than 3 decades. More recently, immunotherapy has seen much progress in a variety of cancers, including advanced and metastatic bladder cancer, in which historical 5-year survival rates are approximately 15%. The advent of T-cell checkpoint inhibitors, especially those directed at programmed death 1 (PD-1) and its ligand (PD-L1), has had a significant effect on the therapy of advanced urothelial cancer. This had led to accelerated approval by the US Food and Drug Administration for atezolizumab and nivolumab in advanced urothelial cancer previously treated with platinum-based chemotherapy. In addition, level 1 evidence supports the use of pembrolizumab over single-agent tubulin-directed chemotherapy in the same setting. Several other treatments with immune-mediating mechanisms of action are in development and hold great promise, including monoclonal antibodies directed at other checkpoint molecules, oncolytic virus therapy, adoptive T-cell therapy, combination immunotherapy, and antibody-drug conjugates. This review focuses on the recent development of T-cell checkpoint inhibitors in advanced and metastatic urothelial cancer and addresses their potential use in combination. It also discusses a spectrum of novel immunotherapies with potential use in urothelial cancer.

A large-scale prospective registration study of the safety and efficacy of sorafenib tosylate in unresectable or metastatic renal cell carcinoma in Japan: results of over 3200 consecutive cases in post-marketing all-patient surveillance

PubMed Central

Akaza, Hideyuki; Oya, Mototsugu; Iijima, Masafumi; Hyodo, Ichinosuke; Gemma, Akihiko; Itoh, Hiroshi; Adachi, Masatoshi; Okayama, Yutaka; Sunaya, Toshiyuki; Inuyama, Lyo

2015-01-01

Objective Real-life safety and efficacy of sorafenib in advanced renal cell carcinoma in a nationwide patient population were evaluated by post-marketing all-patient surveillance. Methods All patients with unresectable or metastatic renal cell carcinoma in Japan who started sorafenib therapy from February 2008 to September 2009 were registered and followed for up to 12 months. Baseline characteristics, treatment status, tumor response, survival and safety data were recorded by the prescribing physicians. Results Safety and efficacy were evaluated in 3255 and 3171 patients, respectively. The initial daily dose was 800 mg in 78.2% of patients. Median duration of treatment was 6.7 months and the mean relative dose intensity was 68.4%. Overall, 2227 patients (68.4%) discontinued the treatment by 12 months, half of which (52.0% of discontinued patients) were due to adverse events. The most common adverse drug reactions were hand–foot skin reaction (59%), hypertension (36%), rash (25%) and increase in lipase/amylase (23%). The median progression-free survival was 7.3 months (95% confidence intervals: 6.7–8.1), and the overall survival rate at 1 year was 75.4% (73.5–77.1). Prognostic factors for overall survival were mostly consistent with those in previous clinical trials in the univariate analysis and largely similar to those for progression-free survival and duration of treatment in the multivariate analysis. Conclusions Sorafenib for the treatment of advanced renal cell carcinoma under the labeled dose was feasible in daily medical practice, for its acceptable toxicity profile and favorable clinical benefit that were consistent with those in clinical trials. PMID:26206897

A large-scale prospective registration study of the safety and efficacy of sorafenib tosylate in unresectable or metastatic renal cell carcinoma in Japan: results of over 3200 consecutive cases in post-marketing all-patient surveillance.

PubMed

Akaza, Hideyuki; Oya, Mototsugu; Iijima, Masafumi; Hyodo, Ichinosuke; Gemma, Akihiko; Itoh, Hiroshi; Adachi, Masatoshi; Okayama, Yutaka; Sunaya, Toshiyuki; Inuyama, Lyo

2015-10-01

Real-life safety and efficacy of sorafenib in advanced renal cell carcinoma in a nationwide patient population were evaluated by post-marketing all-patient surveillance. All patients with unresectable or metastatic renal cell carcinoma in Japan who started sorafenib therapy from February 2008 to September 2009 were registered and followed for up to 12 months. Baseline characteristics, treatment status, tumor response, survival and safety data were recorded by the prescribing physicians. Safety and efficacy were evaluated in 3255 and 3171 patients, respectively. The initial daily dose was 800 mg in 78.2% of patients. Median duration of treatment was 6.7 months and the mean relative dose intensity was 68.4%. Overall, 2227 patients (68.4%) discontinued the treatment by 12 months, half of which (52.0% of discontinued patients) were due to adverse events. The most common adverse drug reactions were hand-foot skin reaction (59%), hypertension (36%), rash (25%) and increase in lipase/amylase (23%). The median progression-free survival was 7.3 months (95% confidence intervals: 6.7-8.1), and the overall survival rate at 1 year was 75.4% (73.5-77.1). Prognostic factors for overall survival were mostly consistent with those in previous clinical trials in the univariate analysis and largely similar to those for progression-free survival and duration of treatment in the multivariate analysis. Sorafenib for the treatment of advanced renal cell carcinoma under the labeled dose was feasible in daily medical practice, for its acceptable toxicity profile and favorable clinical benefit that were consistent with those in clinical trials. © The Author 2015. Published by Oxford University Press.

Biology of Metastatic Renal Cell Carcinoma

PubMed Central

Milella, Michele; Felici, Alessandra

2011-01-01

In the past ten years we have made exceptional progresses in the understanding of RCC biology, particularly by recognizing the crucial pathogenetic role of activation of the HIF/VEGF and mTOR pathways. This has resulted in the successful clinical development of anti-angiogenic and mTOR-targeted drugs, which have profoundly impacted on the natural history of the disease and have improved the duration and quality of RCC patient lives. However, further improvements are still greatly needed: 1) even in patients who obtain striking clinical responses early in the course of treatment, disease will ultimately escape control and progress to a treatment-resistant state, leading to therapeutic failure; 2) prolonged disease control usually requires 'continuous' treatment, even across different treatment lines, making the impact of chronic, low-grade, toxicities on quality of life greater and precluding, for most patients, the possibility of experiencing 'drug-free holidays'; 3) although we have successfully identified classes of drugs (or molecular mechanisms of action) that are effective in a substantial proportion of patients, we still fall short of molecular predictive factors that identify individual patients who will (or will not) benefit from a specific intervention and still proceed on a trial-and-error basis, far from a truly 'personalized' therapeutic approach; 4) finally (and perhaps most importantly), even in the best case scenario, currently available treatments inevitably fail to definitively 'cure' metastatic RCC patients. In this review we briefly summarize recent developments in the understanding of the molecular pathogenesis of RCC, the development of resistance/escape mechanisms, the rationale for sequencing agents with different mechanisms of action, and the importance of host-related factors. Unraveling the complex mechanisms by which RCC shapes host microenvironment and immune response and therapeutic treatments, in turn, shape both cancer cell biology

Biology of metastatic renal cell carcinoma.

PubMed

Milella, Michele; Felici, Alessandra

2011-01-01

In the past ten years we have made exceptional progresses in the understanding of RCC biology, particularly by recognizing the crucial pathogenetic role of activation of the HIF/VEGF and mTOR pathways. This has resulted in the successful clinical development of anti-angiogenic and mTOR-targeted drugs, which have profoundly impacted on the natural history of the disease and have improved the duration and quality of RCC patient lives. However, further improvements are still greatly needed: 1) even in patients who obtain striking clinical responses early in the course of treatment, disease will ultimately escape control and progress to a treatment-resistant state, leading to therapeutic failure; 2) prolonged disease control usually requires 'continuous' treatment, even across different treatment lines, making the impact of chronic, low-grade, toxicities on quality of life greater and precluding, for most patients, the possibility of experiencing 'drug-free holidays'; 3) although we have successfully identified classes of drugs (or molecular mechanisms of action) that are effective in a substantial proportion of patients, we still fall short of molecular predictive factors that identify individual patients who will (or will not) benefit from a specific intervention and still proceed on a trial-and-error basis, far from a truly 'personalized' therapeutic approach; 4) finally (and perhaps most importantly), even in the best case scenario, currently available treatments inevitably fail to definitively 'cure' metastatic RCC patients. In this review we briefly summarize recent developments in the understanding of the molecular pathogenesis of RCC, the development of resistance/escape mechanisms, the rationale for sequencing agents with different mechanisms of action, and the importance of host-related factors. Unraveling the complex mechanisms by which RCC shapes host microenvironment and immune response and therapeutic treatments, in turn, shape both cancer cell biology

Cabozantinib-s-malate and Nivolumab With or Without Ipilimumab in Treating Patients With Metastatic Genitourinary Tumors

ClinicalTrials.gov

2018-04-02

Clear Cell Renal Cell Carcinoma; Metastatic Malignant Neoplasm in the Bone; Metastatic Penile Carcinoma; Renal Pelvis Urothelial Carcinoma; Squamous Cell Carcinoma of the Penis; Stage III Bladder Adenocarcinoma AJCC v6 and v7; Stage III Bladder Squamous Cell Carcinoma AJCC v6 and v7; Stage III Bladder Urothelial Carcinoma AJCC v6 and v7; Stage III Penile Cancer AJCC v7; Stage III Renal Cell Cancer AJCC v7; Stage III Renal Pelvis Cancer AJCC v7; Stage III Ureter Cancer AJCC v7; Stage III Urethral Cancer AJCC v7; Stage IIIa Penile Cancer AJCC v7; Stage IIIb Penile Cancer AJCC v7; Stage IV Bladder Adenocarcinoma AJCC v7; Stage IV Bladder Squamous Cell Carcinoma AJCC v7; Stage IV Bladder Urothelial Carcinoma AJCC v7; Stage IV Penile Cancer AJCC v7; Stage IV Renal Cell Cancer AJCC v7; Stage IV Renal Pelvis Cancer AJCC v7; Stage IV Ureter Cancer AJCC v7; Stage IV Urethral Cancer AJCC v7; Ureter Urothelial Carcinoma; Urethral Urothelial Carcinoma

Long-term survival in an adolescent with widely metastatic renal cell carcinoma with rhabdoid features.

PubMed

Ettinger, L J; Goodell, L A; Javidian, P; Hsieh, Y; Amenta, P

2000-01-01

Renal cell carcinoma is rarely seen in children and adolescents. Patients with widespread disease at diagnosis have a particularly poor survival rate. Currently, all known chemotherapy has been ineffective in improving the median survival in patients with advanced disease. A 13-year-old black boy with stage IV renal cell carcinoma with rhabdoid features is a long-term disease-free survivor after aggressive multiagent chemotherapy. After the initial evaluation and histologic diagnosis of renal cell carcinoma, the patient received three courses of an aggressive chemotherapy regimen consisting of vincristine, doxorubicin, cyclophosphamide with mesna uroprotection, granulocyte colony-stimulating factor and erythropoietin (Epogen). After an almost complete response, a radical nephrectomy was performed and results demonstrated a solitary small nodule with viable tumor. After surgery, he received floxuridine infusion for 14 days by circadian schedule at 28-day intervals for a total of 1 year. The patient is well and free of disease 5 years after initial presentation. The dramatic response to treatment and long-term disease-free survival of this patient suggest this chemotherapeutic approach warrants additional investigation.

The Association Between PD-L1 Expression and the Clinical Outcomes to Vascular Endothelial Growth Factor-Targeted Therapy in Patients With Metastatic Clear Cell Renal Cell Carcinoma

PubMed Central

Shin, Su-Jin; Jeon, Yoon Kyung; Cho, Yong Mee; Lee, Jae-Lyun; Chung, Doo Hyun; Park, Ji Young

2015-01-01

Background. Vascular endothelial growth factor pathway (VEGF)-tyrosine kinase inhibitors (TKIs) are used as the first-line treatment for patients with metastatic clear cell renal cell carcinoma (mCCRCC). Recently, programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) blockade emerged as promising therapy for renal cell carcinoma. However, the expression pattern and prognostic implication of programmed death-ligands (PD-Ls) in mCCRCC patients receiving VEGF-TKI remain unclear. Patients and Methods. PD-L1 and PD-L2 expression in tumor cells and the quantities of PD-1+ tumor-infiltrating lymphocytes were immunohistochemically evaluated in 91 mCCRCC patients treated with VEGF-TKI, and their associations with VEGF-TKI responsiveness and clinical outcome were analyzed. Results. PD-L1 immunopositivity was observed in 17.6% and significantly associated with a high International Society of Urological Pathology grade (p = .031) and sarcomatoid features (p = .014). PD-L2 immunopositivity was observed in 39.6% and was not associated with any of the assessed clinicopathological variables. PD-L1-positive cases showed poor VEGF-TKI responsiveness (p = .012) compared with PD-L1-negative cases. In univariate survival analysis, PD-L1 immunopositivity was significantly associated with shorter overall survival (OS) (p = .037) and progression-free survival (PFS) (p = .043). Multivariate survival analysis revealed that PD-L1 expression was independently associated with poor OS (p = .038) and PFS (p = .013) in addition to tumor necrosis (p = .006; p = .029, respectively) and Memorial Sloan Kettering Cancer Center score (p = .018; p = .032, respectively). PD-L2 expression was neither associated with VEGF-TKI responsiveness nor patients’ outcome. Conclusion. PD-L1 expression was significantly related to lack of VEGF-TKI responsiveness and independently associated with shorter survival in mCCRCC patients after VEGF-TKI treatment. PD-L1 may have a predictive and prognostic value

RCDB: Renal Cancer Gene Database.

PubMed

Ramana, Jayashree

2012-05-18

Renal cell carcinoma or RCC is one of the common and most lethal urological cancers, with 40% of the patients succumbing to death because of metastatic progression of the disease. Treatment of metastatic RCC remains highly challenging because of its resistance to chemotherapy as well as radiotherapy, besides surgical resection. Whereas RCC comprises tumors with differing histological types, clear cell RCC remains the most common. A major problem in the clinical management of patients presenting with localized ccRCC is the inability to determine tumor aggressiveness and accurately predict the risk of metastasis following surgery. As a measure to improve the diagnosis and prognosis of RCC, researchers have identified several molecular markers through a number of techniques. However the wealth of information available is scattered in literature and not easily amenable to data-mining. To reduce this gap, this work describes a comprehensive repository called Renal Cancer Gene Database, as an integrated gateway to study renal cancer related data. Renal Cancer Gene Database is a manually curated compendium of 240 protein-coding and 269 miRNA genes contributing to the etiology and pathogenesis of various forms of renal cell carcinomas. The protein coding genes have been classified according to the kind of gene alteration observed in RCC. RCDB also includes the miRNAsdysregulated in RCC, along with the corresponding information regarding the type of RCC and/or metastatic or prognostic significance. While some of the miRNA genes showed an association with other types of cancers few were unique to RCC. Users can query the database using keywords, category and chromosomal location of the genes. The knowledgebase can be freely accessed via a user-friendly web interface at http://www.juit.ac.in/attachments/jsr/rcdb/homenew.html. It is hoped that this database would serve as a useful complement to the existing public resources and as a good starting point for researchers and

Wide spetcrum mutational analysis of metastatic renal cell cancer: a retrospective next generation sequencing approach

PubMed Central

Fiorentino, Michelangelo; Gruppioni, Elisa; Massari, Francesco; Giunchi, Francesca; Altimari, Annalisa; Ciccarese, Chiara; Bimbatti, Davide; Scarpa, Aldo; Iacovelli, Roberto; Porta, Camillo; Virinder, Sarhadi; Tortora, Giampaolo; Artibani, Walter; Schiavina, Riccardo; Ardizzoni, Andrea; Brunelli, Matteo; Knuutila, Sakari; Martignoni, Guido

2017-01-01

Renal cell cancer (RCC) is characterized by histological and molecular heterogeneity that may account for variable response to targeted therapies. We evaluated retrospectively with a next generation sequencing (NGS) approach using a pre-designed cancer panel the mutation burden of 32 lesions from 22 metastatic RCC patients treated with at least one tyrosine kinase or mTOR inhibitor. We identified mutations in the VHL, PTEN, JAK3, MET, ERBB4, APC, CDKN2A, FGFR3, EGFR, RB1, TP53 genes. Somatic alterations were correlated with response to therapy. Most mutations hit VHL1 (31,8%) followed by PTEN (13,6%), JAK3, FGFR and TP53 (9% each). Eight (36%) patients were wild-type at least for the genes included in the panel. A genotype concordance between primary RCC and its secondary lesion was found in 3/6 cases. Patients were treated with Sorafenib, Sunitinib and Temsirolimus with partial responses in 4 (18,2%) and disease stabilization in 7 (31,8%). Among the 4 partial responders, 1 (25%) was wild-type and 3 (75%) harbored different VHL1 variants. Among the 7 patients with disease stabilization 2 (29%) were wild-type, 2 (29%) PTEN mutated, and single patients (14% each) displayed mutations in VHL1, JAK3 and APC/CDKN2A. Among the 11 non-responders 7 (64%) were wild-type, 2 (18%) were p53 mutated and 2 (18%) VHL1 mutated. No significant associations were found among RCC histotype, mutation variants and response to therapies. In the absence of predictive biomarkers for metastatic RCC treatment, a NGS approach may address single patients to basket clinical trials according to actionable molecular specific alterations. PMID:27741505

Phase I study of orally administered S-1 in combination with epirubicin and oxaliplatin in patients with advanced solid tumors and chemotherapy-naïve advanced or metastatic esophagogastric cancer.

PubMed

Moehler, Markus; Mahlberg, Rolf; Heinemann, Volker; Obermannová, Radka; Kubala, Eugen; Melichar, Bohuslav; Weinmann, Arndt; Scigalla, Paul; Tesařová, Marietta; Janda, Petr; Hédouin-Biville, Fabienne; Mansoor, Wasat

2017-03-01

This phase I study investigated the safety and the maximum tolerated dose (MTD) of the oral fluoropyrimidine S-1 when combined with epirubicin and oxaliplatin (EOS). Patients aged ≥18 years with advanced or metastatic solid tumors were enrolled in a 3 + 3 design with S-1 dose escalation (two planned cohorts) performed according to the occurrence of dose-limiting toxicity (DLT). On day 1 of each 21-day cycle, patients received epirubicin 50 mg/m 2 followed by oxaliplatin 130 mg/m 2 (maximum 8 cycles) and then S-1 [20 mg/m 2 (cohort 1) or 25 mg/m 2 (cohort 2), twice daily]: first dose, evening of day 1; subsequent administration on days 2-14, twice daily; last dose, morning of day 15 (unlimited number of S-1 cycles). After protocol amendment, enrollment in a third cohort was restricted to patients with chemotherapy-naïve advanced or metastatic esophagogastric cancer. DLT was reported for two of the five patients in cohort 2, defining 20 mg/m 2 twice daily as the MTD of S-1 combined with epirubicin and oxaliplatin in heavily pretreated patients. Thirteen patients with chemotherapy-naïve advanced or metastatic esophagogastric cancer were subsequently enrolled and treated at an S-1 dose level of 25 mg/m 2 twice daily; no DLTs were reported; median overall survival was 13.1 months. Of the 11 evaluable patients, three (27 %) had partial responses and seven (64 %) had stable disease. The safety profile was in line with expectations. The promising activity of EOS (S-1 dose level, 25 mg/m 2 twice daily) and acceptable safety profile support further clinical development of this combination for the first-line treatment of patients with advanced or metastatic esophagogastric cancer.

Overall Survival and Updated Results for Sunitinib Compared With Interferon Alfa in Patients With Metastatic Renal Cell Carcinoma

PubMed Central

Motzer, Robert J.; Hutson, Thomas E.; Tomczak, Piotr; Michaelson, M. Dror; Bukowski, Ronald M.; Oudard, Stéphane; Negrier, Sylvie; Szczylik, Cezary; Pili, Roberto; Bjarnason, Georg A.; Garcia-del-Muro, Xavier; Sosman, Jeffrey A.; Solska, Ewa; Wilding, George; Thompson, John A.; Kim, Sindy T.; Chen, Isan; Huang, Xin; Figlin, Robert A.

2009-01-01

Purpose A randomized, phase III trial demonstrated superiority of sunitinib over interferon alfa (IFN-α) in progression-free survival (primary end point) as first-line treatment for metastatic renal cell carcinoma (RCC). Final survival analyses and updated results are reported. Patients and Methods Seven hundred fifty treatment-naïve patients with metastatic clear cell RCC were randomly assigned to sunitinib 50 mg orally once daily on a 4 weeks on, 2 weeks off dosing schedule or to IFN-α 9 MU subcutaneously thrice weekly. Overall survival was compared by two-sided log-rank and Wilcoxon tests. Progression-free survival, response, and safety end points were assessed with updated follow-up. Results Median overall survival was greater in the sunitinib group than in the IFN-α group (26.4 v 21.8 months, respectively; hazard ratio [HR] = 0.821; 95% CI, 0.673 to 1.001; P = .051) per the primary analysis of unstratified log-rank test (P = .013 per unstratified Wilcoxon test). By stratified log-rank test, the HR was 0.818 (95% CI, 0.669 to 0.999; P = .049). Within the IFN-α group, 33% of patients received sunitinib, and 32% received other vascular endothelial growth factor–signaling inhibitors after discontinuation from the trial. Median progression-free survival was 11 months for sunitinib compared with 5 months for IFN-α (P < .001). Objective response rate was 47% for sunitinib compared with 12% for IFN-α (P < .001). The most commonly reported sunitinib-related grade 3 adverse events included hypertension (12%), fatigue (11%), diarrhea (9%), and hand-foot syndrome (9%). Conclusion Sunitinib demonstrates longer overall survival compared with IFN-α plus improvement in response and progression-free survival in the first-line treatment of patients with metastatic RCC. The overall survival highlights an improved prognosis in patients with RCC in the era of targeted therapy. PMID:19487381

Hilar fat infiltration: A new prognostic factor in metastatic clear cell renal cell carcinoma with first-line sunitinib treatment.

PubMed

Kammerer-Jacquet, Solène-Florence; Brunot, Angelique; Bensalah, Karim; Campillo-Gimenez, Boris; Lefort, Mathilde; Bayat, Sahar; Ravaud, Alain; Dupuis, Frantz; Yacoub, Mokrane; Verhoest, Gregory; Peyronnet, Benoit; Mathieu, Romain; Lespagnol, Alexandra; Mosser, Jean; Edeline, Julien; Laguerre, Brigitte; Bernhard, Jean-Christophe; Rioux-Leclercq, Nathalie

2017-10-01

The selection of patients with metastatic clear cell renal cell carcinoma (ccRCC) who may benefit from targeted tyrosine kinase inhibitors has been a challenge, even more so now with the advent of new therapies. Hilar fat infiltration (HFI) is a validated prognostic factor in nonmetastatic ccRCC (TNM 2009 staging system) but has never been studied in metastatic patients. We aimed to assess its phenotype and prognostic effect in patients with metastatic ccRCC treated with first-line sunitinib. In a multicentric study, we retrospectively included 90 patients and studied the corresponding ccRCC at the pathological, immunohistochemical, and molecular levels. Patient and tumor characteristics were compared using univariate and multivariate analysis. All the features were then studied by Cox models for prognostic effect. HFI was found in 42 patients (46.7%), who had worse prognosis (Heng criteria) (P = 0.003), liver metastases (P = 0.036), and progressive diseases at first radiological evaluation (P = 0.024). The corresponding ccRCC was associated with poor pathological prognostic factors that are well known in nonmetastatic ccRCC. For these patients, median progression-free survival was 4 months vs. 13 months (P = 0.02), and median overall survival was 14 months vs. 29 months (P = 0.006). In a multivariate Cox model integrating all the variables, only poor prognosis, according to the Heng criteria and HFI, remained independently associated with both progression-free survival and overall survival. HFI was demonstrated for the first time to be an independent poor prognostic factor. Its potential role in predicting resistance to antiangiogenic therapy warrants further investigation. Copyright © 2017 Elsevier Inc. All rights reserved.

CPI-613 in Treating Patients With Advanced or Metastatic Bile Duct Cancer That Cannot Be Removed By Surgery

ClinicalTrials.gov

2018-05-22

Adult Primary Cholangiocellular Carcinoma; Advanced Adult Primary Liver Cancer; Cholangiocarcinoma of the Extrahepatic Bile Duct; Cholangiocarcinoma of the Gallbladder; Localized Unresectable Adult Primary Liver Cancer; Metastatic Extrahepatic Bile Duct Cancer; Recurrent Adult Primary Liver Cancer; Recurrent Extrahepatic Bile Duct Cancer; Unresectable Extrahepatic Bile Duct Cancer

Whole Blood mRNA Expression-Based Prognosis of Metastatic Renal Cell Carcinoma

PubMed Central

Sosa, Carlos P.; Hillman, David W.; Sanhueza, Cristobal; Dalpiaz, Candace L.; Costello, Brian A.; Quevedo, Fernando J.; Pitot, Henry C.; Dronca, Roxana S.; Ertz, Donna; Cheville, John C.; Donkena, Krishna Vanaja; Kohli, Manish

2017-01-01

The Memorial Sloan Kettering Cancer Center (MSKCC) prognostic score is based on clinical parameters. We analyzed whole blood mRNA expression in metastatic clear cell renal cell carcinoma (mCCRCC) patients and compared it to the MSKCC score for predicting overall survival. In a discovery set of 19 patients with mRCC, we performed whole transcriptome RNA sequencing and selected eighteen candidate genes for further evaluation based on associations with overall survival and statistical significance. In an independent validation of set of 47 patients with mCCRCC, transcript expression of the 18 candidate genes were quantified using a customized NanoString probeset. Cox regression multivariate analysis confirmed that two of the candidate genes were significantly associated with overall survival. Higher expression of BAG1 [hazard ratio (HR) of 0.14, p < 0.0001, 95% confidence interval (CI) 0.04–0.36] and NOP56 (HR 0.13, p < 0.0001, 95% CI 0.05–0.34) were associated with better prognosis. A prognostic model incorporating expression of BAG1 and NOP56 into the MSKCC score improved prognostication significantly over a model using the MSKCC prognostic score only (p < 0.0001). Prognostic value of using whole blood mRNA gene profiling in mCCRCC is feasible and should be prospectively confirmed in larger studies. PMID:29099775

Sapanisertib or Pazopanib Hydrochloride in Treating Patients With Locally Advanced or Metastatic Sarcoma

ClinicalTrials.gov

2018-06-20

High Grade Sarcoma; Metastatic Leiomyosarcoma; Metastatic Malignant Peripheral Nerve Sheath Tumor; Metastatic Synovial Sarcoma; Metastatic Undifferentiated Pleomorphic Sarcoma; Myxofibrosarcoma; Recurrent Leiomyosarcoma; Recurrent Malignant Peripheral Nerve Sheath Tumor; Recurrent Synovial Sarcoma; Recurrent Undifferentiated Pleomorphic Sarcoma; Uterine Corpus Leiomyosarcoma

A case of septic pulmonary embolism associated with renal abscess mimicking pulmonary metastases of renal malignancy.

PubMed

Jung, Jo Sung; Lee, Sang Mi; Kim, Han Jo; Jang, Si-Hyong; Lee, Jeong Won

2014-05-01

We report the case of a 46-year-old woman with acute febrile symptom who had multiple pulmonary nodules and a renal mass. She underwent (18)F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) to find a hidden malignancy and the cause of her fever. FDG PET/CT images demonstrated a renal mass and multiple lung nodules with intense FDG uptake, which was suspicious of a renal malignancy with multiple pulmonary metastatic lesions. CT-guided biopsies of the pulmonary and renal lesions only showed chronic inflammatory infiltrates without evidence of malignancy. She was diagnosed with septic pulmonary embolism from a renal abscess. One month after antibiotic treatment, the follow-up chest and abdomen CT showed improvement of the lung and renal lesions. This is the first case demonstrating the FDG PET/CT finding of septic pulmonary embolism associated with renal abscess in the published literature.

Advances in systemic delivery of anti-cancer agents for the treatment of metastatic cancer.

PubMed

Grundy, Megan; Coussios, Constantin; Carlisle, Robert

2016-07-01

The successful treatment of metastatic cancer is refractory to strategies employed to treat confined, primary lesions, such as surgical resection and radiation therapy, and thus must be addressed by systemic delivery of anti-cancer agents. Conventional systemically administered chemotherapeutics are often ineffective and come with severe dose-limiting toxicities. This review focuses on the recent developments in systemic therapy for metastatic cancer. Firstly, the strategies employed to improve the efficacy of conventional chemotherapeutics by 'passively' and 'actively' targeting them to tumors are discussed. Secondly, recent advances in the use of biologics to better target cancer and to instigate anti-tumor immunity are reviewed. Under the label of 'biologics', antibody-therapies, T cell engaging therapies, oncolytic virotherapies and cell-based therapies are examined and evaluated. Improving specificity of action, and engaging the immune system appear to be key goals in the development of novel or reformulated anti-cancer agents for the treatment of metastatic cancer. One of the largest areas of opportunity in this field will be the identification of robust predictive biomarkers for use in conjunction with these agents. Treatment regimens that combine an agent to elicit an immune response (such as an oncolytic virus), and an agent to potentiate/mediate that immune response (such as immune checkpoint inhibitors) are predicted to be more effective than treatment with either agent alone.

Genomics and epigenomics of clear cell renal cell carcinoma: recent developments and potential applications.

PubMed

Rydzanicz, Małgorzata; Wrzesiński, Tomasz; Bluyssen, Hans A R; Wesoły, Joanna

2013-12-01

Majority of clear cell renal cell carcinomas (ccRCCs) are diagnosed in the advanced metastatic stage resulting in dramatic decrease of patient survival. Thereby, early detection and monitoring of the disease may improve prognosis and treatment results. Recent technological advances enable the identification of genetic events associated with ccRCC and reveal significant molecular heterogeneity of ccRCC tumors. This review summarizes recent findings in ccRCC genomics and epigenomics derived from chromosomal aberrations, DNA sequencing and methylation, mRNA, miRNA expression profiling experiments. We provide a molecular insight into ccRCC pathology and recapitulate possible clinical applications of genomic alterations as predictive and prognostic biomarkers. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Long-term outcome of patients with multiple [corrected] myeloma-related advanced renal failure following auto-SCT.

PubMed

Glavey, S V; Gertz, M A; Dispenzieri, A; Kumar, S; Buadi, F; Lacy, M; Hayman, S R; Kapoor, P; Dingli, D; McCurdy, A; Hogan, W J; Gastineau, D A; Leung, N

2013-11-01

Renal failure commonly complicates multiple myeloma (MM) and is associated with reduced survival. It is not clear whether auto-SCT results in improved renal function or attainment of independence from dialysis in patients with advanced renal impairment due to MM. We conducted a retrospective cohort study of all patients who underwent auto-SCT for MM complicated by advanced renal failure at our institution over a 10-year period (2000-2010). We aimed to assess the association between auto-SCT and renal outcome in patients with serum creatinine (SCr) over 3 mg/dL, attributable to MM, including those who were dialysis dependent. Thirty patients (2.8% of all auto-SCT patients) met inclusion criteria. Fourteen of 15 patients who were dialysis dependent before auto-SCT remained dialysis dependent in the long term despite hematological response (HR). Of the remaining 15 patients with SCr >3 mg/dL, an improvement in glomerular filtration rate (GFR) from 15 to 19.4 mL/min/1.73 m(2) was noted post auto-SCT (P=0.035); however, neither HR post auto-SCT or pre-existing renal function were independently associated with renal outcome. Auto-SCT was not associated with independence from dialysis in patients with renal failure due to MM at our institution. Although auto-SCT was associated with an improvement in GFR in patients with SCr >3 mg/dL, this improvement was not related to HR.

Glembatumumab Vedotin, Nivolumab, and Ipilimumab in Treating Patients With Advanced Metastatic Solid Tumors That Cannot Be Removed by Surgery

ClinicalTrials.gov

2018-06-11

Advanced Malignant Solid Neoplasm; Estrogen Receptor Negative; GPNMB Positive; HER2/Neu Negative; Metastatic Malignant Solid Neoplasm; Metastatic Melanoma; Progesterone Receptor Negative; Stage III Breast Cancer AJCC v7; Stage III Cutaneous Melanoma AJCC v7; Stage III Uveal Melanoma AJCC v7; Stage IIIA Cutaneous Melanoma AJCC v7; Stage IIIB Cutaneous Melanoma AJCC v7; Stage IIIC Cutaneous Melanoma AJCC v7; Stage IV Breast Cancer AJCC v6 and v7; Stage IV Cutaneous Melanoma AJCC v6 and v7; Stage IV Uveal Melanoma AJCC v7; Triple-Negative Breast Carcinoma; Unresectable Solid Neoplasm

Targeted agents for patients with advanced/metastatic pancreatic cancer: A protocol for systematic review and network meta-analysis.

PubMed

Di, Baoshan; Pan, Bei; Ge, Long; Ma, Jichun; Wu, Yiting; Guo, Tiankang

2018-03-01

Pancreatic cancer (PC) is a devastating malignant tumor. Although surgical resection may offer a good prognosis and prolong survival, approximately 80% patients with PC are always diagnosed as unresectable tumor. National Comprehensive Cancer Network's (NCCN) recommended gemcitabine-based chemotherapy as efficient treatment. While, according to recent studies, targeted agents might be a better available option for advanced or metastatic pancreatic cancer patients. The aim of this systematic review and network meta-analysis will be to examine the differences of different targeted interventions for advanced/metastatic PC patients. We will conduct this systematic review and network meta-analysis using Bayesian method and according to Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) statement. To identify relevant studies, 6 electronic databases including PubMed, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of science, CNKI (Chinese National Knowledge Infrastructure), and CBM (Chinese Biological Medical Database) will be searched. The risk of bias in included randomized controlled trials (RCTs) will be assessed using the Cochrane Handbook version 5.1.0. And we will use GRADE approach to assess the quality of evidence from network meta-analysis. Data will be analyzed using R 3.4.1 software. To the best of our knowledge, this systematic review and network meta-analysis will firstly use both direct and indirect evidence to compare the differences of different targeted agents and targeted agents plus chemotherapy for advanced/metastatic pancreatic cancer patients. This is a protocol of systematic review and meta-analysis, so the ethical approval and patient consent are not required. We will disseminate the results of this review by submitting to a peer-reviewed journal.

Learning curve for the management of tyrosine kinase inhibitors as the first line of treatment for patients with metastatic renal cancer.

PubMed

Lendínez-Cano, G; Osman García, I; Congregado Ruiz, C B; Conde Sánchez, J M; Medina López, R A

2018-03-07

To analyse the learning curve for the management of tyrosine kinase inhibitors as the first line of treatment for patients with metastatic renal cancer. We evaluated 32 consecutive patients treated in our department for metastatic renal cancer with tyrosine kinase inhibitors (pazopanib or sunitinib) as first-line treatment between September 2012 and November 2015. We retrospectively analysed this sample. We measured the time to the withdrawal of the first-line treatment, the time to progression and overall survival using Kaplan-Meier curves. The learning curve was analysed with the cumulative sum (CUSUM) methodology. In our series, the median time to the withdrawal of the first-line treatment was 11 months (95% CI 4.9-17.1). The mean time to progression was 30.4 months (95% CI 22.7-38.1), and the mean overall survival was 34.9 months (95% CI 27.8-42). By applying the CUSUM methodology, we obtained a graph for the CUSUM value of the time to withdrawal of the first-line treatment (CUSUM TW), observing 3 well-differentiated phases: phase 1 or initial learning phase (1-15), phase 2 (16-26) in which the management of the drug progressively improved and phase 3 (27-32) of maximum experience or mastery of the management of these drugs. The number of treated patients needed to achieve the proper management of these patients was estimated at 15. Despite the limitations of the sample size and follow-up time, we estimated (in 15 patients) the number needed to reach the necessary experience in the management of these patients with tyrosine kinase inhibitors. We observed no relationship between the time to the withdrawal of the first-line treatment for any cause and progression. Copyright © 2018 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.

Sunitinib benefits patients with renal cell carcinoma

Cancer.gov

Findings from clinical trial patients with metastatic renal cell carcinoma, a common kidney cancer, show they did not have accelerated tumor growth after treatment with sunitinib, in contrast to some study results in animals.

Podocalyxin EBP50 Ezrin Molecular Complex Enhances the Metastatic Potential of Renal Cell Carcinoma Through Recruiting Rac1 Guanine Nucleotide Exchange Factor ARHGEF7

PubMed Central

Hsu, Yung-Ho; Lin, Wei-Ling; Hou, Yi-Ting; Pu, Yeong-Shiau; Shun, Chia-Tung; Chen, Chi-Ling; Wu, Yih-Yiing; Chen, Jen-Yau; Chen, Tso-Hsiao; Jou, Tzuu-Shuh

2010-01-01

Podocalyxin was initially identified in glomerular podocytes to critically maintain the structural and functional integrity of the glomerular ultrafiltrative apparatus. Lately, it has emerged as a malignant marker in tumors arising from a variety of tissue origins. By immunohistochemistry, we identified that 9.6% of renal cell carcinoma patients overexpress this protein. This subset of patients had significantly shorter disease-specific and overall survivals, and, importantly, we established podocalyxin overexpression as an independent prognostic factor for latent distant metastasis with multivariate analysis. Podocalyxin down-regulation by small interfering RNA led to defective migration in model renal tubular cells, which was corrected by re-expression of podocalyxin. The activity of the small GTPase Rac1, a well-characterized modulator of cell migration, was diminished by podocalyxin knock-down. Conversely, podocalyxin overexpression in human embryonic kidney cells up-regulated Rac1 activity, which depended on a complex formed by podocalyxin, ERM-binding phosphoprotein 50, ezrin, and ARHGEF7, a Rac1 activator. Therefore, podocalyxin can serve as a biomarker to identify renal cell carcinoma patients with higher metastatic potential for more aggressive intervention at earlier clinical stages. PMID:20395446

Outcome of papillary versus clear cell renal cell carcinoma varies significantly in non-metastatic disease

PubMed Central

Edelmann, Dominic; Benner, Axel; Zigeuner, Richard; Borgmann, Hendrik; Wolff, Ingmar; Krabbe, Laura M.; Musquera, Mireia; Dell’Oglio, Paolo; Capitanio, Umberto; Klatte, Tobias; Cindolo, Luca; May, Matthias; Brookman-May, Sabine D.

2017-01-01

Renal cell carcinoma (RCC) comprises a heterogenous group of tumors. Traditionally, papillary RCC (pRCC) is associated with a favorable outcome compared to clear cell RCC (ccRCC), while other series report equivalent or worse prognosis. In this paper we comparatively evaluate outcome of pRCC versus ccRCC in two large multi-institutional databases (cohort study), including distribution of pRCC subtypes 1 and 2. Retrospective data of 1,943 surgically treated pRCC patients from 17 European/ North American centers between 1984–2015 were compared to 5,600 ccRCC patients from a database comprising 11 European/ North American centers (1984–2011). Median follow-up was 64.6 months. Differences between pRCC, subtypes, and ccRCC were compared with t-tests, Chi^2-tests, and exact Fisher tests. Cancer-specific mortality was analyzed with cumulative incidence curves and Cox cause-specific hazard models. The robustness of our results was examined with sensitivity analyses. We present that cancer-specific mortality rates and variables as stage, lymph node, and distant metastasis differ significantly between groups. Furthermore, we demonstrate that patients with non-metastatic pRCC had a significantly better cancer-specific mortality (HR 0.76, p = 0.007), when compared to ccRCC. Additionally, pRCC type 2 versus ccRCC exhibited no difference in cancer-specific mortality (HR 0.9, p = 0.722), whereas pRCC type 1 versus ccRCC displayed a risk of death reduced by 69% (p = 0.044). Taken together, outcome of pRCC versus ccRCC varies significantly in non-metastatic disease. Furthermore, pRCC type 2 exhibited no difference in cancer-specific mortality, whereas pRCC type 1 displayed a significantly reduced risk of death. Consequently, there is urgent need to respect histopathological entities and their subtypes, when assigning follow-up or targeted therapy to RCC patients. PMID:28934212

Phase I Study of Concomitant Pemetrexed and Cisplatin Plus External Beam Radiation Therapy in Patients with Locally Advanced or Metastatic Esophageal or Gastroesophageal Junction Carcinomas.

PubMed

Elquza, Emad; Babiker, Hani M; Howell, Krisha J; Kovoor, Andrew I; Brown, Thomas David; Patel, Hitendra; Malangone, Steven A; Borad, Mitesh J; Dragovich, Tomislav

2016-01-01

To establish the maximum tolerated dose (MTD) and safety profile of bi-weekly Pemetrexed (PEM) when combined with weekly cisplatin (CDDP) and standard dose external beam radiation (EBRT) in patients with locally advanced or metastatic esophageal and gastroesophageal junction (GEJ) carcinomas. We conducted an open label, single institution, phase I dose escalation study designed to evaluate up to 15-35 patients with advanced or metastatic esophageal and GEJ carcinomas. 10 patients were treated with bi-weekly PEM, weekly CDDP, and EBRT. The MTD of bi-weekly PEM was determined to be 500 mg/m(2).

Vascular Functional Imaging and Physiological Environment of Hyperplasia, Non-Metastatic and Metastatic Breast Cancer

DTIC Science & Technology

1997-10-01

Specific Aim 1). The overall goal of this research proposal is to use noninvasive Magnetic Resonance (MR) Imaging (I) and Spectroscopy (S) to answer the... spectroscopy in establishing the role of nm23 genes in tumor metabolism and metastatic dissemination. INTRODUCTION Despite continuing advances in the...cellular mechanisms by which the nm23 protein suppresses metastatic phenotypic expression is as yet unknown. Here we have used 3 1P NMR spectroscopy to

A network meta-analysis on the efficacy of sixteen targeted drugs in combination with chemotherapy for treatment of advanced/metastatic colorectal cancer

PubMed Central

Ba-Sang, Dan-Zeng; Long, Zi-Wen; Teng, Hao; Zhao, Xu-Peng; Qiu, Jian; Li, Ming-Shan

2016-01-01

Objective A network meta-analysis was conducted comparing the short-term efficacies of 16 targeted drugs in combination with chemotherapy for treatment of advanced/metastatic colorectal cancer (CRC). Results Twenty-seven RCTs were ultimately incorporated into this network meta-analysis. Compared with chemotherapy alone, bevacizumab + chemotherapy, panitumumab + chemotherapy and conatumumab + chemotherapy had higher PR rate. Bevacizumab + chemotherapy, cetuximab + chemotherapy, panitumumab + chemotherapy, trebananib + chemotherapy and conatumumab + chemotherapy had higher ORR rate in comparison to chemotherapy alone. Furthermore, bevacizumab + chemotherapy had higher DCR rate than chemotherapy alone. The results of our cluster analysis showed that chemotherapy combined with bevacizumab, cetuximab, panitumumab, conatumumab, ganitumab, or brivanib + cetuximab had better efficacies for the treatment of advanced/metastatic CRC in comparison to chemotherapy alone. Materials and Methods Electronic databases were comprehensively searched for potential and related randomized controlled trials (RCTs). Direct and indirect evidence were incorporated for evaluation of stable disease (SD), progressive disease (PD), complete response (CR), partial response (PR), disease control rate (DCR) and overall response ratio (ORR) by calculating odds ratio (OR) and 95% confidence intervals (CI), and using the surface under the cumulative ranking curve (SUCRA). Conclusions These results indicated that bevacizumab + chemotherapy, panitumumab + chemotherapy, conatumumab + chemotherapy and brivanib + cetuximab + chemotherapy may have better efficacies for the treatment of advanced/metastatic CRC. PMID:27806321

Carbonic anhydrase IX as a potential biomarker of efficacy in metastatic clear-cell renal cell carcinoma patients receiving sorafenib or placebo: analysis from the treatment approaches in renal cancer global evaluation trial (TARGET).

PubMed

Choueiri, Toni K; Cheng, Suchun; Qu, Angela Q; Pastorek, Jaromir; Atkins, Michael B; Signoretti, Sabina

2013-11-01

Retrospective data analyses have suggested that carbonic anhydrase IX (CAIX) may have a predictive role in patients with metastatic clear cell renal cell carcinoma (ccRCC) receiving high dose interleukin-2 or sorafenib. We examined the predictive value of CAIX in estimating treatment outcome in patients receiving sorafenib vs. placebo as part of the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) study. Paraffin embedded tumor tissues were collected from 133 patients from the TARGET study (n = 903). The percentage of CAIX-positive cells was assessed by a single pathologist. The impact of CAIX expression on progression-free survival (PFS, primary endpoint) and tumor shrinkage (TS, secondary endpoint) was analyzed. Clinical characteristics were similarly distributed between patients with low vs. high CAIX staining, as well as patients with available CAIX data vs. not. Median PFS for patients with high CAIX vs. low CAIX expression was 5.5 and 5.4 months, respectively, on the sorafenib arm (P = 0.97), and 1.5 and 1.7 months on the placebo arm (P = 0.76). Median TS for patients with high CAIX status was -14.9% vs. -12.6% in patients with low CAIX status (P = 0.63) on the sorafenib arm, and +1.3% (high CAIX) vs. +4.8% (low CAIX) in patients on the placebo arm (P = 0.60). Despite suggestive retrospective evidence, data from the TARGET study did not find CAIX expression status to be either predictive of clinical benefit for treatment with sorafenib or of prognostic value in patients with metastatic ccRCC following cytokine therapy. Copyright © 2013 Elsevier Inc. All rights reserved.

Renal cell metastases versus liver hemangioma.

PubMed

Mydlo, J H; Shore, N; Herr, H W

1991-03-01

We present the case of a man with presumed metastatic renal cell carcinoma based on radiologic examination and weight loss, who refused treatment of any kind for one year. A surgical exploration to control hematuria revealed a Stage I tumor.

[Efficacy and safety of TS-1 monotherapy for advanced/metastatic breast cancer - an observational study by the Kumamoto Breast Cancer Cooperative Group(KBCCG)].

PubMed

Yamamoto, Yutaka; Nishimura, Reiki; Tanigawa, Tomio; Kawano, Ichiro; Hayashi, Kyoji; Kuramoto, Masafumi; Yamamoto-Ibusuki, Mutsuko; Iwase, Hirotaka

2014-10-01

TS-1, an oral fluoropyrimidine, is known to be effective for the treatment of various carcinomas including advanced/metastatic breast cancer.The Kumamoto Breast Cancer Cooperative Group(KBCCG)conducted an observational study, wherein, the efficacy and safety of TS-1 monotherapy was analyzed in 35 patients with recurrent or metastatic breast cancer.The median time to cancer progression was 3.7 months, overall response rate was 12%, and clinical benefit rate was 32%. Adverse events were observed in 27 patients(77%), and adverse events of Grade >3 were observed in 7 patients(20%). The rate of treatment-related Grade 3 and 4 adverse events increased, and was associated with poor levels of creatinine clearance(Ccr)ie <60mL/min.This study suggests that TS-1 monotherapy can potentially be used as a salvage treatment for advanced/metastatic breast cancer owing to its safety and efficacy.Measuring the level of Ccr before TS-1 therapy should be considered to avoid severe adverse events.

Sarcomatoid renal cell carcinoma: Biology and treatment advances.

PubMed

Mouallem, Nemer El; Smith, Steven C; Paul, Asit K

2018-06-01

Sarcomatoid transformation in renal cell carcinoma, so called sacromatoid RCC (sRCC), is associated with an aggressive behavior and a poor prognosis. Current therapeutic approaches are largely ineffective. Recent studies looking into the genomic and molecular characterization of sRCCs have provided insights into the biology and pathogenesis of this entity. These advances in molecular signatures may help development of effective treatment strategies. We herein present a review of recent developments in the pathology, biology, and treatment modalities in sRCC. Copyright © 2017 Elsevier Inc. All rights reserved.

Efficacy and safety of sorafenib for advanced renal cell carcinoma: real-world data of patients with renal impairment.

PubMed

Tatsugami, Katsunori; Oya, Mototsugu; Kabu, Koki; Akaza, Hideyuki

2018-04-10

We retrospectively analysed the efficacy and safety of sorafenib in patients with advanced renal cell carcinoma with renal impairment. Patients were divided into two groups by an estimated glomerular filtration rate (eGFR) cut-off of 45 mL/min/1.73 m 2 . Background factors considered to affect prognosis were well balanced by propensity score matching between the groups. Demographics, dose modification, adverse events, tumour response, progression-free survival, and renal function (eGFR) were evaluated. Among 935 and 2008 patients with an eGFR of <45 and ≥45, respectively, 613 pairs were matched. The mean starting dose was significantly lower in patients with an eGFR of <45; however, the mean daily dose, median treatment duration, progression-free survival, and tumour response were similar between the groups. In terms of safety, no significant differences were found in serious adverse events, although cytopaenia (16.6% vs 10.6%) and renal dysfunction (4.4% vs 0.7%) were higher in patients with an eGFR of <45 than ≥45 in all adverse events. There were also no differences in dose modification, including dose reduction, dose interruption, and treatment discontinuation. Throughout the 12-month observation period, sorafenib in patients with an eGFR of <45 and ≥45 showed similar safety and efficacy, and treatment was continued without affecting renal function.

Immune checkpoint inhibitors in advanced renal cell carcinoma: experience to date and future directions.

PubMed

Atkins, M B; Clark, J I; Quinn, D I

2017-07-01

In recent years, there has been dramatic expansion of the treatment armamentarium for patients with advanced renal cell carcinoma (aRCC), including drugs targeting vascular endothelial growth factor and mammalian target of rapamycin (mTOR) pathways. Despite these advances, patient outcomes remain suboptimal, underscoring the need for therapeutic interventions with novel mechanisms of action. The advent of immunotherapy with checkpoint inhibitors has led to significant changes in the treatment landscape for several solid malignancies. Specifically, drugs targeting the programmed death 1 (PD-1) and cytotoxic T-lymphocyte associated antigen (CTLA-4) pathways have demonstrated considerable clinical efficacy and gained regulatory approval as single-agent or combination therapy for the treatment of patients with metastatic melanoma, non-small cell lung cancer, aRCC, advanced squamous cell carcinoma of the head and neck, urothelial cancer and Hodgkin lymphoma. In aRCC, the PD-1 inhibitor nivolumab was approved in both the United States and Europe for the treatment of patients who have received prior therapy, based on improved overall survival compared with the mTOR inhibitor everolimus. Other checkpoint inhibitors, including the CTLA-4 inhibitor ipilimumab in combination with several agents, and the PD-L1 inhibitor atezolizumab, are in various stages of clinical development in patients with aRCC. In this review, current evidence related to the clinical use of checkpoint inhibitors for the treatment of patients with aRCC is discussed, including information on the frequency and management of unconventional responses and the management of immune-related adverse events. In addition, perspectives on the future use of checkpoint inhibitors are discussed, including the potential value of treatment beyond progression, the potential use in earlier lines of care or in combination with other agents, and the identification of biomarkers to guide patient selection and enable

Readiness to participate in advance care planning: A qualitative study of renal failure patients, families and healthcare providers.

PubMed

Hutchison, Lauren A; Raffin-Bouchal, Donna S; Syme, Charlotte A; Biondo, Patricia D; Simon, Jessica E

2017-09-01

Objectives Advance care planning is the process by which people reflect upon their wishes and values for healthcare, discuss their choices with family and friends and document their wishes. Readiness represents a key predictor of advance care planning participation; however, the evidence for addressing readiness is scarce within the renal failure context. Our objectives were to assess readiness for advance care planning and barriers and facilitators to advance care planning uptake in a renal context. Methods Twenty-five participants (nine patients, nine clinicians and seven family members) were recruited from the Southern Alberta Renal Program. Semi-structured interviews were recorded, transcribed and then analyzed using interpretive description. Results Readiness for advance care planning was driven by individual values perceived by a collaborative encounter between clinicians and patients/families. If advance care planning is not valued, then patients/families and clinicians are not ready to initiate the process. Patients and clinicians are delaying conversations until "illness burden necessitates," so there is little "advance" care planning, only care planning in-the-moment closer to the end of life. Discussion The value of advance care planning in collaboration with clinicians, patients and their surrogates needs reframing as an ongoing process early in the patient's illness trajectory, distinguished from end-of-life decision making.

Contrast media enhancement reduction predicts tumor response to presurgical molecular-targeting therapy in patients with advanced renal cell carcinoma.

PubMed

Hosogoe, Shogo; Hatakeyama, Shingo; Kusaka, Ayumu; Hamano, Itsuto; Tanaka, Yoshimi; Hagiwara, Kazuhisa; Hirai, Hideaki; Morohashi, Satoko; Kijima, Hiroshi; Yamamoto, Hayato; Tobisawa, Yuki; Yoneyama, Tohru; Yoneyama, Takahiro; Hashimoto, Yasuhiro; Koie, Takuya; Ohyama, Chikara

2017-07-25

A quantitative tumor response evaluation to molecular-targeting agents in advanced renal cell carcinoma (RCC) is debatable. We aimed to evaluate the relationship between radiologic tumor response and pathological response in patients with advanced RCC who underwent presurgical therapy. Of 34 patients, 31 underwent scheduled radical nephrectomy. Presurgical therapy agents included axitinib (n = 26), everolimus (n = 3), sunitinib (n = 1), and axitinib followed by temsirolimus (n = 1). The major presurgical treatment-related adverse event was grade 2 or 3 hypertension (44%). The median radiologic tumor response by RECIST, Choi, and CMER were -19%, -24%, and -49%, respectively. Among the radiologic tumor response tests, CMER showed a higher association with tumor necrosis in surgical specimens than others. Ki67/MIB1 status was significantly decreased in surgical specimens than in biopsy specimens. The magnitude of the slope of the regression line associated with the tumor necrosis percentage was greater in CMER than in Choi and RECIST. Between March 2012 and December 2016, we prospectively enrolled 34 locally advanced and/or metastatic RCC who underwent presurgical molecular-targeting therapy followed by radical nephrectomy. Primary endpoint was comparison of radiologic tumor response among Response Evaluation Criteria in Solid Tumors (RECIST), Choi, and contrast media enhancement reduction (CMER). Secondary endpoint included pathological downstaging, treatment related adverse events, postoperative complications, Ki67/MIB1 status, and tumor necrosis. CMER may predict tumor response after presurgical molecular-targeting therapy. Larger prospective studies are needed to develop an optimal tumor response evaluation for molecular-targeting therapy.

External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study

PubMed Central

Heng, Daniel Y C; Xie, Wanling; Regan, Meredith M; Harshman, Lauren C; Bjarnason, Georg A; Vaishampayan, Ulka N; Mackenzie, Mary; Wood, Lori; Donskov, Frede; Tan, Min-Han; Rha, Sun-Young; Agarwal, Neeraj; Kollmannsberger, Christian; Rini, Brian I; Choueiri, Toni K

2014-01-01

Summary Background The International Metastatic Renal-Cell Carcinoma Database Consortium model offers prognostic information for patients with metastatic renal-cell carcinoma. We tested the accuracy of the model in an external population and compared it with other prognostic models. Methods We included patients with metastatic renal-cell carcinoma who were treated with first-line VEGF-targeted treatment at 13 international cancer centres and who were registered in the Consortium’s database but had not contributed to the initial development of the Consortium Database model. The primary endpoint was overall survival. We compared the Database Consortium model with the Cleveland Clinic Foundation (CCF) model, the International Kidney Cancer Working Group (IKCWG) model, the French model, and the Memorial Sloan-Kettering Cancer Center (MSKCC) model by concordance indices and other measures of model fit. Findings Overall, 1028 patients were included in this study, of whom 849 had complete data to assess the Database Consortium model. Median overall survival was 18·8 months (95% 17·6–21·4). The predefined Database Consortium risk factors (anaemia, thrombocytosis, neutrophilia, hypercalcaemia, Karnofsky performance status <80%, and <1 year from diagnosis to treatment) were independent predictors of poor overall survival in the external validation set (hazard ratios ranged between 1·27 and 2·08, concordance index 0·71, 95% CI 0·68–0·73). When patients were segregated into three risk categories, median overall survival was 43·2 months (95% CI 31·4–50·1) in the favourable risk group (no risk factors; 157 patients), 22·5 months (18·7–25·1) in the intermediate risk group (one to two risk factors; 440 patients), and 7·8 months (6·5–9·7) in the poor risk group (three or more risk factors; 252 patients; p<0·0001; concordance index 0·664, 95% CI 0·639–0·689). 672 patients had complete data to test all five models. The concordance index of the CCF

A phase 2 study of the sphingosine-1-phosphate antibody sonepcizumab in patients with metastatic renal cell carcinoma.

PubMed

Pal, Sumanta K; Drabkin, Harry A; Reeves, James A; Hainsworth, John D; Hazel, Susan E; Paggiarino, Dario A; Wojciak, Jon; Woodnutt, Gary; Bhatt, Rupal S

2017-02-15

Upregulation of sphingosine-1-phosphate (S1P) may mediate resistance to vascular endothelial growth factor (VEGF)-directed therapies and inhibit antitumor immunity. Antagonism of S1P in preclinical models appears to overcome this resistance. In this phase 2 study, the authors assessed the activity of sonepcizumab, a first-in-class inhibitor of S1P, in patients with metastatic renal cell carcinoma (mRCC) with a history of prior VEGF-directed therapy. Patients were required to have clear cell mRCC and to have received treatment with at least 1 prior VEGF-directed agent. Prior treatment with immunotherapeutic agents and ≤1 mammalian target of rapamycin inhibitors was permitted. The primary endpoint of the study was progression-free survival. Additional endpoints included response rate and safety, and overall survival (OS) performed post hoc. A total of 40 patients were enrolled with a median of 3 prior therapies (range, 1-5 prior therapies), 78% of whom had intermediate-risk disease by second-line International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. Although the current study did not achieve its primary endpoint based on the 2-month progression-free survival, a median OS of 21.7 months was observed. Four patients (10%) demonstrated a partial response, with a median duration of response of 5.9 months. No grade 3/4 treatment-related adverse events were observed in >5% of patients (adverse events were graded and recorded for each patient using Common Terminology Criteria for Adverse Events [version 4.0]); the most frequent grade 1/2 treatment-related adverse events were fatigue (30%), weight gain (18%), constipation (15%), and nausea (15%). Biomarker studies demonstrated an increase in S1P concentrations with therapy. Comprehensive genomic profiling of 3 patients with a clinical benefit of >24 months indicated von Hippel-Lindau (VHL) and polybromo-1 (PBRM1) alterations. The encouraging OS and favorable safety profile observed with

Interleukin-21: updated review of Phase I and II clinical trials in metastatic renal cell carcinoma, metastatic melanoma and relapsed/refractory indolent non-Hodgkin's lymphoma.

PubMed

Hashmi, Mehmood H; Van Veldhuizen, Peter J

2010-05-01

In advanced renal cell cancer and malignant melanoma, the current FDA approved immune modulators, such as IL-2, are the only agents which provide a durable complete remission. These responses, however, occur in < 10% of treated patients and their applicability is limited to selected patients because of their toxicity. The identification of new immunotherapeutic agents with an improved response rate and toxicity profile would represent a significant advancement in the treatment of these malignancies. This is a comprehensive review of IL-21 including its pharmacology and current developmental status. A literature review was performed using all PubMed listed publications involving IL-21, including original research articles, reviews and abstracts. It also includes a review of current ongoing trials and information from the official product website. Recombinant IL-21 (rIL-21) is a new immune modulator currently undergoing Phase I and II testing. It is a cytokine with a four helix structure that has structural and sequence homology to IL-2 and -15, but also possesses many unique biological properties. In this review, we evaluate the development, pharmacologic properties, safety profile and current clinical efficacy of rIL-21. rIL-21 has an acceptable safety profile and encouraging single agent activity in early phase renal cell carcinoma and melanoma clinical trials.

Piwi-interacting RNAs as novel prognostic markers in clear cell renal cell carcinomas.

PubMed

Busch, Jonas; Ralla, Bernhard; Jung, Monika; Wotschofsky, Zofia; Trujillo-Arribas, Elena; Schwabe, Philipp; Kilic, Ergin; Fendler, Annika; Jung, Klaus

2015-06-14

Piwi-interacting RNAs (piRNAs) are small RNAs of 27-30 nucleotides mapping to transposons or clustering in repeat genomic regions. Preliminary studies suggest an important role in cancerogenesis. This study is the first one investigating their prognostic impact in clear cell renal cell cancer (ccRCC) patients. Three piRNAs (piR-30924, piR-57125, and piR-38756) selected on the basis of initial piRNA microarray analyses were determined using RT-qPCR in non-metastatic (n = 76) and metastatic (n = 30) ccRCC tissue at the time of nephrectomy in comparison to normal renal tissue (n = 77) and tissue from distant ccRCC metastases (n = 13). Primary clinical end points were recurrence-free and overall survival. piR-57125 showed lower expression in metastatic than in non-metastatic tumors, whereas the expression of piR-30924 and piR-38756 increased in metastatic tumors. The higher expression of piR-30924 and piR-38756 as well as the lower expression of piR-57125 in metastatic primary tumors were significantly associated with tumor recurrence and overall survival. Multivariate Cox regression analyses revealed both piR-30924 and piR-57125 as independent prognostic predictors. This impact was even more pronounced in non-metastatic patients. This study demonstrates that the expression levels of these piRNAs in primary non-metastatic and metastatic ccRCC tissue can serve as potential prognostic biomarkers in combination with clinicopathological factors.

Cost-effectiveness of pazopanib versus sunitinib for metastatic renal cell carcinoma in the United Kingdom

PubMed Central

Amdahl, Jordan; Diaz, Jose; Sharma, Arati; Park, Jinhee; Chandiwana, David

2017-01-01

Background Sunitinib and pazopanib are the only two targeted therapies for the first-line treatment of locally advanced or metastatic renal cell carcinoma (mRCC) recommended by the United Kingdom’s National Institute for Health and Care Excellence. Pazopanib demonstrated non-inferior efficacy and a differentiated safety profile versus sunitinib in the phase III COMPARZ trial. The current analysis provides a direct comparison of the cost-effectiveness of pazopanib versus sunitinib from the perspective of the United Kingdom’s National Health Service based on data from COMPARZ and other sources. Methods A partitioned-survival analysis model with three health states (alive with no progression, alive with progression, or dead) was used to estimate the incremental cost per quality-adjusted life-year (QALY) gained for pazopanib versus sunitinib over five years (duration of follow-up for final survival analysis in COMPARZ). The proportion of patients in each health state over time was based on Kaplan–Meier distributions for progression-free and overall survival from COMPARZ. Utility values were based on EQ-5D data from the pivotal study of pazopanib versus placebo. Costs were based on medical resource utilisation data from COMPARZ and unit costs from secondary sources. Probabilistic and deterministic sensitivity analyses were conducted to assess uncertainty of model results. Results In the base case, pazopanib was estimated to provide more QALYs (0.0565, 95% credible interval [CrI]: −0.0920 to 0.2126) at a lower cost (−£1,061, 95% CrI: −£4,328 to £2,067) versus sunitinib. The probability that pazopanib yields more QALYs than sunitinib was estimated to be 76%. For a threshold value of £30,000 per QALY gained, the probability that pazopanib is cost-effective versus sunitinib was estimated to be 95%. Pazopanib was dominant in most scenarios examined in deterministic sensitivity analyses. Conclusions Pazopanib is likely to be a cost-effective treatment option

Trametinib and Navitoclax in Treating Patients With Advanced or Metastatic Solid Tumors

ClinicalTrials.gov

2018-06-08

Advanced Malignant Solid Neoplasm; KRAS Gene Mutation; Metastatic Malignant Solid Neoplasm; NRAS Gene Mutation; Recurrent Colorectal Carcinoma; Recurrent Lung Carcinoma; Recurrent Malignant Solid Neoplasm; Recurrent Pancreatic Carcinoma; Stage III Colorectal Cancer AJCC v7; Stage III Lung Cancer AJCC v7; Stage III Pancreatic Cancer AJCC v6 and v7; Stage IIIA Colorectal Cancer AJCC v7; Stage IIIB Colorectal Cancer AJCC v7; Stage IIIC Colorectal Cancer AJCC v7; Stage IV Colorectal Cancer AJCC v7; Stage IV Lung Cancer AJCC v7; Stage IV Pancreatic Cancer AJCC v6 and v7; Stage IVA Colorectal Cancer AJCC v7; Stage IVB Colorectal Cancer AJCC v7; Unresectable Malignant Neoplasm

A retrospective review of combination chemohormonal therapy as initial treatment for locally advanced or metastatic adenocarcinoma of the prostate.

PubMed

Amato, Robert J; Teh, Bin S; Henary, Haby; Khan, Muhammad; Saxena, Somyata

2009-01-01

Chemotherapy for hormone-refractory prostate cancer reduces PSA levels and enhances overall survival (OS), suggesting that administration in earlier disease stages may be beneficial. If expansion of an androgen-independent clone present during androgen deprivation mediates the transformation from an androgen-dependent to an androgen-independent phenotype, combination chemohormonal therapy would be effective initial treatment for locally advanced or metastatic prostate cancers. A retrospective review was conducted to evaluate results. Chemohormonal therapy outcomes were retrospectively evaluated in men with locally advanced or metastatic prostate cancer seen at our institution between January 2001 and February 2003. Chemotherapy consisted of three 8-week cycles (once weekly intravenous doxorubicin 20 mg/m(2) and thrice daily oral ketoconazole 400 mg in weeks 1, 3, and 5; once weekly intravenous docetaxel 35 mg/m(2) and thrice daily oral estramustine 280 mg in weeks 2, 4, and 6; and no therapy in weeks 7 and 8). Hormone therapy consisted of hormonal ablation during and after antiandrogen therapy after chemotherapy. Data for 31 men (median age, 63 years [range, 41-74 years]; white, 97% [30/31]) were reviewed. At 1 year, median PSA level had fallen 99.3% (range, 91.7%-99.9%) from a baseline value of 14.3 ng/ml (range, 1.9-497.9 ng/mL). Median time to progression was 34+ months (range, 14-68+ months). Median OS was 56+ months (range, 17-73+ months). Combination chemohormonal therapy for locally advanced or metastatic prostate cancer safely and effectively reduces PSA levels and increases OS. We are now testing this approach in a prospective, Phase II randomized clinical trial.

Everolimus and Vatalanib in Treating Patients With Advanced Solid Tumors

ClinicalTrials.gov

2018-01-12

Gastrinoma; Glucagonoma; Insulinoma; Metastatic Gastrointestinal Carcinoid Tumor; Metastatic Pheochromocytoma; Pancreatic Polypeptide Tumor; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Islet Cell Carcinoma; Recurrent Melanoma; Recurrent Neuroendocrine Carcinoma of the Skin; Recurrent Non-small Cell Lung Cancer; Recurrent Pheochromocytoma; Recurrent Renal Cell Cancer; Somatostatinoma; Stage III Neuroendocrine Carcinoma of the Skin; Stage IV Melanoma; Stage IV Non-small Cell Lung Cancer; Stage IV Renal Cell Cancer; Thyroid Gland Medullary Carcinoma; Unspecified Adult Solid Tumor, Protocol Specific

Primary Adult Renal Ewing's Sarcoma: A Rare Entity

PubMed Central

Mukkunda, Ravindra; Venkitaraman, Ramachandran; Thway, Khin; Min, Toon; Fisher, Cyril; Horwich, Alan; Judson, Ian

2009-01-01

Background. Ewing's sarcoma of extraskeletal origin is uncommon and that is of primary renal origin in adults are rare. There is no consensus on the optimal management of Ewing's tumors of renal origin. Methods. A retrospective review of the clinical features, treatment, and outcome of adult patients with primary renal extra-skeletal Ewing's sarcoma who were treated at the Royal Marsden hospital from January 1993–December 2007 is reported. Results. Seven adult patients with primary renal Ewing's sarcoma were identified. All four patients with nonmetastatic disease had radical nephrectomy and received adjuvant chemotherapy +/− radiotherapy. Two developed metastatic disease while on adjuvant chemotherapy, and one patient relapsed after 55 months. The three patients with metastatic disease at presentation did not have nephrectomy and were treated with chemotherapy. All three patients had disease progression with a dismal outcome. Only one patient in the whole group is alive and disease free. The median overall survival was 62.8 months, and the median disease-free survival in patients with nonmetastatic disease after combined modality treatment was 30.3 months. Conclusion. Primary adult renal Ewing's sarcoma is an aggressive tumor with a propensity for early metastasis. Radical nephrectomy with adjuvant combination chemotherapy produced the best results but the outlook remained poor with only one patient experiencing long disease-free survival. PMID:19478963

Combination of continuous renal replacement therapies (CRRT) and extracorporeal membrane oxygenation (ECMO) for advanced cardiac patients.

PubMed

Yap, Hon-Jek; Chen, Yung-Chang; Fang, Ji-Tseng; Huang, Chiu-Ching

2003-03-01

The critically ill patients may require mechanical ventilation, cardiac mechanical support, and other types of critical support. Extracorporeal membrane oxygenation (ECMO) is a supportive therapy, which provides good cardiopulmonary and end-organ support. Continuous renal replacement therapies (CRRT) exhibit important advantages in terms of clinical tolerance and blood purification. This investigation aims to evaluate the acute renal failure in cardiac patients under ECMO, and assess the effect of combining these two technologies, ECMO and CRRT. Between December 1998 and June 2001, 10 adult cardiac patients were treated on ECMO. Five of them were treated with both ECMO and CRRT. The clinical outcomes were retrospectively analyzed. Of the 10 patients studied, five were men and five were women. The mean age of survivors and non-survivors was 37.00 +/- 14.54 years and 46.17 +/- 7.41 years, respectively. The overall mortality rate was 60%. Survivors did not differ significantly from non-survivors in age or gender. The APACHE II scores on the first day of ECMO support between survival and non-survival were 19.00 +/- 9.38 and 24.67 +/- 3.50 (P value = 0.392) (Table 2), which demonstrates no significant differences too. The cause of death in most patients was related to organ system failure during the 24 h immediately before ECMO started. Five patients with acute renal failure treated by CRRT were eventually died. The median and mean survival in this group on CRRT was 40.50 +/- 18.07 h and 92.60 +/- 60.50 h. We conclude that mortality rate for acute renal failure in cardiac patients under ECMO continues to be high. Our data suggest that acute renal failure is generally a part of multiorgan failure. This unique form of acute renal failure, causes generalized edema and fluid overload despite still low serum creatinine and azotemia, and deteriorates rapidly to death. From this study shows, advanced cardiac failure may need more aggressive and early initiation of ECMO support

Single incision laparoscopic pancreas resection for pancreatic metastasis of renal cell carcinoma.

PubMed

Barbaros, Umut; Sümer, Aziz; Demirel, Tugrul; Karakullukçu, Nazlı; Batman, Burçin; Içscan, Yalın; Sarıçam, Gülay; Serin, Kürçsat; Loh, Wei-Liang; Dinççağ, Ahmet; Mercan, Selçuk

2010-01-01

Transumbilical single incision laparoscopic surgery (SILS) offers excellent cosmetic results and may be associated with decreased postoperative pain, reduced need for analgesia, and thus accelerated recovery. Herein, we report the first transumbilical single incision laparoscopic pancreatectomy case in a patient who had renal cell cancer metastasis on her pancreatic corpus and tail. A 59-year-old female who had metastatic lesions on her pancreas underwent laparoscopic subtotal pancreatectomy through a 2-cm umbilical incision. Single incision pancreatectomy was performed with a special port (SILS port) and articulated equipment. The procedure lasted 330 minutes. Estimated blood loss was 100mL. No perioperative complications occurred. The patient was discharged on the seventh postoperative day with a low-volume (20mL/day) pancreatic fistula that ceased spontaneously. Pathology result of the specimen was renal cell cancer metastases. This is the first reported SILS pancreatectomy case, demonstrating that even advanced surgical procedures can be performed using the SILS technique in well-experienced centers. Transumbilical single incision laparoscopic pancreatectomy is feasible and can be performed safely in experienced centers. SILS may improve cosmetic results and allow accelerated recovery for patients even with malignancy requiring advanced laparoscopic interventions.

Pazopanib in Metastatic Renal Cancer: A "Real-World" Experience at National Cancer Institute "Fondazione G. Pascale".

PubMed

Cecere, Sabrina C; Rossetti, Sabrina; Cavaliere, Carla; Della Pepa, Chiara; Di Napoli, Marilena; Crispo, Anna; Iovane, Gelsomina; Piscitelli, Raffaele; Sorrentino, Domenico; Ciliberto, Gennaro; Maiolino, Piera; Muto, Paolo; Perdonà, Sisto; Berretta, Massimiliano; Pignata, Sandro; Facchini, Gaetano; D'Aniello, Carmine

2016-01-01

Pazopanib is an oral angiogenesis inhibitor, currently approved for treatment of metastatic renal cell carcinoma (mRCC) and soft tissue sarcoma. The present study analyzed the outcomes of pazopanib in first-line treatment of mRCC, in a single Italian cancer center. In the light of the retrospective, observational nature and the unselected population, our experience can be defined a "real-world" study. The medical records of 38 mRCC patients treated with front-line pazopanib were retrospectively reviewed and analyzed. The progression free survival (PFS) and the overall survival (OS) were the primary endpoints, while secondary objectives included objective response rate (ORR), disease control rate (DCR), and treatment tolerability. Pazopanib achieved a median PFS (mPFS) of 12.7 months (95% CI, 6.9-18.5 months). The median OS (mOS) was 26.2 months (95% CI, 12.6-39.9 months); the observed ORR and DCR were 30.3 and 72.7%, respectively, with a median duration of response of 11 weeks. mPFS appeared not to be influenced by number of co-morbidities (< 3 vs. ≥3), gender, Fuhrman grade and age. Conversely, the ORR and the DCR positively affect the mPFS (HR = 0.05 [95% CI, 0.05-0.55], p = 0.01; HR = 0.10 [95% CI, 0.02-0.43], p = 0.002, respectively). A worse outcome was associated with a lower mPFS in patients with liver metastases (p = 0.2) and with a high tumor burden (number of metastatic sites < 6 vs. ≥6) (p = 0.08). Worst OS was observed in patients aged ≥70 years old (HR = 6.91 [95% CI, 1.49-31.91], p = 0.01). The treatment was well-tolerated: no grade 4 adverse events, nor discontinuation due to toxicities was reported. Grade 3 hypertension affected positively the OS reaching the statistical significance (HR = 0.22 [95% CI, 0.05-0.8], p = 0.03). Thyroid dysfunction (hypo and hyperthyroidism) seems to correlate with better outcome in terms of a longer mPFS (HR = 0.12 [95% CI, 0.02-0.78], p = 0.02). Our results are consistent with those reported in prospective phase

Prognostic significance of pathological response of primary tumor and metastatic axillary lymph nodes after neoadjuvant chemotherapy for locally advanced breast carcinoma.

PubMed

Machiavelli, M R; Romero, A O; Pérez, J E; Lacava, J A; Domínguez, M E; Rodríguez, R; Barbieri, M R; Romero Acuña, L A; Romero Acuña, J M; Langhi, M J; Amato, S; Ortiz, E H; Vallejo, C T; Leone, B A

1998-01-01

The prognostic significance of pathological response of primary tumor and metastatic axillary lymph nodes after neoadjuvant chemotherapy was assessed in patients with noninflammatory locally advanced breast carcinoma. Between January 1989 and April 1995, 148 consecutive patients with locally advanced breast carcinoma participated in the study. Of these, 140 fully evaluable patients (67, stage IIIA; 73, stage IIIB) were treated with three courses of 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC), followed by modified radical mastectomy when technically feasible or definitive radiation therapy. The median age was 53 years (range, 26 to 75 years); 55% of patients were postmenopausal. Objective response was recorded in 99 of 140 patients (71%; 95% confidence interval, 63% to 79%). Complete response occurred in 11 patients (8%), and partial response occurred in 88 patients (63%). No change was recorded in 37 patients (26%), and progressive disease occurred in 4 patients (3%). One hundred and thirty-six patients underwent the planned surgery. Maximal pathological response of the primary tumor (in situ carcinoma or minimal microscopic residual tumor) was observed in 24 (18%); 112 patients (82%) presented minimal pathological response of the primary tumor (gross residual tumor). The number of metastatic axillary nodes after neoadjuvant chemotherapy was as follows: N0, 39 patients (29%); N1-N3, 35 patients (26%); > N3, 62 patients (45%). Considering the initial TNM status, 75% of the patients had decreases in tumor compartment after neoadjuvant chemotherapy. Also, 31% and 23% of patients with clinical N1 and N2, respectively, showed uninvolved axillary lymph nodes. A significant correlation was noted between pathological response of primary tumor and the number of metastatic axillary lymph nodes. Median disease-free survival was 34 months, whereas median overall survival was 66 months. Pathological responses of both primary tumor and metastatic axillary lymph nodes

Different impact of aspirin on renal progression in patients with predialysis advanced chronic kidney disease with or without previous stroke.

PubMed

Hsiao, Kuang-Chih; Huang, Jing-Yang; Lee, Chun-Te; Hung, Tung-Wei; Liaw, Yung-Po; Chang, Horng-Rong

2017-04-01

The benefit of reducing the risk of stroke against increasing the risk of renal progression associated with antiplatelet therapy in patients with advanced chronic kidney disease (CKD) is controversial. We enrolled 1301 adult patients with advanced CKD treated with erythropoiesis stimulating agents from January 1, 2002 to June 30, 2009 from the 2005 Longitudinal Health Insurance Database in Taiwan. All of the patients were followed until the development of the primary or secondary endpoints, or the end of the study (December 31, 2011). The primary endpoint was the development of ischemic stroke, and the secondary endpoints included hospitalization for bleeding events, cardiovascular mortality, all-cause mortality, and renal failure. The adjusted cumulative probability of events was calculated using multivariate Cox proportional regression analysis. Adjusted survival curves showed that the usage of aspirin was not associated with ischemic stroke, hospitalization for bleeding events, cardiovascular mortality or all-cause mortality, however, it was significantly associated with renal failure. In subgroup analysis, aspirin use was associated with renal failure in the patients with no history of stroke (HR, 1.41; 95% CI, 1.14-1.73), and there was a borderline interaction between previous stroke and the use of aspirin on renal failure (interaction p=0.0565). There was no significant benefit in preventing ischemic stroke in the patients with advanced CKD who received aspirin therapy. Furthermore, the use of aspirin was associated with the risk of renal failure in the patients with advanced CKD without previous stroke. Copyright © 2016 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Advances in diagnosis and treatment of metastatic cervical cancer

PubMed Central

2016-01-01

Cervical cancer is one of the most common cancers in women worldwide. The outcome of patients with metastatic cervical cancer is poor. We reviewed the relevant literature concerning the treatment and diagnosis of metastatic cervical cancer. There are two types of metastasis related to different treatments and survival rates: hematogenous metastasis and lymphatic metastasis. Patients with hematogenous metastasis have a higher risk of death than those with lymphatic metastasis. In terms of diagnosis, fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) and PET-computed tomography are effective tools for the evaluation of distant metastasis. Concurrent chemoradiotherapy and subsequent chemotherapy are well-tolerated and efficient for lymphatic metastasis. As for lung metastasis, chemotherapy and/or surgery are valuable treatments for resistant, recurrent metastatic cervical cancer and chemoradiotherapy may be the optimal choice for stage IVB cervical cancer. Chemotherapy and bone irradiation are promising for bone metastasis. A better survival is achieved with multimodal therapy. Craniotomy or stereotactic radiosurgery is an optimal choice combined with radiotherapy for solitary brain metastases. Chemotherapy and palliative brain radiation may be considered for multiple brain metastases and other organ metastases. PMID:27171673

Advances in diagnosis and treatment of metastatic cervical cancer.

PubMed

Li, Haoran; Wu, Xiaohua; Cheng, Xi

2016-07-01

Cervical cancer is one of the most common cancers in women worldwide. The outcome of patients with metastatic cervical cancer is poor. We reviewed the relevant literature concerning the treatment and diagnosis of metastatic cervical cancer. There are two types of metastasis related to different treatments and survival rates: hematogenous metastasis and lymphatic metastasis. Patients with hematogenous metastasis have a higher risk of death than those with lymphatic metastasis. In terms of diagnosis, fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) and PET-computed tomography are effective tools for the evaluation of distant metastasis. Concurrent chemoradiotherapy and subsequent chemotherapy are well-tolerated and efficient for lymphatic metastasis. As for lung metastasis, chemotherapy and/or surgery are valuable treatments for resistant, recurrent metastatic cervical cancer and chemoradiotherapy may be the optimal choice for stage IVB cervical cancer. Chemotherapy and bone irradiation are promising for bone metastasis. A better survival is achieved with multimodal therapy. Craniotomy or stereotactic radiosurgery is an optimal choice combined with radiotherapy for solitary brain metastases. Chemotherapy and palliative brain radiation may be considered for multiple brain metastases and other organ metastases.

Second-line treatment for metastatic clear cell renal cell cancer: experts' consensus algorithms.

PubMed

Rothermundt, C; von Rappard, J; Eisen, T; Escudier, B; Grünwald, V; Larkin, J; McDermott, D; Oldenburg, J; Porta, C; Rini, B; Schmidinger, M; Sternberg, C N; Putora, P M

2017-04-01

Second-line systemic treatment options for metastatic clear cell renal cell cancer (mccRCC) are diverse and treatment strategies are variable among experts. Our aim was to investigate the approach for the second-line treatment after first-line therapy with a tyrosine kinase inhibitor (TKI). Recently two phase III trials have demonstrated a potential role for nivolumab (NIV) and cabozantinib (CAB) in this setting. We aimed to estimate the impact of these trials on clinical decision making. Eleven international experts were asked to provide their treatment strategies for second-line systemic therapy for mccRCC in the current setting and once NIV and CAB will be approved and available. The treatment strategies were analyzed with the objective consensus approach. The analysis of the decision trees revealed everolimus (EVE), axitinib (AXI), NIV and TKI switch (sTKI) as therapeutic options after first-line TKI therapy in the current situation and mostly NIV and CAB in the future setting. The most commonly used criteria for treatment decisions were duration of response, TKI tolerance and zugzwang a composite of several related criteria. In contrast to the first-line setting, recommendations for second-line systemic treatment of mccRCC among experts were not as heterogeneous. The agents mostly used after disease progression on a first-line TKI included: EVE, AXI, NIV and sTKI. In the future setting of NIV and CAB availability, NIV was the most commonly chosen drug, whereas several experts identified situations where CAB would be preferred.

Therapy of Treatment-Related Hypertension in Metastatic Renal-Cell Cancer Patients Receiving Sunitinib.

PubMed

Ivanyi, Philipp; Beutel, Gernot; Drewes, Nicole; Pirr, Jens; Kielstein, Jan T; Morgan, Michael; Ganser, Arnold; Grünwald, Viktor

2017-04-01

Treatment-related hypertension (tHTN) is frequent during sunitinib treatment. However, data on risk factors and treatment of tHTN remain scarce. Patients with metastatic renal-cell carcinoma treated with sunitinib from June 2004 to December 2011 were included. Medical records were retrospectively analyzed for tHTN risk factors and antihypertensive treatments (AHT). Descriptive statistics, Cox regression, and competitive risk models were applied. A total of 51 (70.8%) of 72 patients developed tHTN after a median sunitinib treatment of 28 days. Mean blood pressure increased from 130/75 (range, 90 to 190/58 to 101) mm Hg on day 1 to 140/80 (range, 90 to 190/60 to 120, P < .001) mm Hg on day 28. Standard dose of sunitinib, age > 50 years, and prehypertension were identified as independent risk factors for tHTN. Thirty-eight patients (72.5%) in the tHTN subgroup received modification of AHT. Calcium channel blockers (CCB) were identified as the best at controlling tHTN compared to other drugs (P = .045). The combination of AHT was more potent than a dose increase of a single-drug AHT, and early AHT intervention was more efficacious than delayed start of therapy. Patients at risk for tHTN require more rigorous blood pressure measurement. CCB seemed to be most potent and efficient, and an early combination of different classes of AHT was more efficacious than full-dose, single-agent AHT. Copyright © 2016 Elsevier Inc. All rights reserved.

Inhibition of Focal Adhesion Kinase (FAK) Leads to Abrogation of the Malignant Phenotype in Aggressive Pediatric Renal Malignancies

PubMed Central

Megison, Michael L.; Gillory, Lauren A.; Stewart, Jerry E.; Nabers, Hugh C.; Mrozcek-Musulman, Elizabeth; Beierle, Elizabeth A.

2014-01-01

Despite the tremendous advances in the treatment of childhood kidney tumors, there remain subsets of pediatric renal tumors that continue to pose a therapeutic challenge, mainly malignant rhabdoid kidney tumors and non-osseous renal Ewing sarcoma. Children with advanced, metastatic or relapsed disease have a disease-free survival rate under 30%. Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that is important in many facets of tumor development and progression. FAK has been found in other pediatric solid tumors and in adult renal cellular carcinoma, leading us to hypothesize that FAK would be present in pediatric kidney tumors and would impact their cellular survival. In the current study, we showed that FAK was present and phosphorylated in pediatric kidney tumor specimens. We also examined the effects of FAK inhibition upon G401 and SK-NEP-1 cell lines utilizing a number of parallel approaches to block FAK including RNAi and small molecule FAK inhibitors. FAK inhibition resulted in decreased cellular survival, invasion and migration, and increased apoptosis. Further, small molecule inhibition of FAK led to decreased tumor growth in a nude mouse SK-NEP-1 xenograft model. The findings from this study will help to further our understanding of the regulation of tumorigenesis in rare pediatric renal tumors, and may provide desperately needed novel therapeutic strategies and targets for these rare, but difficult to treat, malignancies. PMID:24464916

Dose-finding trial of a combined regimen with bevacizumab, immunotherapy, and chemotherapy in patients with metastatic renal cell cancer: An Italian Oncology Group for Clinical Research (GOIRC) study.

PubMed

Buti, Sebastiano; Lazzarelli, Silvia; Chiesa, Matteo Dalla; Simonelli, Cecilia; Re, Giovanni Lo; Lheshi, Arvin; Simon, Spazzapan; Mattioli, Rodolfo; Caminiti, Caterina; Mazza, Giancarlo; Donini, Maddalena; Passalacqua, Rodolfo

2010-09-01

The aim of this study was to look for the maximum tolerated dose (MTD) of gemcitabine and 5-fluorouracil in a new regimen also containing the antiangiogenic bevacizumab and immunotherapy (IT) for the treatment of metastatic renal cell cancer. The primary objective of this multicenter dose-finding study was to establish the MTD of chemotherapy (CT) in combination with fixed doses of IT and bevacizumab. The secondary objective was to assess the combination's activity. Five escalated dose levels of CT with intravenous gemcitabine and 5-fluorouracil (days 1 and 8 every 28 d), were associated together with intravenous bevacizumab (10 mg/kg on days 1 and 15 every 28 d), subcutaneous interleukin-2 (1 MIU/m² bid on days 8, 9, 15, 16, and 1 MIU/m²/d on days 10-12 and 17-19), and interferon-α-2a (3 MIU on days 10, 12, 17, 19). Of the 27 enrolled patients, 59% had been pretreated. The MTD was not reached. The highest CT dose studied was gemcitabine 1000 mg/m² and 5-fluorouracil 600 mg/m². More frequent grade 3 to 4 toxicities included neutropenia (63%), thrombocytopenia (33%), and fever (26%). The response rate was 33% according to the Response Evaluation Criteria in Solid Tumors. This is the first study that explored the feasibility and safety of combined bevacizumab, IT, and CT in metastatic renal cell cancer. The activity of this regimen is interesting and its efficacy warrants further trials.

Changes in renal function after discontinuation of vitamin D analogues in advanced chronic kidney disease.

PubMed

Caravaca, Francisco; Caravaca-Fontán, Fernando; Azevedo, Lilia; Luna, Enrique

In routine clinical practice, the prescription of vitamin D analogues (VDA) in patients with chronic kidney disease (CKD) is often associated with a decline of the estimated renal function. The reason for this is not fully understood. To analyse the effects of VDA discontinuation in advanced CKD and to determine the factors associated with changes in renal function. Retrospective cohort study of adult patients with advanced CKD. The case subgroup was treated with VDA and this medication was discontinued at baseline (the first visit). The control subgroup was not treated with VDA and they were selected according to comparability principles for CKD progression by propensity score matching. The primary outcome measure was a change to both the estimated glomerular filtration rate (MDRD-GFR) and the measured glomerular filtration rate (mGFR by combined creatinine and urea clearances). Baseline parameters related to mineral metabolism and creatinine generation were analysed as potential determinants of renal function changes. The study sample consisted of 67 cases and 67 controls. Renal function improved in 67% of cases and worsened in 72% of controls (p<0.0001). Changes in MDRD-GFR for the case subgroup and the control subgroup were +0.455±0.997 vs. -0.436±1.103ml/min/1.73 m 2 /month (p<0.0001), respectively. Total creatinine excretion was slightly higher in cases than in controls but the difference was not significant. According to multivariate logistic and linear regression analyses, baseline total serum calcium was one of the best determinants of both renal function recovery (Odds ratio=3.49; p=0.001), and of the extent of renal function recovery (beta=0.276; p=0.001). Discontinuation of VDA treatment in CKD patients is associated with significant recovery of estimated renal function. The extent of these changes is mainly associated with baseline total serum calcium. Copyright © 2017 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All

Prediction of Everolimus Toxicity and Prognostic Value of Skeletal Muscle Index in Patients With Metastatic Renal Cell Carcinoma.

PubMed

Auclin, Edouard; Bourillon, Camille; De Maio, Eleonora; By, Marie Agnes; Seddik, Sofiane; Fournier, Laure; Auvray, Marie; Dautruche, Antoine; Vano, Yann-Alexandre; Thibault, Constance; Joly, Florence; Brunereau, Laurent; Gomez-Roca, Carlos; Chevreau, Christine; Elaidi, Reza; Oudard, Stéphane

2017-06-01

The objective of the study was to assess the prognostic role of skeletal muscle index (SMI) in metastatic renal cell carcinoma (mRCC) patients treated with everolimus, and its effect of on everolimus-induced toxicity. Consecutive mRCC patients treated with everolimus between February 2007 and November 2014 underwent computed tomography scans at a single center performed by the same radiologist. SMI was assessed before everolimus treatment using the L3 cross-sectional area. Overall survival (OS) was analyzed according to SMI value. Results were adjusted using the International Metastatic Database Consortium (IMDC) prognostic group, body mass index (BMI), and/or number of previous tyrosine kinase inhibitor lines (NPL). One hundred twenty-four mRCC patients (mean age, 60.21 years) were treated with everolimus as second- or third-line (82.3%) or > third-line (17.7%) therapy. Most patients (87.9%) had clear cell carcinoma. IMDC prognostic group was "favorable" (32.3%), "intermediate" (50%), or "poor" (17.7%). Median SMI was 40.75. OS was longer in patients from the highest versus lowest SMI tercile: 21.9 versus 10 months (P = .002). Continuous SMI at baseline was not significantly associated with OS after adjustment for IMDC prognostic group, BMI, or NPL but the highest versus lowest SMI tercile was an independent prognostic factor in multivariate analysis (P = .025). There was no difference in everolimus toxicity between SMI tercile groups. SMI was an independent prognostic factor for mRCC patients treated with everolimus. Whether this provides additional prognostic value to IMDC criteria needs to be confirmed in a larger cohort. SMI does not seem to be predictive of everolimus-induced toxicity. Copyright © 2017 Elsevier Inc. All rights reserved.

THE INFLUENCE OF ADVANCED AGE ON THE HEPATIC AND RENAL TOXICITY OF CHLOROFORM

EPA Science Inventory

THE INFLUENCE OF ADVANCED AGE ON THE HEPATIC AND RENAL TOXICITY OF CHLOROFORM (CHC13). A McDonald, Y M Sey and J E Simmons. NHEERL, ORD, U.S. EPA, RTP, NC.
Disinfection, by chlorination or by ozonation followed by treatment with either chlorine or chloramine, of water containi...

Treatment of renal cell carcinoma: Current status and future directions.

PubMed

Barata, Pedro C; Rini, Brian I

2017-11-01

Answer questions and earn CME/CNE Over the past 12 years, medical treatment for renal cell carcinoma (RCC) has transitioned from a nonspecific immune approach (in the cytokine era), to targeted therapy against vascular endothelial growth factor (VEGF), and now to novel immunotherapy agents. Multiple agents-including molecules against vascular endothelial growth factor, platelet-derived growth factor, and related receptors; inhibitors of other targets, such as the mammalian target of rapamycin and the MET and AXL tyrosine-protein kinase receptors; and an immune-checkpoint inhibitor-have been approved based on significant activity in patients with advanced RCC. Despite these advances, important questions remain regarding biomarkers of efficacy, patient selection, and the optimal combination and sequencing of agents. The purpose of this review is to summarize present management and future directions in the treatment of metastatic RCC. CA Cancer J Clin 2017;67:507-524. © 2017 American Cancer Society. © 2017 American Cancer Society.

Sorafenib for Metastatic Thyroid Cancer

Cancer.gov

A summary of results from an international phase III trial that compared sorafenib (Nexavar®) and a placebo for the treatment of locally advanced or metastatic differentiated thyroid cancer that is no longer responding to treatment with radioactive iodine

Using Laboratory Test Results at Hospital Admission to Predict Short-term Survival in Critically Ill Patients With Metastatic or Advanced Cancer.

PubMed

Cheng, Lee; DeJesus, Alma Y; Rodriguez, Maria A

2017-04-01

Accurately estimating the life expectancy of critically ill patients with metastatic or advanced cancer is a crucial step in planning appropriate palliative or supportive care. We evaluated the results of laboratory tests performed within two days of hospital admission to predict the likelihood of death within 14 days. We retrospectively selected patients 18 years or older with metastatic or advanced cancer who were admitted to intensive care units or palliative and supportive care services in our hospital. We evaluated whether the following are independent predictors in a logistic regression model: age, sex, comorbidities, and the results of seven commonly available laboratory tests. The end point was death within 14 days in or out of the hospital. Of 901 patients in the development cohort and 45% died within 14 days. The risk of death within 14 days after admission increased with increasing age, lactate dehydrogenase levels, and white blood cell counts and decreasing albumin levels and platelet counts (P < 0.01). The model predictions were confirmed using a separate validation cohort. The areas under the receiver operating characteristic curves were 0.74 and 0.70 for the development and validation cohorts, respectively, indicating good discriminatory ability for the model. Our results suggest that laboratory test results performed within two days of admission are valuable in predicting death within 14 days for patients with metastatic or advanced cancer. Such results may provide an objective assessment tool for physicians and help them initiate conversations with patients and families about end-of-life care. Copyright © 2017 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

Clinical activity of sunitinib rechallenge in metastatic renal cell carcinoma-Results of the REchallenge with SUnitinib in MEtastatic RCC (RESUME) Study.

PubMed

Oudard, Stéphane; Geoffrois, Lionnel; Guillot, Aline; Chevreau, Christine; Deville, Jean-Laurent; Falkowski, Sabrina; Boyle, Helen; Baciuchka, Marjorie; Gimel, Pierre; Laguerre, Brigitte; Laramas, Mathieu; Pfister, Christian; Topart, Delphine; Rolland, Frédéric; Legouffe, Eric; Denechere, Gwénaël; Amela, Eric Yaovi; Abadie-Lacourtoisie, Sophie; Gross-Goupil, Marine

2016-07-01

To assess the efficacy and tolerability of sunitinib rechallenge in the third-line or later setting in patients with metastatic renal cell carcinoma (mRCC). This observational study comprised 61 mRCC patients at 19 centres in France who received sunitinib rechallenge between January 2006 and May 2013. Patients received first-line sunitinib, ≥1 different targeted therapies, and then sunitinib rechallenge. Patient/disease characteristics, tolerability, treatment modalities, and outcomes of therapeutic lines were recorded. The primary end-point was progression-free survival (PFS) in sunitinib rechallenge. Analyses included 52 patients; median age was 59 years, 75% were male, and 98% had clear-cell mRCC and prior nephrectomy. At sunitinib rechallenge versus first-line, patients had poorer performance (Karnofsky performance status 90-100: 30% versus 81%) and Memorial Sloan Kettering Cancer Centre prognostic risk (poor risk: 18% versus 3%). Overall, 20%, 65%, 12%, and 4% received sunitinib rechallenge as third-, fourth-, fifth-, and sixth-line therapy, respectively, at 14.6 months (median) after stopping initial treatment. With first-line sunitinib and rechallenge, median PFS was 18.4 and 7.9 months, respectively; objective response rate was 54% and 15%. Two of eight rechallenge responders had not achieved first-line response. Median overall survival was 55.9 months. The sunitinib rechallenge safety profile was as expected, with no new adverse events reported. Sunitinib rechallenge is a feasible treatment option with potential clinical benefit for mRCC patients. Disease progression with first-line sunitinib may not be associated with complete or irreversible resistance to therapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

Ixabepilone in Treating Patients With Advanced Urinary Tract Cancer

ClinicalTrials.gov

2013-01-23

Distal Urethral Cancer; Metastatic Transitional Cell Cancer of the Renal Pelvis and Ureter; Proximal Urethral Cancer; Recurrent Bladder Cancer; Recurrent Transitional Cell Cancer of the Renal Pelvis and Ureter; Recurrent Urethral Cancer; Regional Transitional Cell Cancer of the Renal Pelvis and Ureter; Stage III Bladder Cancer; Stage IV Bladder Cancer; Transitional Cell Carcinoma of the Bladder; Urethral Cancer Associated With Invasive Bladder Cancer

Single Incision Laparoscopic Pancreas Resection for Pancreatic Metastasis of Renal Cell Carcinoma

PubMed Central

Sümer, Aziz; Demirel, Tugrul; Karakullukçu, Nazlι; Batman, Burçin; İçscan, Yalιn; Sarιçam, Gülay; Serin, Kürçsat; Loh, Wei-Liang; Dinççağ, Ahmet; Mercan, Selçuk

2010-01-01

Background: Transumbilical single incision laparoscopic surgery (SILS) offers excellent cosmetic results and may be associated with decreased postoperative pain, reduced need for analgesia, and thus accelerated recovery. Herein, we report the first transumbilical single incision laparoscopic pancreatectomy case in a patient who had renal cell cancer metastasis on her pancreatic corpus and tail. Methods: A 59-year-old female who had metastatic lesions on her pancreas underwent laparoscopic subtotal pancreatectomy through a 2-cm umbilical incision. Results: Single incision pancreatectomy was performed with a special port (SILS port) and articulated equipment. The procedure lasted 330 minutes. Estimated blood loss was 100mL. No perioperative complications occurred. The patient was discharged on the seventh postoperative day with a low-volume (20mL/day) pancreatic fistula that ceased spontaneously. Pathology result of the specimen was renal cell cancer metastases. Conclusion: This is the first reported SILS pancreatectomy case, demonstrating that even advanced surgical procedures can be performed using the SILS technique in well-experienced centers. Transumbilical single incision laparoscopic pancreatectomy is feasible and can be performed safely in experienced centers. SILS may improve cosmetic results and allow accelerated recovery for patients even with malignancy requiring advanced laparoscopic interventions. PMID:21605524

Superior therapeutic efficacy of nab-paclitaxel over cremophor-based paclitaxel in locally advanced and metastatic models of human pancreatic cancer.

PubMed

Rajeshkumar, N V; Yabuuchi, Shinichi; Pai, Shweta G; Tong, Zeen; Hou, Shihe; Bateman, Scott; Pierce, Daniel W; Heise, Carla; Von Hoff, Daniel D; Maitra, Anirban; Hidalgo, Manuel

2016-08-09

Albumin-bound paclitaxel (nab-paclitaxel, nab-PTX) plus gemcitabine (GEM) combination has demonstrated efficient antitumour activity and statistically significant overall survival of patients with metastatic pancreatic ductal adenocarcinoma (PDAC) compared with GEM monotherapy. This regimen is currently approved as a standard of care treatment option for patients with metastatic PDAC. It is unclear whether cremophor-based PTX combined with GEM provide a similar level of therapeutic efficacy in PDAC. We comprehensively explored the antitumour efficacy, effect on metastatic dissemination, tumour stroma and survival advantage following GEM, PTX and nab-PTX as monotherapy or in combination with GEM in a locally advanced, and a highly metastatic orthotopic model of human PDAC. Nab-PTX treatment resulted in significantly higher paclitaxel tumour plasma ratio (1.98-fold), robust stromal depletion, antitumour efficacy (3.79-fold) and survival benefit compared with PTX treatment. PTX plus GEM treatment showed no survival gain over GEM monotherapy. However, nab-PTX in combination with GEM decreased primary tumour burden, metastatic dissemination and significantly increased median survival of animals compared with either agents alone. These therapeutic effects were accompanied by depletion of dense fibrotic tumour stroma and decreased proliferation of carcinoma cells. Notably, nab-PTX monotherapy was equivalent to nab-PTX plus GEM in providing survival advantage to mice in a highly aggressive metastatic PDAC model, indicating that nab-PTX could potentially stop the progression of late-stage pancreatic cancer. Our data confirmed that therapeutic efficacy of PTX and nab-PTX vary widely, and the contention that these agents elicit similar antitumour response was not supported. The addition of PTX to GEM showed no survival advantage, concluding that a clinical combination of PTX and GEM may unlikely to provide significant survival advantage over GEM monotherapy and may not be a

Upper tract urothelial carcinoma topical issue 2016: treatment of metastatic cancer.

PubMed

Pham, M N; Apolo, A B; De Santis, M; Galsky, M D; Leibovich, B C; Pisters, L L; Siefker-Radtke, A O; Sonpavde, G; Steinberg, G D; Sternberg, C N; Tagawa, S T; Weizer, A Z; Woods, M E; Milowsky, M I

2017-03-01

To review the management of metastatic upper tract urothelial carcinoma (UTUC) including recent advances in targeted and immune therapies as an update to the 2014 joint international consultation on UTUC, co-sponsored by the Société Internationale d'Urologie and International Consultation on Urological Diseases. A PubMed database search was performed between January 2013 and May 2016 related to the treatment of metastatic UTUC, and 54 studies were selected for inclusion. The management of patients with metastatic UTUC is primarily an extrapolation from evidence guiding the management of metastatic urothelial carcinoma of the bladder. The first-line therapy for metastatic UTUC is platinum-based combination chemotherapy. Standard second-line therapies are limited and ineffective. Patients with UTUC who progress following platinum-based chemotherapy are encouraged to participate in clinical trials. Recent advances in genomic profiling present exciting opportunities to guide the use of targeted therapy. Immunotherapy with checkpoint inhibitors has demonstrated extremely promising results. Retrospective studies provide support for post-chemotherapy surgery in appropriately selected patients. The management of metastatic UTUC requires a multi-disciplinary approach. New insights from genomic profiling using targeted therapies, novel immunotherapies, and surgery represent promising avenues for further therapeutic exploration.

[Pleural metastases of renal carcinoma].

PubMed

Giigoruk, O G; Lazarev, A F; Doroshenko, V S

2007-01-01

Metastases in renal carcinoma are diagnosed at initial diagnosis in 25% examinees. Traditional renal carcinoma has higher metastatic potential, is associated with worse survival of the patients compared to papillary cancer. We studied cytological characteristics of renal carcinoma metastases to the pleura in comparison with histological studies of the primary lesion using immunohistochemical findings. We examined cytologically pleural liquid in renal carcinoma metastases to the pleura in 6 patients (2.3% of carcinomatous pleuricies). High efficacy was shown by a cytocentrifuge CYTOSPIN-4. In 3 cases initial cancer was renal cell carcinoma, pleural exudation developed 2 years later, clear cell carcinoma appeared 6 years later and papillary cancer--10 years later. In the other 3 cases malignant cells were detected in new-onset cases. Renal carcinoma was diagnosed in one case. Cytological preparations were studied with identification of cytological signs typical for classic clear cell, granulocell and papillary renal cancer. Immunohistochemical examination of primary tumor lesion in the kidney discovered high proliferative activity of tumor cells by Ki-67 index to 5.28%. The tumors had solitary Bcl-2 positive cells. Expression of mutant p-53 took place in 0.93%. Her-2/neu hyperexpression was not found in the tumors of the above patients. Such immunohistochemical parameters point to poor prognosis. This is confirmed by renal carcinoma metastases to the pleura.

Novel therapies in advanced renal cell carcinoma: management of adverse events from sorafenib and sunitinib.

PubMed

Ivanyi, Philipp; Winkler, Thomas; Ganser, Arnold; Reuter, Christoph; Grünwald, Viktor

2008-03-01

Sorafenib and Sunitinib are the first tyrosine kinase inhibitors licensed for the treatment of advanced renal cell carcinoma. In contrast to conventional chemotherapy, targeted therapies have distinct and specific side effects. Selective review in Medline and the data base of the American Society of Clinical Oncology on the treatment and side effects of tyrosine kinase inhibitors in renal cell carcinoma, drawing on the authors' own experience. Tyrosine kinase inhibitors are characterized by a variety of uncommon side effects, such as lassitude, mucosal inflammation and skin changes. The detection and treatment of adverse events are critical for interdisciplinary cancer treatment in order to ensure patients' safety. This article offers an overview of the unwanted effects of drug therapy in the management of renal cell carcinoma.

Pulmonary metastatic calcification with respiratory insufficiency in patients on maintenance haemodialysis.

PubMed Central

Justrabo, E; Genin, R; Rifle, G

1979-01-01

A uraemic patient undergoing chronic haemodialysis developed diffuse metastatic pulmonary calcification and died from acute respiratory insufficiency after renal transplantation. Thirteen similar cases previously published are reviewed, with emphasis on the clinical and anatomical features of such calcinosis. The pathogenesis of this calcification in patients on maintenance haemodialysis and some rules for its prevention are discussed. Images PMID:483215

Apatinib: A Review in Advanced Gastric Cancer and Other Advanced Cancers.

PubMed

Scott, Lesley J

2018-05-01

Apatinib [Aitan ® (brand name in China)], also known as rivoceranib, is a novel, small molecule, selective vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor and is the second anti-angiogenic drug to be approved in China for the treatment of advanced or metastatic gastric cancer. This article summarizes the pharmacological properties of apatinib and reviews its clinical use in chemotherapy-experienced patients with advanced gastric adenocarcinoma, including gastroesophageal adenocarcinoma (GEA), or with other advanced cancers such as non-small cell lung cancer (NSCLC), breast cancer, gynaecological cancers, hepatocellular carcinoma (HCC), thyroid cancer and sarcomas. As third- or subsequent-line therapy, oral apatinib significantly prolonged median progression-free survival (PFS) and overall survival (OS) compared with placebo and had a manageable safety profile in Chinese patients with advanced or metastatic gastric cancer or GEA participating in randomized, double-blind, multicentre, phase 2 and 3 trials. More limited evidence also supports it use as subsequent-line treatment in Chinese patients with other advanced or metastatic solid tumours, including NSCLC, breast cancer and HCC. Further clinical experience and long-term pharmacovigilance data are required to more definitively establish the efficacy and safety profile of apatinib, including its use in combination with other chemotherapy agents and its role in the management of other types of advanced or metastatic solid tumours. In the meantime, given its convenient administration regimen and the limited treatment options and poor prognosis for patients with advanced or metastatic solid tumours, apatinib is an important, emerging treatment option for adult patients with advanced gastric adenocarcinoma or GEA who have progressed or relapsed after chemotherapy.

CheckMate 025 Randomized Phase 3 Study: Outcomes by Key Baseline Factors and Prior Therapy for Nivolumab Versus Everolimus in Advanced Renal Cell Carcinoma.

PubMed

Escudier, Bernard; Sharma, Padmanee; McDermott, David F; George, Saby; Hammers, Hans J; Srinivas, Sandhya; Tykodi, Scott S; Sosman, Jeffrey A; Procopio, Giuseppe; Plimack, Elizabeth R; Castellano, Daniel; Gurney, Howard; Donskov, Frede; Peltola, Katriina; Wagstaff, John; Gauler, Thomas C; Ueda, Takeshi; Zhao, Huanyu; Waxman, Ian M; Motzer, Robert J

2017-12-01

The randomized, phase 3 CheckMate 025 study of nivolumab (n=410) versus everolimus (n=411) in previously treated adults (75% male; 88% white) with advanced renal cell carcinoma (aRCC) demonstrated significantly improved overall survival (OS) and objective response rate (ORR). To investigate which baseline factors were associated with OS and ORR benefit with nivolumab versus everolimus. Subgroup OS analyses were performed using Kaplan-Meier methodology. Hazard ratios were estimated using the Cox proportional hazards model. Nivolumab 3mg/kg every 2 wk or everolimus 10mg once daily. The minimum follow-up was 14 mo. Baseline subgroup distributions were balanced between nivolumab and everolimus arms. Nivolumab demonstrated an OS improvement versus everolimus across subgroups, including Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium risk groups; age <65 and ≥65 yr; one and two or more sites of metastases; bone, liver, and lung metastases; number of prior therapies; duration of prior therapy; and prior sunitinib, pazopanib, or interleukin-2 therapy. The benefit with nivolumab versus everolimus was noteworthy for patients with poor MSKCC risk (hazard ratio 0.48, 95% confidence interval 0.32-0.70). The mortality rate at 12 mo for all subgroups was lower with nivolumab compared with everolimus. ORR also favored nivolumab. The incidence of grade 3 or 4 treatment-related adverse events across subgroups was lower with nivolumab. Limitations include the post hoc analysis and differing sample sizes between groups. The trend for OS and ORR benefit with nivolumab for multiple subgroups, without notable safety concerns, may help to guide treatment decisions, and further supports nivolumab as the standard of care in previously treated patients with aRCC. We investigated the impact of demographic and pretreatment features on survival benefit and tumor response with nivolumab versus everolimus in advanced renal

Refractory sciatica could be a sign of malignancy: A unique case presentation.

PubMed

Arunachalam, Karuppiah

2016-01-04

t Renal cell carcinoma is one of the highly aggressive tumors and notorious for late presentations. It is associated with high morbidity and mortality. Renal cell carcinoma is known for rare metastatic sites. In clinical practice, it is often important not to anchor to a particular diagnosis but rather revisit and revaluate entire history and clinical examination. We describe a case of metastatic renal cell carcinoma that was initially treated as sciatica and later found to have advanced debilitating malignancy. Internal medicine physicians should be able to recognize one of the rare metastatic sites of renal cell carcinoma and understand the importance of imaging studies if patient has persisting sciatica symptoms without improvement.

Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial

PubMed Central

Halabi, Susan; Sanford, Ben L.; Hahn, Olwen; Michaelson, M. Dror; Walsh, Meghara K.; Feldman, Darren R.; Olencki, Thomas; Picus, Joel; Small, Eric J.; Dakhil, Shaker; George, Daniel J.; Morris, Michael J.

2017-01-01

Purpose Cabozantinib is an oral potent inhibitor of vascular endothelial growth factor receptor 2, MET, and AXL and is a standard second-line therapy for metastatic renal cell carcinoma (mRCC). This randomized phase II multicenter trial evaluated cabozantinib compared with sunitinib as first-line therapy in patients with mRCC. Patients and Methods Eligible patients had untreated clear cell mRCC and Eastern Cooperative Oncology Group performance status of 0 to 2 and were intermediate or poor risk per International Metastatic Renal Cell Carcinoma Database Consortium criteria. Patients were randomly assigned at a one-to-one ratio to cabozantinib (60 mg once per day) or sunitinib (50 mg once per day; 4 weeks on, 2 weeks off). Progression-free survival (PFS) was the primary end point. Objective response rate (ORR), overall survival, and safety were secondary end points. Results From July 2013 to April 2015, 157 patients were randomly assigned (cabozantinib, n = 79; sunitinib, n = 78). Compared with sunitinib, cabozantinib treatment significantly increased median PFS (8.2 v 5.6 months) and was associated with a 34% reduction in rate of progression or death (adjusted hazard ratio, 0.66; 95% CI, 0.46 to 0.95; one-sided P = .012). ORR was 33% (95% CI, 23% to 44%) for cabozantinib versus 12% (95% CI, 5.4% to 21%) for sunitinib. All-causality grade 3 or 4 adverse events were 67% for cabozantinib and 68% for sunitinib and included diarrhea (cabozantinib, 10% v sunitinib, 11%), fatigue (6% v 15%), hypertension (28% v 22%), palmar-plantar erythrodysesthesia (8% v 4%), and hematologic adverse events (3% v 22%). Conclusion Cabozantinib demonstrated a significant clinical benefit in PFS and ORR over standard-of-care sunitinib as first-line therapy in patients with intermediate- or poor-risk mRCC. PMID:28199818

Congenital renal rhabdoid tumor with placental metastases: immunohistochemistry, cytogenetic, and ultrastructural findings.

PubMed

de Tar, Michael; Sanford Biggerstaff, Julie

2006-01-01

Malignant congenital tumors of fetal origin are rare lesions, the most common type being congenital neuroblastoma. Although prenatal diagnosis is possible in large tumors, occasionally the tumor will be diagnosed first by its metastatic involvement of the placenta. Placental metastases can reflect either maternal or fetal primary sites, and each has relatively specific patterns of placental involvement. We describe the clinical and pathologic features of a widely metastatic congenital renal rhabdoid tumor with its placental and autopsy findings, and include the immunohistochemical, cytogenetic, and ultrastructural features. The pathologic features of the placenta in congenital renal rhabdoid tumor with placental metastasis have not been previously described. The examination of the placenta in this case led to the initial diagnosis and obviated the need for additional diagnostic procedures.

Pembrolizumab in Treating Participants With Metastatic, Recurrent or Locally Advanced Cancer and Genomic Instability

ClinicalTrials.gov

2018-03-22

BRCA1 Gene Mutation; BRCA2 Gene Mutation; Locally Advanced Solid Neoplasm; Metastatic Malignant Solid Neoplasm; POLD1 Gene Mutation; POLE Gene Mutation; Recurrent Malignant Solid Neoplasm; Recurrent Ovarian Carcinoma; Stage III Breast Cancer AJCC v7; Stage III Ovarian Cancer AJCC v8; Stage IIIA Breast Cancer AJCC v7; Stage IIIA Ovarian Cancer AJCC v8; Stage IIIB Breast Cancer AJCC v7; Stage IIIB Ovarian Cancer AJCC v8; Stage IIIC Breast Cancer AJCC v7; Stage IIIC Ovarian Cancer AJCC v8; Stage IV Breast Cancer AJCC v6 and v7; Stage IV Ovarian Cancer AJCC v8; Stage IVA Ovarian Cancer AJCC v8; Stage IVB Ovarian Cancer AJCC v8

Xp11.2 translocation renal carcinoma with placental metastasis: a case report.

PubMed

Bovio, Ian M; Allan, Robert W; Oliai, Bahram R; Hampton, Troy; Rush, Demaretta S

2011-02-01

Renal cell carcinomas with sporadic Xp11.2 translocations are uncommon malignancies in children and young adults associated with several different reciprocal translocations involving the TFE3 gene located on chromosome Xp11.2. Placental metastases are extremely rare, with only a handful of cases reported. This study reports the case of a 20-year-old woman with an Xp11.2 translocation renal carcinoma that metastasized to the placenta. This is the first reported case of a renal cell carcinoma metastatic to the placenta and highlights the aggressive behavior of Xp11 translocation renal cell carcinomas.

A phase ii study of gemcitabine and capecitabine in patients with advanced renal cell cancer: Southwest Oncology Group Study S0312.

PubMed

Van Veldhuizen, Peter J; Hussey, Michael; Lara, Primo N; Mack, Philip C; Gandour-Edwards, Regina; Clark, Joseph I; Lange, Marianne K; Crawford, David E

2009-10-01

Gemcitabine plus capecitabine has moderate efficacy in patients with advanced renal cell cancer (RCC) but has considerable toxicity. We evaluated the efficacy and toxicity of a modified dose-schedule of this doublet in patients with metastatic RCC. Chemotherapy-naive patients were treated with gemcitabine at 900 mg/m2 on days 1, 8, and 15 and with capecitabine at 625 mg/m2 twice daily on days 1 through 21, and every 28 days thereafter. The primary end point was response rate (RR). No further evaluation of this regimen would be pursued if the RR was ≤ 5%. In an exploratory analysis, we also evaluated potential markers of prognosis and treatment response, including thymidylate synthase, PTEN, pAKT, pmTOR, XRCC1, and ERCC1. Of 43 patients, 1 was ineligible and 2 were not analyzable. There was 1 complete response and 3 partial responses, for an overall RR of 10% (95% CI = 3, 24). Nineteen patients (48%) had stable disease. The 6-month freedom-from-treatment-failure and overall survival rates were 20% (95% CI = 8, 32) and 75% (95% CI = 62, 88), respectively. Median survival time was 23 months (95% CI = 10, 37). One patient each experienced grade 4 neutropenia, fatigue, thrombocytopenia, and hemolysis with renal failure. The most common grade 3 toxicities were neutropenia (12 patients), fatigue (5), and leucopenia (4). Patients with a best response of stable disease or better were more likely to have decreased expression of PTEN and increased expression of pmTOR. Gemcitabine plus capecitabine at this reduced dose-schedule benefits a small percentage of patients with RCC with an acceptable toxicity profile.

Resources and Costs Associated with the Treatment of Advanced and Metastatic Gastric Cancer in the Mexican Public Sector: A Patient Chart Review.

PubMed

Quintana, Miguel; Toriz, José A; Novick, Diego; Jones, Kyla; Botello, Brenda S; Silva, Juan Alejandro

2018-06-01

Little evidence is available on the management and cost of treating patients with advanced or metastatic gastric cancer (GC). This study evaluates patient characteristics, treatment patterns, and resource utilization for these patients in Mexico. Data were collected from three centers of investigation (tertiary level). Patients were ≥18 years of age, diagnosed between 1 January 2009 and 1 January 2015, had advanced or metastatic GC, received first-line fluoropyrimidine/platinum, and had ≥3 months follow-up after discontinuing first-line treatment. Data were summarized using descriptive statistics. The study sample totaled 180. Patients' mean age was 57.2 years (±12.4) and 57.0% were male; 151 (83.9%) patients received second-line chemotherapy. A total of 16 and 19 regimens were identified in first- and second-line therapy. Of the sample, 51 (28.3%) received third-line therapy, and <10% received more than three lines of active chemotherapy. Supportive care received in first- and second-line chemotherapy, included pain interventions (12.2 and 7.9%), nutritional support (3.3 and 1.3%), radiotherapy (6.1 and 16.6%), and transfusions (13.3 and 10.6%), respectively. Using Mexican Institute of Social Security (IMSS) tariffs, the average total cost per patient-month in first- and second-line therapy was US$1230 [95% confidence interval (CI) 1034-1425] and US$1192 (95% CI 913-1471), respectively. Administration and acquisition of chemotherapy comprised the majority of costs. This study shows considerable variation in first- and second-line chemotherapy regimens of patients with advanced or metastatic GC. Understanding GC treatment patterns in Mexico will help address unmet needs.

Salvage Lenvatinib Therapy in Metastatic Anaplastic Thyroid Cancer.

PubMed

Iñiguez-Ariza, Nicole M; Ryder, Mabel M; Hilger, Crystal R; Bible, Keith C

2017-07-01

Historical anaplastic thyroid cancer (ATC) outcomes have been terrible, with a median survival of only five months and <20% one-year survival. Improved outcomes are now achieved with aggressive initial therapy in stages IVA and IVB disease, but patients with distant metastatic disease (stage IVC) still do poorly; improved therapies are sorely needed. Kinase inhibitors have emerged as promising agents in the therapy of advanced medullary and differentiated thyroid cancer, but there are limited data regarding the use of lenvatinib in ATC. The aim of this study was to delineate clinical outcomes in a series of patients with advanced ATC in response to lenvatinib therapy. A retrospective analysis was conducted involving all lenvatinib-treated Mayo Clinic ATC patients in 2015. Of 28 distinct ATC patients seen in 2015, three (11%) with metastatic disease of ECOG performance status 2-3 were treated with lenvatinib. Two patients were male; age range at ATC diagnosis was 57-84 years. All three patients attained successful local control of their disease with surgery and/or combined chemoradiotherapy. Lenvatinib was offered as the second, third, or fourth line of therapy at the time of metastatic disease progression. Two patients incurred minor responses to therapy, with structural regression of distant metastatic tumor disease soon after starting lenvatinib treatment (at one to two months), while one patient achieved stable disease, but no Response Evaluation Criteria In Solid Tumors partial responses resulted. Overall survival after starting lenvatinib was two, six, and seven months. Fatigue and hypertension were prominent, and one patient developed pulmonary emboli while on lenvatinib. This initial single-institution experience suggests that lenvatinib may have some disease-modifying activity in metastatic ATC that is otherwise refractory to cytotoxic chemotherapy. Unfortunately, observed benefits were transient, and toxicities were prominent. Clinical trials are required

A Study of Varlilumab and Atezolizumab in Patients With Advanced Cancer

ClinicalTrials.gov

2018-04-26

Carcinoma, Renal Cell; Kidney Diseases; Kidney Neoplasms; Urogenital Neoplasms; Urologic Diseases; Urologic Neoplasms; Neoplasms by Histologic Type; Neoplasms; Clear-cell Metastatic Renal Cell Carcinoma; Melanoma; Triple Negative Breast Cancer; Bladder Cancer; Head and Neck Cancer; Non-small Cell Lung Cancer

Temsirolimus and Vinorelbine Ditartrate in Treating Patients With Unresectable or Metastatic Solid Tumors

ClinicalTrials.gov

2016-06-09

Extensive Stage Small Cell Lung Cancer; Hereditary Paraganglioma; Male Breast Cancer; Malignant Paraganglioma; Metastatic Gastrointestinal Carcinoid Tumor; Metastatic Pheochromocytoma; Pancreatic Polypeptide Tumor; Recurrent Breast Cancer; Recurrent Cervical Cancer; Recurrent Endometrial Carcinoma; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Islet Cell Carcinoma; Recurrent Neuroendocrine Carcinoma of the Skin; Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Pheochromocytoma; Recurrent Prostate Cancer; Recurrent Renal Cell Cancer; Recurrent Small Cell Lung Cancer; Recurrent Uterine Sarcoma; Regional Gastrointestinal Carcinoid Tumor; Regional Pheochromocytoma; Stage III Cervical Cancer; Stage III Endometrial Carcinoma; Stage III Neuroendocrine Carcinoma of the Skin; Stage III Ovarian Epithelial Cancer; Stage III Ovarian Germ Cell Tumor; Stage III Prostate Cancer; Stage III Renal Cell Cancer; Stage III Uterine Sarcoma; Stage IIIA Breast Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Breast Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Stage IV Endometrial Carcinoma; Stage IV Neuroendocrine Carcinoma of the Skin; Stage IV Non-small Cell Lung Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Ovarian Germ Cell Tumor; Stage IV Prostate Cancer; Stage IV Renal Cell Cancer; Stage IV Uterine Sarcoma; Stage IVA Cervical Cancer; Stage IVB Cervical Cancer; Thyroid Gland Medullary Carcinoma

FDA Approval Summary: Temsirolimus as Treatment for Advanced Renal Cell Carcinoma

PubMed Central

Prowell, Tatiana M.; Ibrahim, Amna; Farrell, Ann T.; Justice, Robert; Mitchell, Shan Sun; Sridhara, Rajeshwari; Pazdur, Richard

2010-01-01

This report summarizes the U.S. Food and Drug Administration (FDA)'s approval of temsirolimus (Torisel®), on May 30, 2007, for the treatment of advanced renal cell carcinoma (RCC). Information provided includes regulatory history, study design, study results, and literature review. A multicenter, three-arm, randomized, open-label study was conducted in previously untreated patients with poor-prognosis, advanced RCC. The study objectives were to compare overall survival (OS), progression-free survival (PFS), objective response rate, and safety in patients receiving interferon (IFN)-α versus those receiving temsirolimus alone or in combination with IFN-α. In the second planned interim analysis of the intent-to-treat population (n = 626), there was a statistically significant longer OS time in the temsirolimus (25 mg) arm than in the IFN-α arm (median, 10.9 months versus 7.3 months; hazard ratio [HR], 0.73; p = .0078). The combination of temsirolimus (15 mg) and IFN-α did not lead to a significant difference in OS compared with IFN-α alone. There was also a statistically significant longer PFS time for the temsirolimus (25 mg) arm than for the IFN-α arm (median, 5.5 months versus 3.1 months; HR, 0.66, p = .0001). Common adverse reactions reported in patients receiving temsirolimus were rash, asthenia, and mucositis. Common laboratory abnormalities were anemia, hyperglycemia, hyperlipidemia, and hypertriglyceridemia. Serious but rare cases of interstitial lung disease, bowel perforation, and acute renal failure were observed. Temsirolimus has demonstrated superiority in terms of OS and PFS over IFN-α and provides an additional treatment option for patients with advanced RCC. PMID:20332142

A Study to Assess the Efficacy of IMAB362 Plus mFOLFOX6 Compared With Placebo Plus mFOLFOX6 as First-line Treatment of Subjects With Claudin (CLDN) 18.2 Positive, HER2-Negative, Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma

ClinicalTrials.gov

2018-05-30

Locally Advanced Unresectable Gastroesophageal Junction (GEJ) Adenocarcinoma or Cancer; Locally Advanced Unresectable Gastric Adenocarcinoma or Cancer; Metastatic Gastric Adenocarcinoma or Cancer; Metastatic Gastroesophageal Junction (GEJ) Adenocarcinoma

Multicenter phase II trial of combination therapy with meloxicam, a cox-2 inhibitor, and natural interferon-alpha for metastatic renal cell carcinoma.

PubMed

Shinohara, Nobuo; Kumagai, Akira; Kanagawa, Kouichi; Maruyama, Satoru; Abe, Takashige; Sazawa, Ataru; Nonomura, Katsuya

2009-11-01

We conducted a Phase II trial to investigate the efficacy of combined therapy with meloxicam, a cyclooxygenase-2 inhibitor and natural interferon (IFN)-alpha in renal cell carcinoma patients with distant metastasis. The subjects of this study were patients with untreated renal cell carcinoma who were diagnosed from the results of imaging or pathological studies and who had measurable lesions according to the Response Evaluation Criteria in Solid Tumors (RECIST). Patients could be enrolled in the study irrespective of whether nephrectomy had been performed. Treatment involved the subcutaneous injection of natural IFN-alpha at 3 x 10(6) or 5 x 10(6) U three times weekly plus oral administration of meloxicam at 10 mg once daily. A total of 43 patients were enrolled in the present study, included 11 patients without nephrectomy, 23 patients with a high C-reactive protein (CRP) level and 23 patients with extrapulmonary metastasis. Four patients of complete response and 12 patients of partial response were confirmed, given an overall response rate of 37.2% (95% confidence interval, 23.0-53.3%). Stable disease for 6 months or longer was also obtained in 14 patients. The median time to progression was 14 months. Adverse events (AEs) observed were mainly flu-like symptoms due to cytokine. Although the Grade 3 or 4 AEs were fatigue, hepatic dysfunction, arthritis and gastric ulcer, all but one (gastric ulcer) were immediately improved by discontinuation of this combined therapy. The combination of meloxicam and natural IFN-alpha is considered to be an active regimen with tolerable toxicities as a first-line treatment of metastatic renal cell carcinoma.

Bioengineering in renal transplantation: technological advances and novel options.

PubMed

Yeo, Wee-Song; Zhang, Yao-Chun

2017-06-06

End-stage kidney disease (ESKD) is one of the most prevalent diseases in the world with significant morbidity and mortality. Current modes of renal replacement therapy include dialysis and renal transplantation. Although dialysis is an acceptable mode of renal replacement therapy, it does have its shortcomings, which include poorer life expectancy compared with renal transplantation, risk of infections and vascular thrombosis, lack of vascular access and absence of biosynthetic functions of the kidney. Renal transplantation, in contrast, is the preferred option of renal replacement therapy, with improved morbidity and mortality rates and quality of life, compared with dialysis. Renal transplantation, however, may not be available to all patients with ESKD. Some of the key factors limiting the availability and efficiency of renal transplantation include shortage of donor organs and the constant risk of rejection with complications associated with over-immunosuppression respectively. This review focuses chiefly on the potential roles of bioengineering in overcoming limitations in renal transplantation via the development of cell-based bioartificial dialysis devices as bridging options before renal transplantation, and the development of new sources of organs utilizing cell and organ engineering.

[c-MET Oncogene in Renal Cell Carcinomas].

PubMed

Erlmeier, F; Weichert, W; Autenrieth, M; Ivanyi, P; Hartmann, A; Steffens, S

2016-12-01

c-Met plays a significant role in multiple cellular processes. Being encoded by a proto-oncogene, tyrosine kinase supports aggressive tumour behaviour such as tumour invasiveness and formation of metastases. For some subtypes of renal cell carcinoma studies have shown a association between c-Met expression and clinical outcome or prognosis. Therefore, c-Met represents a prognostic marker in renal cell carcinoma.Furthermore, c-MET will play a decisive role as a possible target for targeted therapies in the era of personalised medicine. Especially for RCC, the dual inhibition of VEGF and c-MET tyrosine kinase in cases of metastatic, treatment-resistant tumours is gaining clinical relevance. The role of c-Met has not been fully elucidated for all subtypes of renal cell carcinomas. The relevance of c-Met for the remaining subtypes of renal tumours has yet to be clarified. © Georg Thieme Verlag KG Stuttgart · New York.

Ribociclib and Doxorubicin in Treating Patients With Metastatic or Advanced Soft Tissue Sarcomas That Cannot Be Removed by Surgery

ClinicalTrials.gov

2018-05-09

Metastatic Angiosarcoma; Metastatic Epithelioid Sarcoma; Metastatic Fibrosarcoma; Metastatic Leiomyosarcoma; Metastatic Liposarcoma; Metastatic Malignant Peripheral Nerve Sheath Tumor; Metastatic Synovial Sarcoma; Metastatic Undifferentiated Pleomorphic Sarcoma; Myxofibrosarcoma; Pleomorphic Rhabdomyosarcoma; Stage III Soft Tissue Sarcoma; Stage IV Soft Tissue Sarcoma; Undifferentiated (Embryonal) Sarcoma

Bevacizumab plus interferon-α versus sunitinib for first-line treatment of renal cell carcinoma in Italy: a cost-minimization analysis.

PubMed

Ravasio, Roberto; Ortega, Cinzia; Sabbatini, Roberto; Porta, Camillo

2011-01-01

Renal cell carcinoma (RCC) is the most common form of kidney cancer. Immunotherapy with interferon-α (IFNα) and interleukin-2 (IL-2) has been the historical therapy of choice for the treatment of locally advanced or metastatic RCC prior to the more recent development of targeted therapies, including sunitinib and bevacizumab (combined with IFNα). Clinically and statistically significant advantages have been shown with both sunitinib and the combination of bevacizumab + IFNα versus IFNα alone in the treatment of advanced or metastatic RCC. The present study evaluated the incremental costs of bevacizumab + IFNα versus sunitinib for the first-line treatment of advanced or metastatic RCC assuming similar efficacy for these treatments. The efficacy profiles of bevacizumab + IFNα or sunitinib alone have been shown (indirectly) to be similar in patients with RCC; indeed, median progression-free survival (PFS) with either treatment is in the 10- to 11-month range. Therefore, a cost-minimization analysis was performed, focusing on direct medical costs only (drugs, administration and management of adverse events). The analysis considered the perspective of the Italian National Health Service (NHS), comparing the cost of bevacizumab (10 mg/kg) plus IFNα (9, 6 or 3 million IU [MIU]) versus sunitinib (50 mg) as first-line therapies for advanced or metastatic clear-cell RCC. The average cost per treated patient (year 2010 values) was assessed for the two treatment options at 11 months (median PFS). Assuming a PFS of 11 months for both treatment options, bevacizumab + IFNα (9 MIU) would be a lower cost strategy (cost savings of €2052 per patient) than sunitinib. This difference arises mainly from the reduction in the acquisition cost of bevacizumab to the NHS (risk-sharing agreement). The cost advantages for bevacizumab would increase in parallel with a reduction in IFNα dosing; for example, with IFNα 6 MIU the corresponding cost savings would be

Sunitinib-induced hypothyroidism predicts progression-free survival in metastatic renal cell carcinoma patients.

PubMed

Buda-Nowak, Anna; Kucharz, Jakub; Dumnicka, Paulina; Kuzniewski, Marek; Herman, Roman Maria; Zygulska, Aneta L; Kusnierz-Cabala, Beata

2017-04-01

Sunitinib is a tyrosine kinase inhibitor (TKI) used in treatment of metastatic renal cell carcinoma (mRCC), gastrointestinal stromal tumors and pancreatic neuroendocrine tumors. One of the most common side effects related to sunitinib is hypothyroidism. Recent trials suggest correlation between the incidence of hypothyroidism and treatment outcome in patients treated with TKI. This study evaluates whether development of hypothyroidism is a predictive marker of progression-free survival (PFS) in patients with mRCC treated with sunitinib. Twenty-seven patients diagnosed with clear cell mRCC, after nephrectomy and in 'good' or 'intermediate' MSKCC risk prognostic group, were included in the study. All patients received sunitinib as a first-line treatment on a standard schedule (initial dose 50 mg/day, 4 weeks on, 2 weeks off). The thyroid-stimulating hormone serum levels were obtained at the baseline and every 12 weeks of treatment. In statistic analyses, we used Kaplan-Meier method for assessment of progression-free survival; for comparison of survival, we used log-rank test. In our study, the incidence of hypothyroidism was 44%. The patients who had developed hypothyroidism had better median PFS to patients with normal thyroid function 28,3 months [95% (CI) 20.4-36.2 months] versus 9.8 months (6.4-13.1 months). In survival analysis, we perceive that thyroid dysfunction is a predictive factor of a progression-free survival (PFS). In the unified group of patients, the development of hypothyroidism during treatment with sunitinib is a positive marker for PFS. During that treatment, thyroid function should be evaluated regularly.

Overall Survival of Patients with Locally Advanced or Metastatic Esophageal Squamous Cell Carcinoma Treated with Nimotuzumab in the Real World.

PubMed

Saumell, Yaimarelis; Sanchez, Lizet; González, Sandra; Ortiz, Ramón; Medina, Edadny; Galán, Yaima; Lage, Agustin

2017-12-01

Despite improvements in surgical techniques and treatments introduced into clinical practice, the overall survival of patients with esophageal squamous cell carcinoma remains low. Several epidermal growth factor receptor inhibitors are being evaluated in the context of clinical trials, but there is little evidence of effectiveness in real-world conditions. This study aimed at assessing the effectiveness of nimotuzumab combined with onco-specific treatment in Cuban real-life patients with locally advanced or metastatic esophageal squamous cell carcinoma. A comparative and retrospective effectiveness study was performed. The 93 patients treated with nimotuzumab were matched, with use of propensity score matching, with patients who received a diagnosis of locally advanced or metastatic squamous cell carcinoma of the esophagus in three Cuban provinces reported between 2011 and 2015 to the National Cancer Registry. The Kaplan-Meier method was used to estimate event-time distributions. Log-rank statistics were used for comparisons of overall survival between groups. A two-component mixture model assuming a Weibull distribution was fitted to assess the effect of nimotuzumab on short-term and long-term survival populations. There was an increase in median overall survival in patients treated with nimotuzumab (11.9 months versus 6.5 months without treatment) and an increase in the 1-year survival rate (54.0% versus 21.9% without treatment). The 2-year survival rates were 21.1% for patients treated with nimotuzumab and 0% in the untreated cohort. There were statistically significant differences in survival between groups treated and not treated with nimotuzumab, both in the short-term survival population (6.0 months vs 4.0 months, p = 0.009) and in the long-term survival population (18.0 months vs 11.0 months, p = 0.001). Our study shows that nimotuzumab treatment concurrent with chemoradiotherapy increases the survival of real-world patients with locally advanced

Disparate effects of single endothelin A and B receptor blocker therapy on the progression of renal injury in advanced renovascular disease

PubMed Central

Chade, Alejandro R.; Stewart, Nicholas J.; Peavy, Patrick R.

2013-01-01

We hypothesized that chronic specific endothelin (ET)-A receptor blockade therapy would reverse renal dysfunction and injury in advanced experimental renovascular disease. To test this, unilateral renovascular disease was induced in 19 pigs and after 6 weeks, single-kidney hemodynamics and function was quantified in vivo using computed-tomography. All pigs with renovascular disease were divided such that 7 were untreated, 7 were treated with ET-A blockers, and 5 were treated with ET-B blockers. Four weeks later, all pigs were re-studied in vivo, then euthanized and ex vivo studies performed on the stenotic kidney to quantify microvascular density, remodeling, renal oxidative stress, inflammation, and fibrosis. RBF, GFR, and redox status were significantly improved in the stenotic kidney after ET-A but not ET-B blockade. Furthermore, only ET-A blockade therapy reversed renal microvascular rarefaction and diminished remodeling, which was accompanied by a marked decreased in renal inflammatory and fibrogenic activity. Thus, ET-A but not ET-B blockade ameliorated renal injury in pigs with advanced renovascular disease by stimulating microvascular proliferation and decreasing the progression of microvascular remodeling, renal inflammation and fibrosis in the stenotic kidney. These effects were functionally consequential since ET-A blockade improved single kidney microvascular endothelial function, RBF, and GFR, and decreased albuminuria. PMID:24352153

Role of the neural niche in brain metastatic cancer

PubMed Central

Termini, John; Neman, Josh; Jandial, Rahul

2014-01-01

Metastasis is the relenteless pursuit of cancer to escape its primary site and colonize distant organs. This malignant evolutionary process is biologically heterogeneous, yet one unifying element is the critical role of the microenvironment for arriving metastatic cells. Historically brain metastases were rarely investigated since patients with advanced cancer were considered terminal. Fortunately, advances in molecular therapies have led to patients living longer with metastatic cancer. However, one site remains recalcitrant to our treatment efforts – the brain. The central nervous system is the most complex biological system, which poses unique obstacles but also harbors opportunities for discovery. Much of what we know about the brain microenvironment comes from neuroscience. We suggest that the interrelated cellular responses in traumatic brain injury may guide us towards new perspectives in understanding brain metastases. In this view, brain metastases may be conceptualized as progressive oncologic injury to the nervous system. This review discusses our evolving understanding of the bidirectional interactions between the brain milieu and metastatic cancer. PMID:25035392

Distinctive expression patterns of glycoprotein non-metastatic B and folliculin in renal tumors in patients with Birt–Hogg–Dubé syndrome

PubMed Central

Furuya, Mitsuko; Hong, Seung-Beom; Tanaka, Reiko; Kuroda, Naoto; Nagashima, Yoji; Nagahama, Kiyotaka; Suyama, Takahito; Yao, Masahiro; Nakatani, Yukio

2015-01-01

Birt–Hogg–Dubé syndrome (BHD) is an inherited disorder associated with a germline mutation of the folliculin gene (FLCN). The affected families have a high risk for developing multiple renal cell carcinomas (RCC). Diagnostic markers that distinguish between FLCN-related RCC and sporadic RCC have not been investigated, and many patients with undiagnosed BHD fail to receive proper medical care. We investigated the histopathology of 27 RCCs obtained from 18 BHD patients who were diagnosed by genetic testing. Possible somatic mutations of RCC lesions were investigated by DNA sequencing. Western blotting and immunohistochemical staining were used to compare the expression levels of FLCN and glycoprotein non-metastatic B (GPNMB) between FLCN-related RCCs and sporadic renal tumors (n = 62). The expression of GPNMB was also evaluated by quantitative RT-PCR. Histopathological analysis revealed that the most frequent histological type was chromophobe RCC (n = 12), followed by hybrid oncocytic/chromophobe tumor (n = 6). Somatic mutation analysis revealed small intragenic mutations in six cases and loss of heterozygosity in two cases. Western blot and immunostaining analyses revealed that FLCN-related RCCs showed overexpression of GPNMB and underexpression of FLCN, whereas sporadic tumors showed inverted patterns. GPNMB mRNA in FLCN-related RCCs was 23-fold more abundant than in sporadic tumors. The distinctive expression patterns of GPNMB and FLCN might identify patients with RCCs who need further work-up for BHD. PMID:25594584

Vascular endothelial growth factor-targeted therapy for the treatment of adult metastatic Xp11.2 translocation renal cell carcinoma.

PubMed

Choueiri, Toni K; Lim, Zita Dubauskas; Hirsch, Michelle S; Tamboli, Pheroze; Jonasch, Eric; McDermott, David F; Dal Cin, Paola; Corn, Paul; Vaishampayan, Ulka; Heng, Daniel Y C; Tannir, Nizar M

2010-11-15

Adult "translocation" renal cell carcinoma (RCC), bearing transcription factor E3 (TFE3) gene fusions at Xp11.2, is a recently recognized, unique entity for which prognosis and therapy remain poorly understood. In the current study, the authors investigated the effect of vascular endothelial growth factor (VEGF)-targeted therapy in this distinct subtype of RCC. A retrospective review was conducted to describe the clinical characteristics and outcome of adult patients with metastatic Xp11.2 RCC who had strong TFE3 nuclear immunostaining and received anti-VEGF therapy. Tumor response to anti-VEGF therapy was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS) distributions. Fifteen patients were identified, of whom 10, 3, and 2 received sunitinib, sorafenib, and monoclonal anti-VEGF antibodies, respectively. The median follow-up was 19.1 months, the median age of the patients was 41 years, and the female:male ratio was 4:1. Initial histologic description included clear cell (n = 8 patients), papillary (n = 1 patient), or mixed clear cell/papillary RCC (n = 6 patients). Five patients had received prior systemic therapy. Five patients had undergone fluorescent in situ hybridization analysis and all demonstrated a translocation involving chromosome Xp11.2. When treated with VEGF-targeted therapy, 3 patients achieved a partial response, 7 patients had stable disease, and 5 patients developed progressive disease. The median PFS and OS of the entire cohort were 7.1 months and 14.3 months, respectively. Adult-onset, translocation-associated metastatic RCC is an aggressive disease that affects a younger population of patients with a female predominance. In the current study, VEGF-targeted agents appeared to demonstrate some efficacy. Copyright © 2010 American Cancer Society.

Vascular endothelial growth factor (VEGF)-targeted therapy for the treatment of adult metastatic Xp11.2 translocation renal cell carcinoma

PubMed Central

Choueiri, Toni K.; Lim, Zita Dubauskas; Hirsch, Michelle S.; Tamboli, Pheroze; Jonasch, Eric; McDermott, David F.; Cin, Paola Dal; Corn, Paul; Vaishampayan, Ulka; Heng, Daniel Y.C.; Tannir, Nizar M.

2015-01-01

Introduction Adult “translocation” renal cell carcinoma (RCC), bearing TFE3 gene fusions at Xp11.2, is a recently recognized unique entity for which prognosis and therapy remain poorly understood. We investigated the effect of vascular-endothelial growth factor (VEGF)-targeted therapy in this distinct subtype of RCC. Patients and Methods We conducted a retrospective review to describe the clinical characteristics and outcome of adult patients with metastatic Xp11.2 RCC, who had strong TFE-3 nuclear immunostaining, and received anti-VEGF therapy. Tumor response to anti-VEGF therapy was evaluated by RECIST. Kaplan-Meier methods were used to estimate progression-free survival (PFS) and overall survival (OS) distributions. Results Fifteen patients were identified of which 10, 3, and 2 received sunitinib, sorafenib and monoclonal anti-VEGF antibodies, respectively. The median follow-up was 19.1 months, the median age of the patients was 41 years, and the female:male ratio was 4:1. Initial histologic description included clear cell (n=8), papillary (n=1) or mixed clear cell/papillary RCC (n=6). Five patients had prior systemic therapy. Five patients had FISH analysis and all demonstrated a translocation involving chromosome Xp11.2. When treated with VEGF-targeted therapy, 3 patients had a partial response, 7 patients had stable disease and 5 patients had progressive disease. The median PFS and OS of the entire cohort were 7.1 months and 14.3 months respectively. Conclusion Adult-onset translocation-associated metastatic RCC is an aggressive disease that affects a younger population of patients with a female predominance. VEGF-targeted agents demonstrated some efficacy in this small retrospective series. PMID:20665500

Metastatic patterns and metastatic sites in mucosal melanoma: a retrospective study.

PubMed

Grözinger, Gerd; Mann, Steven; Mehra, Tarun; Klumpp, Bernhard; Grosse, Ulrich; Nikolaou, Konstantin; Garbe, Claus; Clasen, Stephan

2016-06-01

Melanomas arising from mucosa are rare and associated with a poor prognosis. This study aims to provide an analysis of metastatic pathways, time intervals, factors influencing metastatic spread and organs for distant metastases. A total of 116 patients with mucosal melanomas of different sites were included. The mean follow-up interval was 47 ± 52 months. Patients were assigned to two different metastatic pathways, either presenting loco-regional lymph node metastases as first spread or direct distant metastases. The distribution of distant metastases was assessed. Twenty-six patients presented with a pre-existing metastatic spread and were not assigned to pathways. Of the included patients, 44 developed metastases after treatment of the primary tumour; 25 patients directly developed distant metastases; 16 patients developed regional lymph node metastases prior to distant metastases. Location of the primary tumour in the upper airway or GI tract and advanced T stage were significant risk factors of direct distant metastases. Distant metastases are mainly located in the lung, the liver and non-regional lymph nodes. Mucosal melanomas show a high rate of direct distant metastases rather than regional lymph node metastases. Thus the follow-up should always include a whole-body cross-sectional imaging in high-risk tumours. • Mucosal melanomas show a high rate of direct distant metastases. • T stage and primary location are predictors for direct distant metastases. • Distant metastases were mainly found in lung, liver and lymph nodes. • Follow-up of a high-risk mucosal melanoma should include whole-body imaging.

Breast Cancer with Synchronous Renal Cell Carcinoma: A Rare Presentation.

PubMed

Arjunan, Ravi; Kumar, Durgesh; Kumar, K V Veerendra; Premlatha, C S

2016-10-01

Primary cancer arising from multiple organs is a well known fact. Synchronous tumours have been most commonly associated with kidney cancer. Bladder, prostate, colorectal and lung cancer are the most common synchronous primaries with Renal Cell Carcinoma (RCC) identified till date. We found metachronous tumours of breast with RCC in literature search which included both metastatic tumours as well second primaries. Overall, 25 cases of metastatic breast tumours and eight cases of second primary in previously treated RCC have been reported in the literature. Here, we are reporting a case of synchronous presentation of carcinoma breast with RCC which is very rare because most of the multiple malignancies reported in the literature are metastatic tumours or metachronous breast malignancy with RCC.

Breast Cancer with Synchronous Renal Cell Carcinoma: A Rare Presentation

PubMed Central

Arjunan, Ravi; Kumar, K V Veerendra; Premlatha, C S

2016-01-01

Primary cancer arising from multiple organs is a well known fact. Synchronous tumours have been most commonly associated with kidney cancer. Bladder, prostate, colorectal and lung cancer are the most common synchronous primaries with Renal Cell Carcinoma (RCC) identified till date. We found metachronous tumours of breast with RCC in literature search which included both metastatic tumours as well second primaries. Overall, 25 cases of metastatic breast tumours and eight cases of second primary in previously treated RCC have been reported in the literature. Here, we are reporting a case of synchronous presentation of carcinoma breast with RCC which is very rare because most of the multiple malignancies reported in the literature are metastatic tumours or metachronous breast malignancy with RCC. PMID:27891445

A pooled analysis of sequential therapies with sorafenib and sunitinib in metastatic renal cell carcinoma.

PubMed

Stenner, Frank; Chastonay, Rahel; Liewen, Heike; Haile, Sarah R; Cathomas, Richard; Rothermundt, Christian; Siciliano, Raffaele D; Stoll, Susanna; Knuth, Alexander; Buchler, Tomas; Porta, Camillo; Renner, Christoph; Samaras, Panagiotis

2012-01-01

To evaluate the optimal sequence for the receptor tyrosine kinase inhibitors (rTKIs) sorafenib and sunitinib in metastatic renal cell cancer. We performed a retrospective analysis of patients who had received sequential therapy with both rTKIs and integrated these results into a pooled analysis of available data from other publications. Differences in median progression-free survival (PFS) for first- (PFS1) and second-line treatment (PFS2), and for the combined PFS (PFS1 plus PFS2) were examined using weighted linear regression. In the pooled analysis encompassing 853 patients, the median combined PFS for first-line sunitinib and 2nd-line sorafenib (SuSo) was 12.1 months compared with 15.4 months for the reverse sequence (SoSu; 95% CI for difference 1.45-5.12, p = 0.0013). Regarding first-line treatment, no significant difference in PFS1 was noted regardless of which drug was initially used (0.62 months average increase on sorafenib, 95% CI for difference -1.01 to 2.26, p = 0.43). In second-line treatment, sunitinib showed a significantly longer PFS2 than sorafenib (average increase 2.66 months, 95% CI 1.02-4.3, p = 0.003). The SoSu sequence translates into a longer combined PFS compared to the SuSo sequence. Predominantly the superiority of sunitinib regarding PFS2 contributed to the longer combined PFS in sequential use. Copyright © 2012 S. Karger AG, Basel.

The Impact of Renin-Angiotensin System Blockade on Renal Outcomes and Mortality in Pre-Dialysis Patients with Advanced Chronic Kidney Disease.

PubMed

Oh, Yun Jung; Kim, Sun Moon; Shin, Byung Chul; Kim, Hyun Lee; Chung, Jong Hoon; Kim, Ae Jin; Ro, Han; Chang, Jae Hyun; Lee, Hyun Hee; Chung, Wookyung; Lee, Chungsik; Jung, Ji Yong

2017-01-01

Renin-angiotensin-system (RAS) blockade is thought to slow renal progression in patients with chronic kidney disease (CKD). However, it remains uncertain if the habitual use of RAS inhibitors affects renal progression and outcomes in pre-dialysis patients with advanced CKD. In this multicenter retrospective cohort study, we identified 2,076 pre-dialysis patients with advanced CKD (stage 4 or 5) from a total of 33,722 CKD patients. RAS blockade users were paired with non-users for analyses using inverse probability of treatment-weighted (IPTW) and propensity score (PS) matching. The outcomes were renal death, all-cause mortality, hospitalization for hyperkalemia, and interactive factors as composite outcomes. RAS blockade users showed an increased risk of renal death in PS-matched analysis (hazard ratio [HR], 1.381; 95% CI, 1.071-1.781; P = 0.013), which was in agreement with the results of IPTW analysis (HR, 1.298; 95% CI, 1.123-1.500; P < 0.001). The risk of composite outcomes was higher in RAS blockade users in IPTW (HR, 1.154; 95% CI, 1.016-1.310; P = 0.027), but was marginal significance in PS matched analysis (HR, 1.243; 95% CI, 0.996-1.550; P = 0.054). The habitual use of RAS blockades in pre-dialysis patients with advanced CKD may have a detrimental effect on renal outcome without improving all-cause mortality. Further studies are warranted to determine whether withholding RAS blockade may lead to better outcomes in these patients.

Neutrophil-to-lymphocyte Ratio, Platelet-to-lymphocyte Ratio, and C-reactive Protein as New and Simple Prognostic Factors in Patients With Metastatic Renal Cell Cancer Treated With Tyrosine Kinase Inhibitors: A Systemic Review and Meta-analysis.

PubMed

Semeniuk-Wojtaś, Aleksandra; Lubas, Arkadiusz; Stec, Rafał; Syryło, Tomasz; Niemczyk, Stanisław; Szczylik, Cezary

2018-02-02

Inflammation plays a crucial role in cancer development. In this study, we evaluate the prognostic values of systemic inflammation markers such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and C-reactive protein (CRP) for the progression-free survival and overall survival in patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors. PubMed and the Cochrane Library databases were searched for published studies on the effect of NLR, PLR, and CRP in patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors. In the meta-analysis, NLR (hazard ratio [HR], 2.01; 95% confidence interval [CI], 1.27-3.18; P = .003) and PLR (HR, 6.96; 95% CI, 5.04-9.62; P < .001) had a significant influence on progression-free survival, whereas all considered proinflammatory markers had a significant impact on overall survival: NLR (HR, 2.14; 95% CI, 1.67-2.73; P < .001), PLR (HR, 14.67; 95% CI, 11.10-19.57; P < .001), and CRP (HR, 1.96; 95% CI, 1.26-3.05; P = .003). Inflammation markers such as NLR, PLR, and CRP are predictors of clinical outcome and could provide additional information to individualize treatment. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

The Place of FDG PET/CT in Renal Cell Carcinoma: Value and Limitations

PubMed Central

Liu, Yiyan

2016-01-01

Unlike for most other malignancies, application of FDG PET/CT is limited for renal cell carcinoma (RCC), mainly due to physiological excretion of 18F-fluoro-2-deoxy-2-d-glucose (FDG) from the kidneys, which decreases contrast between renal lesions and normal tissue, and may obscure or mask the lesions of the kidneys. Published clinical observations were discordant regarding the role of FDG PET/CT in diagnosing and staging RCC, and FDG PET/CT is not recommended for this purpose based on current national and international guidelines. However, quantitative FDG PET/CT imaging may facilitate the prediction of the degree of tumor differentiation and allows for prognosis of the disease. FDG PET/CT has potency as an imaging biomarker to provide useful information about patient’s survival. FDG PET/CT can be effectively used for postoperative surveillance and restaging with high sensitivity, specificity, and accuracy, as early diagnosis of recurrent/metastatic disease can drastically affect therapeutic decision and alter outcome of patients. FDG uptake is helpful for differentiating benign or bland emboli from tumor thrombosis in RCC patients. FDG PET/CT also has higher sensitivity and accuracy when compared with bone scan to detect RCC metastasis to the bone. FDG PET/CT can play a strong clinical role in the management of recurrent and metastatic RCC. In monitoring the efficacy of new target therapy such as tyrosine kinase inhibitors (TKIs) treatment for advanced RCC, FDG PET/CT has been increasingly used to assess the therapeutic efficacy, and change in FDG uptake is a strong indicator of biological response to TKI. PMID:27656421

Health-related quality-of-life parameters as independent prognostic factors in advanced or metastatic bladder cancer.

PubMed

Roychowdhury, D F; Hayden, A; Liepa, A M

2003-02-15

This retrospective analysis examined prognostic significance of health-related quality-of-life (HRQoL) parameters combined with baseline clinical factors on outcomes (overall survival, time to progressive disease, and time to treatment failure) in bladder cancer. Outcome and HRQoL (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30) data were collected prospectively in a phase III study assessing gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in locally advanced or metastatic bladder cancer. Prespecified baseline clinical factors (performance status, tumor-node-metastasis staging, visceral metastases [VM], alkaline phosphatase [AP] level, number of metastatic sites, prior radiotherapy, disease measurability, sex, time from diagnosis, and sites of disease) and selected HRQoL parameters (global QoL; all functional scales; symptoms: pain, fatigue, insomnia, dyspnea, anorexia) were evaluated using Cox's proportional hazards model. Factors with individual prognostic value (P <.05) on outcomes in univariate models were assessed for joint prognostic value in a multivariate model. A final model was developed using a backward selection strategy. Patients with baseline HRQoL were included (364 of 405, 90%). The final model predicted longer survival with low/normal AP levels, no VM, high physical functioning, low role functioning, and no anorexia. Positive prognostic factors for time to progressive disease were good performance status, low/normal AP levels, no VM, and minimal fatigue; for time to treatment failure, they were low/normal AP levels, minimal fatigue, and no anorexia. Global QoL was a significant predictor of outcome in univariate analyses but was not retained in the multivariate model. HRQoL parameters are independent prognostic factors for outcome in advanced bladder cancer; their prognostic importance needs further evaluation.

A phase 2 study of vatalanib in metastatic melanoma patients.

PubMed

Cook, Natalie; Basu, Bristi; Biswas, Swethajit; Kareclas, Paula; Mann, Colette; Palmer, Cheryl; Thomas, Anne; Nicholson, Steve; Morgan, Bruno; Lomas, David; Sirohi, Bhawna; Mander, Adrian P; Middleton, Mark; Corrie, Pippa G

2010-10-01

A phase 2 study of vatalanib (PTK787/ZK222584) an oral tyrosine kinase inhibitor of VEGFR 1, 2 and 3 was undertaken in patients with metastatic melanoma. Adults with pathologically confirmed metastatic melanoma, WHO Performance status 0-2, and adequate haematological, hepatic and renal function, were treated with vatalanib until disease progression. The trial used Fleming's single stage design. Tumour control rate (CR+PR+SD) was 35% at 16 weeks, with objective response seen in only 1 patient. Median progression-free survival was 1.8 months (95% CI 1.8-3.7 months) and median overall survival was 6.5 months (95% CI 3.9-10.2 months). Vatalanib stabilised disease in a proportion of patients, although overall survival was disappointing. Copyright © 2010 Elsevier Ltd. All rights reserved.

Renal cell -like carcinoma of the nasal cavity: a case report and review of the literature.

PubMed

Zhenwei-Chen; Zhaoming-Wang; Hongqi-Shi; Qinwei-Liu

2017-10-17

Sinonasal renal cell-like carcinoma (SRCLC) is an extremely rare low malignant tumor arising in the sinonasal tract, with histological mimicry of renal cell carcinoma. We present a case of sinonasal renal cell-like carcinoma in a 63-year-old male patient. Computer tomography(CT) scanning revealed a soft tissue mass at the left nasal cavity and choana. Histologically, the predominant tumor architecture was follicular to glandular with intervening fibrous septa. The tumor cells were uniform cuboidal to polyhedral with abundant clear or eosinophilic cytoplasm. Immunohistochemically, the tumor cells were strongly positive for CK7, EMA, vimentin, SOX10, S-100, and focally positive for CA9. During 6 months of follow-up, there was no clinical or radiological evidence of recurrence or metastasis. SRCLC has microscopic features which overlap with tumors that contain clear cells. Thus, several other tumors must be considered in the differential diagnosis of a tumor of the sinonasal region with clear cells, especially metastatic renal clear cell carcinoma. SRCLC is an indolent tumor and none of the reported SRCLC patients had metastatic disease.

Advanced glycation end products in children with chronic renal failure and type 1 diabetes.

PubMed

Misselwitz, Joachim; Franke, Sybille; Kauf, Eberhard; John, Ulrike; Stein, Günter

2002-05-01

Serum levels of advanced glycation end products (AGEs) are markedly elevated in adults with chronic renal failure (CRF) and diabetes mellitus. Accumulation of AGEs in tissues contributes to the development of long-term complications. Up to now little has been known about the formation of AGEs in childhood. We determined serum levels of the well known AGEs pentosidine and Nvarepsilon-carboxymethyllysine (CML) in children with CRF (n=12), end-stage renal disease (ESRD) (n=9), renal transplantation (n=12), and type 1 diabetes mellitus (n=42) and in healthy children (n=20). Pentosidine was measured by high-performance liquid chromatography (HPLC), CML by a competitive enzyme-linked immunosorbent assay (ELISA) system. Serum levels of pentosidine and CML were significantly higher in the children with CRF and ESRD than in controls (P< 0.001), but nearly within the normal range after transplantation. Both AGEs showed a significant negative correlation with creatinine clearance (P< 0.001). During a single session of low-flux hemodialysis, total pentosidine and CML levels did not change. Free pentosidine, however, was reduced by 78% (P=0.04). Diabetic children showed significantly elevated pentosidine levels (P< 0.001) despite normal renal function. We conclude that, similar to adults, increased formation and accumulation of AGEs also exist in children with CRF and type 1 diabetes mellitus. At present the best prevention of AGE-related complications is an early renal transplantation in children with ESRD, as well as a careful metabolic monitoring of diabetics.

Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial

PubMed Central

Motzer, Robert J.; Rini, Brian I.; McDermott, David F.; Redman, Bruce G.; Kuzel, Timothy M.; Harrison, Michael R.; Vaishampayan, Ulka N.; Drabkin, Harry A.; George, Saby; Logan, Theodore F.; Margolin, Kim A.; Plimack, Elizabeth R.; Lambert, Alexandre M.; Waxman, Ian M.; Hammers, Hans J.

2015-01-01

Purpose Nivolumab is a fully human immunoglobulin G4 programmed death–1 immune checkpoint inhibitor antibody that restores T-cell immune activity. This phase II trial assessed the antitumor activity, dose-response relationship, and safety of nivolumab in patients with metastatic renal cell carcinoma (mRCC). Patients and Methods Patients with clear-cell mRCC previously treated with agents targeting the vascular endothelial growth factor pathway were randomly assigned (blinded ratio of 1:1:1) to nivolumab 0.3, 2, or 10 mg/kg intravenously once every 3 weeks. The primary objective was to evaluate the dose-response relationship as measured by progression-free survival (PFS); secondary end points included objective response rate (ORR), overall survival (OS), and safety. Results A total of 168 patients were randomly assigned to the nivolumab 0.3- (n = 60), 2- (n = 54), and 10-mg/kg (n = 54) cohorts. One hundred eighteen patients (70%) had received more than one prior systemic regimen. Median PFS was 2.7, 4.0, and 4.2 months, respectively (P = .9). Respective ORRs were 20%, 22%, and 20%. Median OS was 18.2 months (80% CI, 16.2 to 24.0 months), 25.5 months (80% CI, 19.8 to 28.8 months), and 24.7 months (80% CI, 15.3 to 26.0 months), respectively. The most common treatment-related adverse event (AE) was fatigue (24%, 22%, and 35%, respectively). Nineteen patients (11%) experienced grade 3 to 4 treatment-related AEs. Conclusion Nivolumab demonstrated antitumor activity with a manageable safety profile across the three doses studied in mRCC. No dose-response relationship was detected as measured by PFS. These efficacy and safety results in mRCC support study in the phase III setting. PMID:25452452

Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial.

PubMed

Motzer, Robert J; Rini, Brian I; McDermott, David F; Redman, Bruce G; Kuzel, Timothy M; Harrison, Michael R; Vaishampayan, Ulka N; Drabkin, Harry A; George, Saby; Logan, Theodore F; Margolin, Kim A; Plimack, Elizabeth R; Lambert, Alexandre M; Waxman, Ian M; Hammers, Hans J

2015-05-01

Nivolumab is a fully human immunoglobulin G4 programmed death-1 immune checkpoint inhibitor antibody that restores T-cell immune activity. This phase II trial assessed the antitumor activity, dose-response relationship, and safety of nivolumab in patients with metastatic renal cell carcinoma (mRCC). Patients with clear-cell mRCC previously treated with agents targeting the vascular endothelial growth factor pathway were randomly assigned (blinded ratio of 1:1:1) to nivolumab 0.3, 2, or 10 mg/kg intravenously once every 3 weeks. The primary objective was to evaluate the dose-response relationship as measured by progression-free survival (PFS); secondary end points included objective response rate (ORR), overall survival (OS), and safety. A total of 168 patients were randomly assigned to the nivolumab 0.3- (n = 60), 2- (n = 54), and 10-mg/kg (n = 54) cohorts. One hundred eighteen patients (70%) had received more than one prior systemic regimen. Median PFS was 2.7, 4.0, and 4.2 months, respectively (P = .9). Respective ORRs were 20%, 22%, and 20%. Median OS was 18.2 months (80% CI, 16.2 to 24.0 months), 25.5 months (80% CI, 19.8 to 28.8 months), and 24.7 months (80% CI, 15.3 to 26.0 months), respectively. The most common treatment-related adverse event (AE) was fatigue (24%, 22%, and 35%, respectively). Nineteen patients (11%) experienced grade 3 to 4 treatment-related AEs. Nivolumab demonstrated antitumor activity with a manageable safety profile across the three doses studied in mRCC. No dose-response relationship was detected as measured by PFS. These efficacy and safety results in mRCC support study in the phase III setting. © 2014 by American Society of Clinical Oncology.

The Molecular Landscape of Recurrent and Metastatic Head and Neck Cancers

PubMed Central

Morris, Luc G. T.; Chandramohan, Raghu; West, Lyndsay; Zehir, Ahmet; Chakravarty, Debyani; Pfister, David G.; Wong, Richard J.; Lee, Nancy Y.; Sherman, Eric J.; Baxi, Shrujal S.; Ganly, Ian; Singh, Bhuvanesh; Shah, Jatin P.; Shaha, Ashok R.; Boyle, Jay O.; Patel, Snehal G.; Roman, Benjamin R.; Barker, Christopher A.; McBride, Sean M.; Chan, Timothy A.; Dogan, Snjezana; Hyman, David M.; Berger, Michael F.; Solit, David B.; Riaz, Nadeem; Ho, Alan L.

2016-01-01

IMPORTANCE Recurrent and/or metastatic head and neck cancer is usually incurable. Implementation of precision oncology for these patients has been limited by incomplete understanding of the molecular alterations underlying advanced disease. At the same time, the molecular profiles of many rare head and neck cancer types are unknown. These significant gaps in knowledge need to be addressed to rationally devise new therapies. OBJECTIVE To illuminate the distinct biology of recurrent and metastatic head and neck cancers and review implementation of precision oncology for patients with advanced disease. DESIGN, SETTING, AND PARTICIPANTS After exclusions, 151 patients with advanced, treatment-resistant head and neck tumors, including squamous cell carcinoma (HNSCC), adenoid cystic carcinoma (ACC), and other salivary and cutaneous cancers, whose tumors were sequenced between January 2014 and July 2015 at Memorial Sloan Kettering were recruited. Next-generation sequencing of tumors as part of clinical care included high-depth (median 600×) exonic coverage of 410 cancer genes and whole-genome copy number analysis. INTERVENTIONS Next-generation sequencing of tumors and matched normal DNA. MAIN OUTCOMES AND MEASURES Feasibility, the frequency of actionable molecular alterations, the effect on decision making, and identification of alterations associated with recurrent and metastatic disease. RESULTS Overall, 151 patients (95 men and 56 women; mean [range] age, 61.8 [17-100] years) were included in the study. Next-generation sequencing ultimately guided therapy in 21 of 151 patients (14%) (13 of 53 [25%] of patients with HNSCC) by refining diagnoses and matching patients to specific therapies, in some cases with dramatic responses on basket studies. Molecular alterations were potentially actionable in 28 of 135 patients (21%). The genetic profiles of recurrent and metastatic tumors were often distinct from primary tumors. Compared to primary human papillomavirus (HPV

Epidemiology and therapies for metastatic sarcoma

PubMed Central

Amankwah, Ernest K; Conley, Anthony P; Reed, Damon R

2013-01-01

Sarcomas are cancers arising from the mesenchymal layer that affect children, adolescents, young adults, and adults. Although most sarcomas are localized, many display a remarkable predilection for metastasis to the lungs, liver, bones, subcutaneous tissue, and lymph nodes. Additionally, many sarcoma patients presenting initially with localized disease may relapse at metastatic sites. While localized sarcomas can often be cured through surgery and often radiation, controversies exist over optimal management of patients with metastatic sarcoma. Combinations of chemotherapy are the most effective in many settings, and many promising new agents are under active investigation or are being explored in preclinical models. Metastatic sarcomas are excellent candidates for novel approaches with additional agents as they have demonstrated chemosensitivity and affect a portion of the population that is motivated toward curative therapy. In this paper, we provide an overview on the common sarcomas of childhood (rhabdomyosarcoma), adolescence, and young adults (osteosarcoma, Ewing sarcoma, synovial sarcoma, and malignant peripheral nerve sheath tumor) and older adults (leiomyosarcoma, liposarcoma, and undifferentiated high grade sarcoma) in terms of the epidemiology, current therapy, promising therapeutic directions and outcome with a focus on metastatic disease. Potential advances in terms of promising therapy and biologic insights may lead to more effective and safer therapies; however, more clinical trials and research are needed for patients with metastatic sarcoma. PMID:23700373

Sunitinib-Induced Acute Interstitial Nephritis in a Thrombocytopenic Renal Cell Cancer Patient.

PubMed

Azar, Ibrahim; Esfandiarifard, Saghi; Sinai, Pedram; Wazir, Ali; Foulke, Llewellyn; Mehdi, Syed

2017-01-01

Sunitinib, a multitargeted tyrosine kinase inhibitor (TKI), is currently the standard of care for patients with metastatic renal cell carcinoma. Renal adverse events associated with sunitinib include proteinuria, renal insufficiency secondary to focal segmental glomerulosclerosis (FSGS), and thrombotic microangiopathy. We describe the second reported instance of biopsy-proven sunitinib-induced acute interstitial nephritis (AIN), in a challenging case complicated by thrombocytopenia. The case illustrates the importance of early diagnosis and intervention in ensuring long-term recovery from renal complications. Four other cases of AIN reported along with inhibition of the vascular endothelial growth factor (VEGF) by either TKI (sunitinib and sorafenib) or antibodies (bevacizumab) suggest a possible class effect. Given our experience, we recommend monitoring renal function with VEGF inhibition, and in the case of renal failure in the setting of an unclear diagnosis, we recommend prompt biopsy.

Utilization of advanced-age donors in renal transplantation.

PubMed

Olaverri, J G; Mora Christian, J; Elorrieta, P; Esnaola, K; Rodríguez, P; Marrón, I; Uriarte, I; Landa, M J; Zarraga, S; Gainza, F J; Aranzabal, J; Zabala, J A; Pertusa, C

2011-11-01

The shortage of organ availability in recent years has made it necessary to use grafts from advanced-aged donors to maintain the rate of renal transplantation in our country. The objective of this study was to evaluate the graft function and patient survival using kidneys from deceased donors of over 65 year of age. From 2005 until 2010, we compared the outcomes of patients who received grafts from donors over 65 years old vs less than 65 years. We observed no significant difference in sex, time on dialysis, or cold ischemia time between the groups. As expected the recipient age was significantly different. For the analysis of survival, we used the Tablecloth-Haenzel test and the Kaplan-Meier survival estimator. Actuarial survivals at 3 years after transplantation showed 84.8% among patients transplanted with kidneys from donors over 65 years old versus 97.5% in the control group. The graft survival was 78.8% among expanded criteria versus 86.85% in the control group. When we analyzed graft survival using an "exitus-censured" analysis, we obtained graft survivals of 89.1% in the expanded criteria kidney group versus 88.6% among the controls. We concluded that the use of kidney from donors over 65 years of age allows us to increase the rate of renal transplantation to about 15 to 20 per million population, with good graft and patient survivals provided that the protocol for expanded criteria organs ensured proper macroscopic and microscopic evaluation of the organ for transplantation. Copyright © 2011. Published by Elsevier Inc.

Pazopanib in Metastatic Renal Cancer: A “Real-World” Experience at National Cancer Institute “Fondazione G. Pascale”

PubMed Central

Cecere, Sabrina C.; Rossetti, Sabrina; Cavaliere, Carla; Della Pepa, Chiara; Di Napoli, Marilena; Crispo, Anna; Iovane, Gelsomina; Piscitelli, Raffaele; Sorrentino, Domenico; Ciliberto, Gennaro; Maiolino, Piera; Muto, Paolo; Perdonà, Sisto; Berretta, Massimiliano; Pignata, Sandro; Facchini, Gaetano; D'Aniello, Carmine

2016-01-01

Pazopanib is an oral angiogenesis inhibitor, currently approved for treatment of metastatic renal cell carcinoma (mRCC) and soft tissue sarcoma. The present study analyzed the outcomes of pazopanib in first-line treatment of mRCC, in a single Italian cancer center. In the light of the retrospective, observational nature and the unselected population, our experience can be defined a “real-world” study. The medical records of 38 mRCC patients treated with front-line pazopanib were retrospectively reviewed and analyzed. The progression free survival (PFS) and the overall survival (OS) were the primary endpoints, while secondary objectives included objective response rate (ORR), disease control rate (DCR), and treatment tolerability. Pazopanib achieved a median PFS (mPFS) of 12.7 months (95% CI, 6.9–18.5 months). The median OS (mOS) was 26.2 months (95% CI, 12.6–39.9 months); the observed ORR and DCR were 30.3 and 72.7%, respectively, with a median duration of response of 11 weeks. mPFS appeared not to be influenced by number of co-morbidities (< 3 vs. ≥3), gender, Fuhrman grade and age. Conversely, the ORR and the DCR positively affect the mPFS (HR = 0.05 [95% CI, 0.05–0.55], p = 0.01; HR = 0.10 [95% CI, 0.02–0.43], p = 0.002, respectively). A worse outcome was associated with a lower mPFS in patients with liver metastases (p = 0.2) and with a high tumor burden (number of metastatic sites < 6 vs. ≥6) (p = 0.08). Worst OS was observed in patients aged ≥70 years old (HR = 6.91 [95% CI, 1.49–31.91], p = 0.01). The treatment was well-tolerated: no grade 4 adverse events, nor discontinuation due to toxicities was reported. Grade 3 hypertension affected positively the OS reaching the statistical significance (HR = 0.22 [95% CI, 0.05–0.8], p = 0.03). Thyroid dysfunction (hypo and hyperthyroidism) seems to correlate with better outcome in terms of a longer mPFS (HR = 0.12 [95% CI, 0.02–0.78], p = 0.02). Our results are consistent with those reported in

Merkel Cell Carcinoma Metastatic to Pleural Fluid: A Case Report.

PubMed

Rhee, Ye-Young; Kim, Soo Hee; Kim, Eun Kyung; Kim, Se Hoon

2018-05-01

Merkel cell carcinoma (MCC) is a rare aggressive neuroendocrine carcinoma of the skin that shows locoregional or distant metastasis. Metastasis of MCC to body cavity effusion is extremely rare; only three cases have been reported so far. Metastatic MCC in effusion cytology shows small blue round cells with fine stippled chromatin like other small blue round cell tumors such as small cell lung carcinoma or lymphoma. The diagnosis of metastatic MCC can grant patients good chances at recently advanced therapeutic options. Here, we present a case of metastatic MCC to pleural effusion with characteristic single file-like pattern.

PHGDH as a key enzyme for serine biosynthesis in HIF2α-targeting therapy for renal cell carcinoma

PubMed Central

Yoshino, Hirofumi; Nohata, Nijiro; Miyamoto, Kazutaka; Yonemori, Masaya; Sakaguchi, Takashi; Sugita, Satoshi; Itesako, Toshihiko; Kofuji, Satoshi; Nakagawa, Masayuki; Dahiya, Rajvir; Enokida, Hideki

2018-01-01

Continuous activation of hypoxia-inducible factor (HIF) is important for progression of renal cell carcinoma (RCC) and acquired resistance to anti-angiogenic multi-kinase and mTOR inhibitors. Recently, HIF2α antagonists PT2385 and PT2399 were developed and are being evaluated in a Phase I clinical trial for advanced or metastatic clear cell RCC (ccRCC). However, resistance to HIF2α antagonists would be expected to develop. In this study, we identified signals activated by HIF2α deficiency as candidate mediators of resistance to the multi-kinase inhibitor sunitinib. We established sunitinib-resistant tumor cells in vivo and created HIF2α-deficient variants of these cells using CRISPR/Cas9 technology. Mechanistic investigations revealed that a regulator of the serine biosynthesis pathway, phosphoglycerate dehydrogenase (PHGDH), was upregulated commonly in HIF2α-deficient tumor cells along with the serine biosynthesis pathway itself. Accordingly, treatment with a PHGDH inhibitor reduced the growth of HIF2α-deficient tumor cells in vivo and in vitro by inducing apoptosis. Our findings identify the serine biosynthesis pathway as a source of candidate therapeutic targets to eradicate advanced or metastatic ccRCC resistant to HIF2α antagonists. PMID:28951458

PHGDH as a Key Enzyme for Serine Biosynthesis in HIF2α-Targeting Therapy for Renal Cell Carcinoma.

PubMed

Yoshino, Hirofumi; Nohata, Nijiro; Miyamoto, Kazutaka; Yonemori, Masaya; Sakaguchi, Takashi; Sugita, Satoshi; Itesako, Toshihiko; Kofuji, Satoshi; Nakagawa, Masayuki; Dahiya, Rajvir; Enokida, Hideki

2017-11-15

Continuous activation of hypoxia-inducible factor (HIF) is important for progression of renal cell carcinoma (RCC) and acquired resistance to antiangiogenic multikinase and mTOR inhibitors. Recently, HIF2α antagonists PT2385 and PT2399 were developed and are being evaluated in a phase I clinical trial for advanced or metastatic clear cell RCC (ccRCC). However, resistance to HIF2α antagonists would be expected to develop. In this study, we identified signals activated by HIF2α deficiency as candidate mediators of resistance to the HIF2α antagonists. We established sunitinib-resistant tumor cells in vivo and created HIF2α-deficient variants of these cells using CRISPR/Cas9 technology. Mechanistic investigations revealed that a regulator of the serine biosynthesis pathway, phosphoglycerate dehydrogenase (PHGDH), was upregulated commonly in HIF2α-deficient tumor cells along with the serine biosynthesis pathway itself. Accordingly, treatment with a PHGDH inhibitor reduced the growth of HIF2α-deficient tumor cells in vivo and in vitro by inducing apoptosis. Our findings identify the serine biosynthesis pathway as a source of candidate therapeutic targets to eradicate advanced or metastatic ccRCC resistant to HIF2α antagonists. Cancer Res; 77(22); 6321-9. ©2017 AACR . ©2017 American Association for Cancer Research.

Locally advanced and metastatic basal cell carcinoma: molecular pathways, treatment options and new targeted therapies.

PubMed

Ruiz Salas, Veronica; Alegre, Marta; Garcés, Joan Ramón; Puig, Lluis

2014-06-01

The hedgehog (Hh) signaling pathway has been identified as important to normal embryonic development in living organisms and it is implicated in processes including cell proliferation, differentiation and tissue patterning. Aberrant Hh pathway has been involved in the pathogenesis and chemotherapy resistance of different solid and hematologic malignancies. Basal cell carcinoma (BCC) and medulloblastoma are two well-recognized cancers with mutations in components of the Hh pathway. Vismodegib has recently approved as the first inhibitor of one of the components of the Hh pathway (smoothened). This review attempts to provide current data on the molecular pathways involved in the development of BCC and the therapeutic options available for the treatment of locally advanced and metastatic BCC, and the new targeted therapies in development.

Clinical impact of targeted therapies in patients with metastatic clear-cell renal cell carcinoma

PubMed Central

Nerich, Virginie; Hugues, Marion; Paillard, Marie Justine; Borowski, Laëtitia; Nai, Thierry; Stein, Ulrich; Nguyen Tan Hon, Thierry; Montcuquet, Philippe; Maurina, Tristan; Mouillet, Guillaume; Kleinclauss, François; Pivot, Xavier; Limat, Samuel; Thiery-Vuillemin, Antoine

2014-01-01

Introduction The aim of this retrospective clinical study was to assess, in the context of the recent evolution of systemic therapies, the potential effect of targeted therapies on overall survival (OS) of patients with metastatic clear-cell renal cell carcinoma (mccRCC) in daily practice. Patients and methods All consecutive patients with histologically confirmed mccRCC who received systemic therapy between January 2000 and December 2010 in two oncology treatment centers in our Franche-Comté region in eastern France were included in the analysis. The primary end point was OS. The analysis of prognostic factors was performed using a two-step approach: univariate then multivariate analysis with a stepwise Cox proportional hazards regression model. Results For the entire cohort of 111 patients, the median OS was 17 months (95% confidence interval [CI]; 13–22 months) and the two-year OS was 39%. Three prognostic factors were independent predictors of long survival: prior nephrectomy (hazard ratio =0.38 [0.22–0.64], P<0.0001); systemic therapy by targeted therapy (hazard ratio =0.50 [0.31–0.80], P=0.005); and lack of liver metastasis (hazard ratio =0.43 [0.22–0.82], P=0.002). Median OS was 21 months [14–29 months] for patients who received at least one targeted therapy compared with 12 months [7–15 months] for patients who were treated only by immunotherapy agents (P=0.003). Conclusion Our results suggest that targeted therapies are associated with improved OS in comparison with cytokines, which is in line with other publications. PMID:24600236

Human metastatic melanoma cell lines express high levels of growth hormone receptor and respond to GH treatment

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

Sustarsic, Elahu G.; Department of Biological Sciences, Ohio University, Athens, OH; Junnila, Riia K.

2013-11-08

Highlights: •Most cancer types of the NCI60 have sub-sets of cell lines with high GHR expression. •GHR is highly expressed in melanoma cell lines. •GHR is elevated in advanced stage IV metastatic tumors vs. stage III. •GH treatment of metastatic melanoma cell lines alters growth and cell signaling. -- Abstract: Accumulating evidence implicates the growth hormone receptor (GHR) in carcinogenesis. While multiple studies show evidence for expression of growth hormone (GH) and GHR mRNA in human cancer tissue, there is a lack of quantification and only a few cancer types have been investigated. The National Cancer Institute’s NCI60 panel includesmore » 60 cancer cell lines from nine types of human cancer: breast, CNS, colon, leukemia, melanoma, non-small cell lung, ovarian, prostate and renal. We utilized this panel to quantify expression of GHR, GH, prolactin receptor (PRLR) and prolactin (PRL) mRNA with real-time RT qPCR. Both GHR and PRLR show a broad range of expression within and among most cancer types. Strikingly, GHR expression is nearly 50-fold higher in melanoma than in the panel as a whole. Analysis of human metastatic melanoma biopsies confirmed GHR gene expression in melanoma tissue. In these human biopsies, the level of GHR mRNA is elevated in advanced stage IV tumor samples compared to stage III. Due to the novel finding of high GHR in melanoma, we examined the effect of GH treatment on three NCI60 melanoma lines (MDA-MB-435, UACC-62 and SK-MEL-5). GH increased proliferation in two out of three cell lines tested. Further analysis revealed GH-induced activation of STAT5 and mTOR in a cell line dependent manner. In conclusion, we have identified cell lines and cancer types that are ideal to study the role of GH and PRL in cancer, yet have been largely overlooked. Furthermore, we found that human metastatic melanoma tumors express GHR and cell lines possess active GHRs that can modulate multiple signaling pathways and alter cell proliferation

Atezolizumab in invasive and metastatic urothelial carcinoma.

PubMed

Crist, Michael; Balar, Arjun

2017-12-01

Until recently, there has been little advancement in the management of invasive and metastatic urothelial cancer in over 30 years, and outcomes with cisplatin-based chemotherapy remain unchanged. Inhibitors targeting PD-1 signaling on cytotoxic T-cells have revolutionized bladder cancer therapy leading to durable responses. Atezolizumab is an engineered humanized anti-PD-L1 monoclonal antibody that inhibits PD-L1 binding to PD-1 and B7.1, enhancing immune-mediated tumor killing and is currently approved as second-line treatment after failure of platinum-based chemotherapy as well as first-line in cisplatin-ineligible patients. Areas covered: This article summarizes all reported phase I, II and III clinical trials that assessed the safety and efficacy of atezolizumab in the treatment of locally advanced and metastatic urothelial carcinoma. Expert commentary: Treatment with atezolizumab showed durable response and a toxicity profile that appears favorable to cytotoxic chemotherapy historically in the treatment of metastatic urothelial cancer among individuals who had progressed after prior platinum-based therapy and among those ineligible for treatment with first-line cisplatin. PD-L1 expression and tumor mutation load associate with response, however further research is needed to identify additional markers to improve prediction of response to atezolizumab.

Spontaneous rupture of the renal pelvis presenting as an urinoma in locally advanced rectal cancer

PubMed Central

Garg, Pankaj Kumar; Mohanty, Debajyoti; Rathi, Vinita; Jain, Bhupendra Kumar

2014-01-01

A 29-year-old gentleman underwent a transverse colostomy for intestinal obstruction caused by advanced rectal carcinoma. On the 5th postoperative day, the patient developed a painful swelling on the right side of the abdomen. The contrast enhanced computed tomography of the abdomen revealed a right sided hydronephrosis, a large rent in the renal pelvis, and a large retroperitoneal fluid collection on the right side. Percutaneous nephrostomy and pigtail catheter drainage of the urinoma led to resolution of abdominal swelling. Development of a urinoma as a consequence of rectal carcinoma is highly unusual. Prompt imaging for confirmation of diagnosis, decompression of the renal pelvicalyceal system, and drainage of the urinoma limits morbidity. PMID:24749123

Role of the neural niche in brain metastatic cancer.

PubMed

Termini, John; Neman, Josh; Jandial, Rahul

2014-08-01

Metastasis is the relentless pursuit of cancer to escape its primary site and colonize distant organs. This malignant evolutionary process is biologically heterogeneous, yet one unifying element is the critical role of the microenvironment for arriving metastatic cells. Historically, brain metastases were rarely investigated because patients with advanced cancer were considered terminal. Fortunately, advances in molecular therapies have led to patients living longer with metastatic cancer. However, one site remains recalcitrant to our treatment efforts, the brain. The central nervous system is the most complex biologic system, which poses unique obstacles but also harbors opportunities for discovery. Much of what we know about the brain microenvironment comes from neuroscience. We suggest that the interrelated cellular responses in traumatic brain injury may guide us toward new perspectives in understanding brain metastases. In this view, brain metastases may be conceptualized as progressive oncologic injury to the nervous system. This review discusses our evolving understanding of bidirectional interactions between the brain milieu and metastatic cancer. ©2014 American Association for Cancer Research.

Collection of real-world data on nivolumab's effectiveness in renal cell carcinoma: rationale for an observational study.

PubMed

Bedke, Jens; Grimm, Marc-Oliver; Grünwald, Viktor

2018-05-01

Renal cell carcinoma (RCC) represents the seventh (men) respectively tenth (women) most frequent cancer in western countries. After one or more lines of VEGF-targeted therapy, immunotherapy with nivolumab is strongly recommended in patients with metastatic RCC. Nivolumab is the first, and so far, only approved PD-1 immune checkpoint inhibitor to demonstrate a gain in overall survival in RCC. We describe herein design and rationale of trial CA209653 ('NIS NORA'), a prospective, noninterventional cohort study investigating the effectiveness of nivolumab. This systematic collection of real-world effectiveness data will recruit 323 patients with advanced RCC to provide a precise estimate for overall survival over a 5-year follow-up period (Trial registration: NCT02940639).

Effect of number and location of distant metastases on renal cell carcinoma mortality in candidates for cytoreductive nephrectomy: implications for multimodal therapy.

PubMed

Capitanio, Umberto; Abdollah, Firas; Matloob, Rayan; Salonia, Andrea; Suardi, Nazareno; Briganti, Alberto; Carenzi, Cristina; Rigatti, Patrizio; Montorsi, Francesco; Bertini, Roberto

2013-06-01

To test whether the combination of number and location of distant metastases affects cancer-specific survival in patients with metastatic renal cell carcinoma. Overall, 242 metastatic renal cell carcinoma patients with synchronous metastases at diagnosis underwent cytoreductive nephrectomy at a single institution. Combinations of number and location of distant metastases were coded as: single metastasis and single organ affected, multiple metastases and single organ affected, single metastasis for each of the multiple organs affected, and multiple metastases for each of the multiple organs affected. Covariates included age, symptoms, performance status, American Society of Anesthesiologists score, hemoglobin, lactate dehydrogenase, tumor size, Fuhrman grade, T stage, lymph node status, necrosis, sarcomatoid features and metastasectomy at the time of nephrectomy. The median survival was 34.7 versus 32.3 versus 29.6 versus 8.5 months for single metastasis and single organ affected, multiple metastases and single organ affected single metastasis for each of the multiple organs affected, and multiple metastases for each of the multiple organs affected patients, respectively. At multivariable analyses, the combination of number and location of distant metastases resulted in one of the most informative and independent predictors of cancer-specific survival in metastatic renal cell carcinoma patients. The lung was the location with the highest rate of single organ affected (50.3% vs 35.1% in other sites; P < 0.001). Considering only patients with a single metastasis, no statistically significantly different cancer-specific survival rates were recorded (P > 0.3) among different metastatic organs. Among metastatic renal cell carcinoma patients undergoing cytoreductive nephrectomy, the combination of the number and location of distant metastases is a major independent predictor of cancer-specific survival. Patients with multiple organs affected by multifocal

Effects on quality of life of weekly docetaxel-based chemotherapy in patients with locally advanced or metastatic breast cancer: results of a single-centre randomized phase 3 trial

PubMed Central

2011-01-01

Background To evaluate whether weekly schedules of docetaxel-based chemotherapy were superior to 3-weekly ones in terms of quality of life in locally advanced or metastatic breast cancer. Methods Patients with locally advanced or metastatic breast cancer, aged ≤ 70 years, performance status 0-2, chemotherapy-naive for metastatic disease, were eligible. They were randomized to weekly or 3-weekly combination of docetaxel and epirubicin, if they were not treated with adjuvant anthracyclines, or docetaxel and capecitabine, if treated with adjuvant anthracyclines. Primary end-point was global quality of life change at 6-weeks, measured by EORTC QLQ-C30. With two-sided alpha 0.05 and 80% power for 35% effect size, 130 patients per arm were needed. Results From February 2004 to March 2008, 139 patients were randomized, 70 to weekly and 69 to 3-weekly arm; 129 and 89 patients filled baseline and 6-week questionnaires, respectively. Global quality of life was better in the 3-weekly arm (p = 0.03); patients treated with weekly schedules presented a significantly worsening in role functioning and financial scores (p = 0.02 and p < 0.001). Neutropenia and stomatitis were worse in the 3-weekly arm, where two toxic deaths were observed. Overall response rate was 39.1% and 33.3% in 3-weekly and weekly arms; hazard ratio of progression was 1.29 (95% CI: 0.84-1.97) and hazard ratio of death was 1.38 (95% CI: 0.82-2.30) in the weekly arm. Conclusions In this trial, the weekly schedules of docetaxel-based chemotherapy appear to be inferior to the 3-weekly one in terms of quality of life in patients with locally advanced or metastatic breast cancer. Trial registration ClinicalTrials.gov NCT00540800. PMID:21324184

Effects on quality of life of weekly docetaxel-based chemotherapy in patients with locally advanced or metastatic breast cancer: results of a single-centre randomized phase 3 trial.

PubMed

Nuzzo, Francesco; Morabito, Alessandro; Gravina, Adriano; Di Rella, Francesca; Landi, Gabriella; Pacilio, Carmen; Labonia, Vincenzo; Rossi, Emanuela; De Maio, Ermelinda; Piccirillo, Maria Carmela; D'Aiuto, Giuseppe; Thomas, Renato; Rinaldo, Massimo; Botti, Gerardo; Di Bonito, Maurizio; Di Maio, Massimo; Gallo, Ciro; Perrone, Francesco; de Matteis, Andrea

2011-02-16

To evaluate whether weekly schedules of docetaxel-based chemotherapy were superior to 3-weekly ones in terms of quality of life in locally advanced or metastatic breast cancer. Patients with locally advanced or metastatic breast cancer, aged ≤ 70 years, performance status 0-2, chemotherapy-naive for metastatic disease, were eligible. They were randomized to weekly or 3-weekly combination of docetaxel and epirubicin, if they were not treated with adjuvant anthracyclines, or docetaxel and capecitabine, if treated with adjuvant anthracyclines. Primary end-point was global quality of life change at 6-weeks, measured by EORTC QLQ-C30. With two-sided alpha 0.05 and 80% power for 35% effect size, 130 patients per arm were needed. From February 2004 to March 2008, 139 patients were randomized, 70 to weekly and 69 to 3-weekly arm; 129 and 89 patients filled baseline and 6-week questionnaires, respectively. Global quality of life was better in the 3-weekly arm (p = 0.03); patients treated with weekly schedules presented a significantly worsening in role functioning and financial scores (p = 0.02 and p < 0.001). Neutropenia and stomatitis were worse in the 3-weekly arm, where two toxic deaths were observed. Overall response rate was 39.1% and 33.3% in 3-weekly and weekly arms; hazard ratio of progression was 1.29 (95% CI: 0.84-1.97) and hazard ratio of death was 1.38 (95% CI: 0.82-2.30) in the weekly arm. In this trial, the weekly schedules of docetaxel-based chemotherapy appear to be inferior to the 3-weekly one in terms of quality of life in patients with locally advanced or metastatic breast cancer. ClinicalTrials.gov NCT00540800.

Combination therapy for advanced or metastatic non-small cell lung cancer will be tested in new clinical trial | Center for Cancer Research

Cancer.gov

Non-small cell lung cancer (NSCLC) develops when abnormal lung cells begin to grow out of control. These cells can form into a tumor and spread to other areas of the body. David Schrump, M.D., of the Thoracic and Gastrointestinal Oncology Branch is leading a clinical trial of a new combination treatment for patients with advanced or metastatic NSCLC that cannot be treated

Renal cell tumour characteristics in patients with the Birt-Hogg-Dubé cancer susceptibility syndrome: a retrospective, multicentre study.

PubMed

Benusiglio, Patrick R; Giraud, Sophie; Deveaux, Sophie; Méjean, Arnaud; Correas, Jean-Michel; Joly, Dominique; Timsit, Marc-Olivier; Ferlicot, Sophie; Verkarre, Virginie; Abadie, Caroline; Chauveau, Dominique; Leroux, Dominique; Avril, Marie-Françoise; Cordier, Jean-François; Richard, Stéphane

2014-10-29

The Birt-Hogg-Dubé syndrome is a rare cancer susceptibility syndrome characterised by renal tumours, lung cysts and pneumothoraces, and fibrofolliculomas. It is caused by dominantly inherited mutations in FLCN. Our objective was to report renal tumour characteristics in a large series of patients with the Birt-Hogg-Dubé syndrome. We studied French Birt-Hogg-Dubé patients with a history of renal tumour. We included 33 patients with 21 distinct germline FLCN mutations. Median age at diagnosis of first renal tumour was 46, and age varied from 20 to 83. Twenty cases had one renal tumour, the remainder had two or more tumours. Most cases (23/33, 70%) had oncocytoma or renal cell carcinoma of the chromophobe or hybrid chromophobe-oncocytoma type, three had clear cell carcinoma (9%), and the other seven had carcinoma of papillary, undifferentiated or undetermined histology. Four cases had metastatic disease, although none died of it. Age at renal tumour diagnosis was highly variable, highlighting the need for regular surveillance from young adulthood to old age. Most cases had tumour types classically associated with Birt-Hogg-Dubé, i.e. oncocytoma or renal cell carcinoma of the chromophobe or hybrid type. Nevertheless, 9% had clear cell renal cell carcinoma. Geneticists, urologists and oncologists should therefore be alert to the possibility of Birt-Hogg-Dubé in patients with renal cell carcinoma of clear cell histology, especially if there are associated manifestations. Finally, the behaviour of metastatic carcinoma seemed more indolent than in sporadic renal cancers.

Exposure-response relationships in patients with metastatic renal cell carcinoma receiving sunitinib: maintaining optimum efficacy in clinical practice.

PubMed

Ravaud, Alain; Bello, Carlo L

2011-06-01

Targeted agents such as sunitinib, an oral, multitargeted receptor tyrosine kinase inhibitor, have greatly improved the prognosis for patients with metastatic renal cell carcinoma (mRCC). In this review we analyse data from sunitinib preclinical and clinical studies in detail and consider the key implications for the effective use of sunitinib in clinical practice. Sunitinib has shown efficacy and acceptable tolerability in patients with mRCC in phase II and III clinical studies. In a pivotal phase III study in treatment-naïve patients with mRCC, median progression-free survival for sunitinib-treated patients was double of that with interferon-α (P < 0.001). Median overall survival was 26.4 versus 21.8 months, respectively (P = 0.0510). In preclinical and phase I/II studies, sunitinib inhibits tyrosine kinase inhibitors in a dose-dependent manner, suggesting a correlation between increasing exposure and greater response. A pharmacokinetics/pharmacodynamics meta-analysis investigating the relationship between clinical end points and sunitinib exposure showed that increased sunitinib exposure was associated with a greater probability of objective response, longer time to tumour progression and overall survival, as well as some increased risk of specific adverse events. It is important to consider the relationship between exposure and response to maximize clinical benefit from sunitinib treatment.

Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial.

PubMed

Migden, Michael R; Guminski, Alexander; Gutzmer, Ralf; Dirix, Luc; Lewis, Karl D; Combemale, Patrick; Herd, Robert M; Kudchadkar, Ragini; Trefzer, Uwe; Gogov, Sven; Pallaud, Celine; Yi, Tingting; Mone, Manisha; Kaatz, Martin; Loquai, Carmen; Stratigos, Alexander J; Schulze, Hans-Joachim; Plummer, Ruth; Chang, Anne Lynn S; Cornélis, Frank; Lear, John T; Sellami, Dalila; Dummer, Reinhard

2015-06-01

Patients with advanced basal cell carcinoma have limited treatment options. Hedgehog pathway signalling is aberrantly activated in around 95% of tumours. We assessed the antitumour activity of sonidegib, a Hedgehog signalling inhibitor, in patients with advanced basal cell carcinoma. BOLT is an ongoing multicentre, randomised, double-blind, phase 2 trial. Eligible patients had locally advanced basal cell carcinoma not amenable to curative surgery or radiation or metastatic basal cell carcinoma. Patients were randomised via an automated system in a 1:2 ratio to receive 200 mg or 800 mg oral sonidegib daily, stratified by disease, histological subtype, and geographical region. The primary endpoint was the proportion of patients who achieved an objective response, assessed in the primary efficacy analysis population (patients with fully assessable locally advanced disease and all those with metastatic disease) with data collected up to 6 months after randomisation of the last patient. This trial is registered with ClinicalTrials.gov, number NCT01327053. Between July 20, 2011, and Jan 10, 2013, we enrolled 230 patients, 79 in the 200 mg sonidegib group, and 151 in the 800 mg sonidegib group. Median follow-up was 13·9 months (IQR 10·1-17·3). In the primary efficacy analysis population, 20 (36%, 95% CI 24-50) of 55 patients receiving 200 mg sonidegib and 39 (34%, 25-43) of 116 receiving 800 mg sonidegib achieved an objective response. In the 200 mg sonidegib group, 18 (43%, 95% CI 28-59) patients who achieved an objective response, as assessed by central review, were noted among the 42 with locally advanced basal cell carcinoma and two (15%, 2-45) among the 13 with metastatic disease. In the 800 mg group, 35 (38%, 95% CI 28-48) of 93 patients with locally advanced disease had an objective response, as assessed by central review, as did four (17%, 5-39) of 23 with metastatic disease. Fewer adverse events leading to dose interruptions or reductions (25 [32%] of 79

Development of coronary artery stenosis in a patient with metastatic renal cell carcinoma treated with sorafenib

PubMed Central

2012-01-01

Background Tyrosine kinase inhibitors (TKIs) are currently approved for the treatment of metastatic renal cell carcinoma (mRCC). The cardiotoxic effects of sorafenib and sunitinib may cause hypertension, left ventricular ejection fraction (LVEF) dysfunction and/or congestive heart failure (CHF), and arterial thrombo-embolic events (ATE). Only three cases of coronary artery disease related to sorafenib therapy have been described in the literature, and all were due to arterial vasospasm without evidence of coronary artery stenosis on angiography. Cardiotoxicity is commonly associated with the presence of cardiovascular risk factors, such as a history of hypertension or coronary artery disease. Case presentation We describe a patient who experienced an unusual cardiac event after 2 years of sorafenib treatment. A 58-year-old man with mRCC developed acute coronary syndrome (ischemia/infarction) associated with critical sub-occlusion of the common trunk of the left coronary artery and some of its branches, which was documented on coronary angiography. The patient underwent triple coronary artery bypass surgery, and sorafenib treatment was discontinued. He did not have any cardiovascular risk factors, and his cardiac function and morphology were normal prior to sorafenib treatment. Conclusions Further investigation of a larger patient population is needed to better understand cardiac damage due to TKI treatment. Understanding the usefulness of careful cardiovascular monitoring might be important for the prevention of fatal cardiovascular events, and to avoid discontinuation of therapy for the underlying cancer. PMID:22687270

Effect of Target Therapy on the Content of Transcription and Growth Factors, Protein Kinase TOR, and Activity of Intracellular Proteases in Patients with Metastatic Renal Cell Carcinoma.

PubMed

Spirina, L V; Usynin, E A; Kondakova, I V; Yurmazov, Z A; Slonimskaya, E M

2016-04-01

We analyzed the dynamics of the expression of transcription factors, VEGF and its receptor VEGFR2, serine-threonine protein kinase mTOR and activity of proteasome and calpain in patients with metastatic renal cancer during therapy with tyrosine kinase inhibitor Votrient and mTOR blocker Afinitor. The expression of hypoxic nuclear factor HIF-1α in the tumor tissue decreased during therapy with the target preparations. The decrease of VEGF and its receptor VEGFR2 was observed only in patients treated with mTOR inhibitor. The increase in calpain activity in the tumor tissue was observed in both groups. These findings extend our understanding of the mechanism of action of target anticancer preparations as allow considering the studied markers as predictors in choosing optimal therapy.

Prospective clinical trial of preoperative sunitinib in patients with renal cell carcinoma.

PubMed

Hellenthal, Nicholas J; Underwood, Willie; Penetrante, Remedios; Litwin, Alan; Zhang, Shaozeng; Wilding, Gregory E; Teh, Bin T; Kim, Hyung L

2010-09-01

Sunitinib is an approved treatment for metastatic renal cell carcinoma. We performed a prospective clinical trial to evaluate the safety and clinical response to sunitinib administered before nephrectomy in patients with localized or metastatic clear cell renal cell carcinoma. Patients with biopsy proven clear cell renal cell carcinoma were enrolled in the study and treated with 37.5 mg sunitinib malate daily for 3 months before nephrectomy. The primary end point was safety. In an 18-month period 20 patients were enrolled. The most common toxicities were gastrointestinal symptoms and hematological effects. Grade 3 toxicity developed in 6 patients (30%). No surgical complications were attributable to sunitinib treatment. Of the 20 patients 17 (85%) experienced reduced tumor diameter (mean change -11.8%, range -27% to 11%) and cross-sectional area (mean change -27.9%, range -43% to 23%). Enhancement on contrast enhanced computerized tomography decreased in 15 patients (mean HU change -22%, range -74% to 29%). After tumor reduction 8 patients with cT1b disease underwent laparoscopic partial nephrectomy. Surgical parameters, such as blood loss, transfusion rate, operative time and complications, were similar to those in patients who underwent surgery during the study period and were not enrolled in the trial. Preoperative treatment with sunitinib is safe. Sunitinib decreased the size of primary renal cell carcinoma in 17 of 20 patients. Future trials can be considered to evaluate neoadjuvant sunitinib to maximize nephron sparing and decrease the recurrence of high risk, localized renal cell carcinoma. 2010 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Multidisciplinary treatment of brain metastases derived from clear cell renal cancer incorporating stereotactic radiosurgery.

PubMed

Samlowski, Wolfram E; Majer, Martin; Boucher, Kenneth M; Shrieve, Annabelle F; Dechet, Christopher; Jensen, Randy L; Shrieve, Dennis C

2008-11-01

Brain metastases are a frequent complication in patients with metastatic clear cell renal cancer. Survival after whole-brain radiotherapy (WBRT) is disappointing. A retrospective analysis of multimodality treatment was performed in patients who had received linear accelerator (LINAC)-based stereotactic radiosurgery (SRS). Thirty-two patients underwent SRS-based treatment for 71 metastatic foci between 2000 and 2006. All patients had a Karnofsky performance status >or=70 and all 32 patients had extracranial metastatic disease (Radiation Therapy Oncology Group recursive partitioning analysis [RPA] Class 2). Survival was calculated from the time of diagnosis of brain metastases. The minimum potential follow-up was 1 year after SRS. Univariate and multivariate analysis of potential prognostic factors affecting survival was performed. Twenty-six patients required only 1 SRS treatment (84%) to achieve central nervous system (CNS) control, whereas 5 patients received 2 to 3 treatments (16%). The median survival of renal cancer patients from the diagnosis of brain metastases was 10.1 months (95% confidence interval, 6.4-14.8 months). One-year and 3-year survival rates were 43% and 16%, respectively. The addition of surgery or WBRT did not appear to prolong survival. Immunotherapy after control of brain metastases with SRS appeared to result in significantly improved survival. Survival was also found to be strongly influenced by prognostic stratification of metastatic disease using Motzer or modified risk criteria. The results of the current study demonstrated that SRS-based treatment of patients with up to 5 brain metastases from clear cell renal cancer is feasible and results in excellent CNS control. Survival beyond 3 years from the time of diagnosis of brain metastases was achievable in 16% of patients and was associated with the use of systemic immunotherapy with interleukin-2 and interferon but not antiangiogenic agents.

Combination therapy for advanced or metastatic non-small cell lung cancer will be tested in new clinical trial | Center for Cancer Research

Cancer.gov

Non-small cell lung cancer (NSCLC) develops when abnormal lung cells begin to grow out of control. These cells can form into a tumor and spread to other areas of the body. David Schrump, M.D., of the Thoracic and Gastrointestinal Oncology Branch is leading a clinical trial of a new combination treatment for patients with advanced or metastatic NSCLC that cannot be treated surgically. Read more... 

Thyroid metastasis as initial presentation of clear cell renal carcinoma

PubMed Central

Ramírez-Plaza, César Pablo; Domínguez-López, Marta Elena; Blanco-Reina, Francisco

2015-01-01

Introduction Metastatic tumors account for 1.4–2.5% of thyroid malignancies. About 25–30% of patients with clear cell renal carcinoma (CCRC) have distant metastasis at the time of diagnosis, being the thyroid gland a rare localization [5%]. Presentation of the case A 62-year woman who underwent a cervical ultrasonography and a PAAF biopsy reporting atypical follicular proliferation with a few intranuclear vacuoles “suggestive” of thyroid papillary cancer in the context of a multinodular goiter was reported. A total thyroidectomy was performed and the histology of a clear cell renal carcinoma (CCRC) was described in four nodules of the thyroid gland. A CT scan was performed and a renal giant right tumor was found. The patient underwent an eventful radical right nephrectomy and the diagnosis of CCRC was confirmed. Discussion Thyroid metastasis (TM) from CCRC are usually apparent in a metachronic context during the follow-up of a treated primary (even many years after) but may sometimes be present at the same time than the primary renal tumor. Our case is exceptional because the TM was the first evidence of the CCRC, which was subsequently diagnosed and treated. Conclusion The possibility of finding of an incidental metastatic tumor in the thyroid gland from a previous unknown and non-diganosed primary (as CCRC in our case was) is rare and account only for less than 1% of malignancies. Nonetheless, the thyroid gland is a frequent site of metastasis and the presence of “de novo” thyroid nodules in oncologic patients must be always considered and studied. PMID:25827295

Cost-effectiveness of pazopanib compared with sunitinib in metastatic renal cell carcinoma in Canada

PubMed Central

Amdahl, J.; Diaz, J.; Park, J.; Nakhaipour, H.R.; Delea, T.E.

2016-01-01

Background In Canada and elsewhere, pazopanib and sunitinib—tyrosine kinase inhibitors targeting the vascular endothelial growth factor receptors—are recommended as first-line treatment for patients with metastatic renal cell carcinoma (mrcc). A large randomized noninferiority trial of pazopanib versus sunitinib (comparz) demonstrated that the two drugs have similar efficacy; however, patients randomized to pazopanib experienced better health-related quality of life (hrqol) and nominally lower rates of non-study medical resource utilization. Methods The cost-effectiveness of pazopanib compared with sunitinib for first-line treatment of mrcc from a Canadian health care system perspective was evaluated using a partitioned-survival model that incorporated data from comparz and other secondary sources. The time horizon of 5 years was based on the maximum duration of follow-up in the final analysis of overall survival from the comparz trial. Analyses were conducted first using list prices for pazopanib and sunitinib and then by assuming that the prices of sunitinib and pazopanib would be equivalent. Results Based on list prices, expected costs were CA$10,293 less with pazopanib than with sunitinib. Pazopanib was estimated to yield 0.059 more quality-adjusted life-years (qalys). Pazopanib was therefore dominant (more qalys and lower costs) compared with sunitinib in the base case. In probabilistic sensitivity analyses, pazopanib was dominant in 79% of simulations and was cost-effective in 90%–100% of simulations at a threshold cost-effectiveness ratio of CA$100,000. Assuming equivalent pricing, pazopanib yielded CA$917 in savings in the base case, was dominant in 36% of probabilistic sensitivity analysis simulations, and was cost-effective in 89% of simulations at a threshold cost-effectiveness ratio of CA$100,000. Conclusions Compared with sunitinib, pazopanib is likely to be a cost-effective option for first-line treatment of mrcc from a Canadian health care

Incorporating Neutrophil-to-lymphocyte Ratio and Platelet-to-lymphocyte Ratio in Place of Neutrophil Count and Platelet Count Improves Prognostic Accuracy of the International Metastatic Renal Cell Carcinoma Database Consortium Model

PubMed Central

Chrom, Pawel; Stec, Rafal; Bodnar, Lubomir; Szczylik, Cezary

2018-01-01

Purpose The study investigated whether a replacement of neutrophil count and platelet count by neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) within the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model would improve its prognostic accuracy. Materials and Methods This retrospective analysis included consecutive patients with metastatic renal cell carcinoma treated with first-line tyrosine kinase inhibitors. The IMDC and modified-IMDC models were compared using: concordance index (CI), bias-corrected concordance index (BCCI), calibration plots, the Grønnesby and Borgan test, Bayesian Information Criterion (BIC), generalized R2, Integrated Discrimination Improvement (IDI), and continuous Net Reclassification Index (cNRI) for individual risk factors and the three risk groups. Results Three hundred and twenty-one patients were eligible for analyses. The modified-IMDC model with NLR value of 3.6 and PLR value of 157 was selected for comparison with the IMDC model. Both models were well calibrated. All other measures favoured the modified-IMDC model over the IMDC model (CI, 0.706 vs. 0.677; BCCI, 0.699 vs. 0.671; BIC, 2,176.2 vs. 2,190.7; generalized R2, 0.238 vs. 0.202; IDI, 0.044; cNRI, 0.279 for individual risk factors; and CI, 0.669 vs. 0.641; BCCI, 0.669 vs. 0.641; BIC, 2,183.2 vs. 2,198.1; generalized R2, 0.163 vs. 0.123; IDI, 0.045; cNRI, 0.165 for the three risk groups). Conclusion Incorporation of NLR and PLR in place of neutrophil count and platelet count improved prognostic accuracy of the IMDC model. These findings require external validation before introducing into clinical practice. PMID:28253564

Incorporating Neutrophil-to-lymphocyte Ratio and Platelet-to-lymphocyte Ratio in Place of Neutrophil Count and Platelet Count Improves Prognostic Accuracy of the International Metastatic Renal Cell Carcinoma Database Consortium Model.

PubMed

Chrom, Pawel; Stec, Rafal; Bodnar, Lubomir; Szczylik, Cezary

2018-01-01

The study investigated whether a replacement of neutrophil count and platelet count by neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) within the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model would improve its prognostic accuracy. This retrospective analysis included consecutive patients with metastatic renal cell carcinoma treated with first-line tyrosine kinase inhibitors. The IMDC and modified-IMDC models were compared using: concordance index (CI), bias-corrected concordance index (BCCI), calibration plots, the Grønnesby and Borgan test, Bayesian Information Criterion (BIC), generalized R 2 , Integrated Discrimination Improvement (IDI), and continuous Net Reclassification Index (cNRI) for individual risk factors and the three risk groups. Three hundred and twenty-one patients were eligible for analyses. The modified-IMDC model with NLR value of 3.6 and PLR value of 157 was selected for comparison with the IMDC model. Both models were well calibrated. All other measures favoured the modified-IMDC model over the IMDC model (CI, 0.706 vs. 0.677; BCCI, 0.699 vs. 0.671; BIC, 2,176.2 vs. 2,190.7; generalized R 2 , 0.238 vs. 0.202; IDI, 0.044; cNRI, 0.279 for individual risk factors; and CI, 0.669 vs. 0.641; BCCI, 0.669 vs. 0.641; BIC, 2,183.2 vs. 2,198.1; generalized R 2 , 0.163 vs. 0.123; IDI, 0.045; cNRI, 0.165 for the three risk groups). Incorporation of NLR and PLR in place of neutrophil count and platelet count improved prognostic accuracy of the IMDC model. These findings require external validation before introducing into clinical practice.

Efficacy of triptorelin pamoate 11.25 mg administered subcutaneously for achieving medical castration levels of testosterone in patients with locally advanced or metastatic prostate cancer.

PubMed

Lebret, Thiery; Rouanne, Mathieu; Hublarov, Oleg; Jinga, Viorel; Petkova, Lidiya; Kotsev, Rumen; Sinescu, Ioanel; Dutailly, Pascale

2015-06-01

Gonadotropin-releasing hormone agonists are widely used as androgen deprivation therapy in many men with locally advanced or metastatic prostate cancer. Gonadotropin-releasing hormone agonists are delivered by intramuscular injection every 1, 3 or 6 months, but in some patients subcutaneous injection may be more appropriate. This study assessed the efficacy and safety profile of the gonadotropin-releasing hormone agonist, triptorelin pamoate, when administered by the subcutaneous route. In this multicentre, open-label, single-arm study, androgen deprivation therapy-naïve men with locally advanced or metastatic prostate cancer received the gonadotropin-releasing hormone agonist triptorelin pamoate 11.25 mg (3-month formulation) by the subcutaneous route twice (at baseline and 13 weeks later). The co-primary efficacy endpoints were the proportion of patients with a castration level of serum testosterone (<50 ng/dl) after 4 weeks, and of these, those still castrated after 26 weeks. Of the 126 treated patients, 123 [97.6%; 95% confidence interval (CI): 93.2-99.5)] were castrated 4 weeks after the first subcutaneous injection, and 115/119 patients (96.6%; 95% CI: 91.6-99.1) castrated at 4 weeks maintained castration at 26 weeks. Median prostate-specific antigen levels were reduced by 64.2 and 96.0% at 4 and 26 weeks, respectively. The probability of maintaining a testosterone level <20 ng/dl up to 26 weeks was 90.0% (95% CI: 85.0-95.0). The most frequently occurring treatment-related adverse events were typical of gonadotropin-releasing hormone agonist treatment (hot flushes, increased weight, erectile dysfunction and hyperhidrosis). This study demonstrates that triptorelin pamoate 11.25 mg administered by the subcutaneous route every 3 months is as efficacious and well tolerated as administration via the intramuscular route in men with locally advanced or metastatic prostate cancer.

Efficacy of triptorelin pamoate 11.25 mg administered subcutaneously for achieving medical castration levels of testosterone in patients with locally advanced or metastatic prostate cancer

PubMed Central

Rouanne, Mathieu; Hublarov, Oleg; Jinga, Viorel; Petkova, Lidiya; Kotsev, Rumen; Sinescu, Ioanel; Dutailly, Pascale

2015-01-01

Objectives: Gonadotropin-releasing hormone agonists are widely used as androgen deprivation therapy in many men with locally advanced or metastatic prostate cancer. Gonadotropin-releasing hormone agonists are delivered by intramuscular injection every 1, 3 or 6 months, but in some patients subcutaneous injection may be more appropriate. This study assessed the efficacy and safety profile of the gonadotropin-releasing hormone agonist, triptorelin pamoate, when administered by the subcutaneous route. Methods: In this multicentre, open-label, single-arm study, androgen deprivation therapy-naïve men with locally advanced or metastatic prostate cancer received the gonadotropin-releasing hormone agonist triptorelin pamoate 11.25 mg (3-month formulation) by the subcutaneous route twice (at baseline and 13 weeks later). The co-primary efficacy endpoints were the proportion of patients with a castration level of serum testosterone (<50 ng/dl) after 4 weeks, and of these, those still castrated after 26 weeks. Results: Of the 126 treated patients, 123 [97.6%; 95% confidence interval (CI): 93.2–99.5)] were castrated 4 weeks after the first subcutaneous injection, and 115/119 patients (96.6%; 95% CI: 91.6–99.1) castrated at 4 weeks maintained castration at 26 weeks. Median prostate-specific antigen levels were reduced by 64.2 and 96.0% at 4 and 26 weeks, respectively. The probability of maintaining a testosterone level <20 ng/dl up to 26 weeks was 90.0% (95% CI: 85.0–95.0). The most frequently occurring treatment-related adverse events were typical of gonadotropin-releasing hormone agonist treatment (hot flushes, increased weight, erectile dysfunction and hyperhidrosis). Conclusions: This study demonstrates that triptorelin pamoate 11.25 mg administered by the subcutaneous route every 3 months is as efficacious and well tolerated as administration via the intramuscular route in men with locally advanced or metastatic prostate cancer. PMID:26161143

Economic outcomes of maintenance gefitinib for locally advanced/metastatic non-small-cell lung cancer with unknown EGFR mutations: a semi-Markov model analysis.

PubMed

Zeng, Xiaohui; Li, Jianhe; Peng, Liubao; Wang, Yunhua; Tan, Chongqing; Chen, Gannong; Wan, Xiaomin; Lu, Qiong; Yi, Lidan

2014-01-01

Maintenance gefitinib significantly prolonged progression-free survival (PFS) compared with placebo in patients from eastern Asian with locally advanced/metastatic non-small-cell lung cancer (NSCLC) after four chemotherapeutic cycles (21 days per cycle) of first-line platinum-based combination chemotherapy without disease progression. The objective of the current study was to evaluate the cost-effectiveness of maintenance gefitinib therapy after four chemotherapeutic cycle's stand first-line platinum-based chemotherapy for patients with locally advanced or metastatic NSCLC with unknown EGFR mutations, from a Chinese health care system perspective. A semi-Markov model was designed to evaluate cost-effectiveness of the maintenance gefitinib treatment. Two-parametric Weibull and Log-logistic distribution were fitted to PFS and overall survival curves independently. One-way and probabilistic sensitivity analyses were conducted to assess the stability of the model designed. The model base-case analysis suggested that maintenance gefitinib would increase benefits in a 1, 3, 6 or 10-year time horizon, with incremental $184,829, $19,214, $19,328, and $21,308 per quality-adjusted life-year (QALY) gained, respectively. The most sensitive influential variable in the cost-effectiveness analysis was utility of PFS plus rash, followed by utility of PFS plus diarrhoea, utility of progressed disease, price of gefitinib, cost of follow-up treatment in progressed survival state, and utility of PFS on oral therapy. The price of gefitinib is the most significant parameter that could reduce the incremental cost per QALY. Probabilistic sensitivity analysis indicated that the cost-effective probability of maintenance gefitinib was zero under the willingness-to-pay (WTP) threshold of $16,349 (3 × per-capita gross domestic product of China). The sensitivity analyses all suggested that the model was robust. Maintenance gefitinib following first-line platinum-based chemotherapy for patients

Value of adding the renal pathological score to the kidney failure risk equation in advanced diabetic nephropathy.

PubMed

Yamanouchi, Masayuki; Hoshino, Junichi; Ubara, Yoshifumi; Takaichi, Kenmei; Kinowaki, Keiichi; Fujii, Takeshi; Ohashi, Kenichi; Mise, Koki; Toyama, Tadashi; Hara, Akinori; Kitagawa, Kiyoki; Shimizu, Miho; Furuichi, Kengo; Wada, Takashi

2018-01-01

There have been a limited number of biopsy-based studies on diabetic nephropathy, and therefore the clinical importance of renal biopsy in patients with diabetes in late-stage chronic kidney disease (CKD) is still debated. We aimed to clarify the renal prognostic value of pathological information to clinical information in patients with diabetes and advanced CKD. We retrospectively assessed 493 type 2 diabetics with biopsy-proven diabetic nephropathy in four centers in Japan. 296 patients with stage 3-5 CKD at the time of biopsy were identified and assigned two risk prediction scores for end-stage renal disease (ESRD): the Kidney Failure Risk Equation (KFRE, a score composed of clinical parameters) and the Diabetic Nephropathy Score (D-score, a score integrated pathological parameters of the Diabetic Nephropathy Classification by the Renal Pathology Society (RPS DN Classification)). They were randomized 2:1 to development and validation cohort. Hazard Ratios (HR) of incident ESRD were reported with 95% confidence interval (CI) of the KFRE, D-score and KFRE+D-score in Cox regression model. Improvement of risk prediction with the addition of D-score to the KFRE was assessed using c-statistics, continuous net reclassification improvement (NRI), and integrated discrimination improvement (IDI). During median follow-up of 1.9 years, 194 patients developed ESRD. The cox regression analysis showed that the KFRE,D-score and KFRE+D-score were significant predictors of ESRD both in the development cohort and in the validation cohort. The c-statistics of the D-score was 0.67. The c-statistics of the KFRE was good, but its predictive value was weaker than that in the miscellaneous CKD cohort originally reported (c-statistics, 0.78 vs. 0.90) and was not significantly improved by adding the D-score (0.78 vs. 0.79, p = 0.83). Only continuous NRI was positive after adding the D-score to the KFRE (0.4%; CI: 0.0-0.8%). We found that the predict values of the KFRE and the D-score were

IGFBP-4 activates the Wnt/beta-catenin signaling pathway and induces M-CAM expression in human renal cell carcinoma.

PubMed

Ueno, Koji; Hirata, Hiroshi; Majid, Shahana; Tabatabai, Z Laura; Hinoda, Yuji; Dahiya, Rajvir

2011-11-15

The Wnt/β-catenin signaling pathway is inactivated by Wnt antagonists in most cancers and IGFBP-4 is an antagonist of the Wnt/ β-catenin signaling pathway. However, the function of IGFBP-4 is not currently understood in renal cell carcinoma (RCC). We initially found that the expression of IGFBP-4 was significantly lower in primary RCC and higher in metastatic RCC compared to normal human kidney tissues. To assess the function of IGFBP4, we established IGFBP4 transfectants (primary renal cancer cell line) and performed functional analyses including Tcf reporter assays, cell viability, invasive capability, mortality, and in vivo tumor growth. Interestingly IGFBP-4 transfectants promoted cell growth (in vitro and in vivo), invasion, and motility in primary renal cancer. Tcf transcriptional activity was significantly increased in IGFBP-4 transfectants compared to mock cells and β-catenin expression was increased. Also the β-catenin downstream effector, MT1-MMP showed increased expression in IGFBP4 transfectants. Additionally IGFBP4 induced the expression of M-CAM, a marker of tumor progression. In order to assess the role of IGFBP4 in metastatic renal cancer, IGFBP-4 mRNA in a metastatic renal cancer cell lines (ACHN) was knocked-down using a siRNA technique. The cell growth and motility was decreased in si-IGFBP4 transfected ACHN cells compared to cells transfected with control siRNA. Tcf activity in ACHN cells was also decreased with si-IGFBP-4 transfection. This is a first report documenting that IGFBP-4 expression in RCC activates cell growth, metastasis, Wnt/beta-catenin signaling and may be involved in RCC metastasis. Copyright © 2011 UICC.

Brazilian data of renal cell carcinoma in a public university hospital.

PubMed

Aguiar, Pedro; Padua, Tiago Costa; Guimaraes, Daiane Pereira

2016-01-01

Among renal malignancies, renal cell carcinoma (RCC) accounts for 85% of cases. Stage is a relevant prognostic factor; 5-year survival ranges from 81% to 8% according to the stage of disease. The treatment is based on surgery and molecularly targeted therapy has emerged as a choice for metastatic disease. Retrospective study by reviewing the medical records of patients with RCC treated in the last 10 years at UNIFESP. The primary end point of this trial was to evaluate the overall survival (OS) of the patients. The secondary end point was to evaluate the progression-free survival (PFS) after nephrectomy. 118 patients with RCC were included. The mean age was 58.3 years, 61.9% men; nephrectomy was performed in 90.7%, clear cell was the histology in 85.6%, 44 patients were classified as stage IV at diagnosis. Among these, 34 had already distant metastasis. 29 patients were treated with sunitinib. The median OS among all patients was 55.8 months. The median PFS after nephrectomy was 79.1 months. Sarcomatoid differentiation HR29.74 (95% CI, 4.31-205.26), clinical stage IV HR1.94 (95% CI, 1.37-2.75) and nephrectomy HR0.32 (95% CI, 0.15-0.67) were OS prognostic factors. Sunitinib had clinical activity. Patients treated in our hospital achieved median OS compatible with literature. Nevertheless, this study has shown a high number of patients with advanced disease. For patients with advanced disease, treatment with sunitinib achieved median OS of 28.7 months, consistent with the literature.

Elevated serum progastrin-releasing peptide (31-98) level is a predictor of short response duration after hormonal therapy in metastatic prostate cancer.

PubMed

Yashi, Masahiro; Nukui, Akinori; Kurokawa, Shinsuke; Ochi, Masanori; Ishikawa, Shinya; Goto, Kentaro; Kobayashi, Yutaka; Muraishi, Osamu; Tokue, Akihiko

2003-09-01

The neuroendocrine (NE) pathway has been attracting attention as a mechanism for the androgen-independent progression because the neuropeptide provokes tumor growth and inhibits apoptosis under androgen-deprived milieu in prostate cancer cells. On the basis that serum progastrin-releasing peptide (ProGRP) is elevated in patients with advanced disease stage, we examined the prognostic value of the neuropeptide. Serum ProGRP status was determined with an enzyme-linked immunosorbent assay (ELISA) in 460 men with benign and malignant prostatic diseases, chronic renal failure, and healthy controls. Seventy patients with metastatic prostate cancer including four patients (5.7%) with NE carcinoma who underwent hormonal therapy were enrolled in the prognostic analyses by Cox proportional hazards model. The serum status steadily shifted toward predominant expression of ProGRP with the progression of prostate cancer into metastatic and androgen-independent stages. Univariate analysis revealed that the deteriorated performance status (PS) and extent of bony disease (EOD), and high serum alkaline phosphatase (ALP), serum ProGRP, and nadir prostate-specific antigen (PSA) levels were associated with a lower progression-free survival (PFS) rate (P < 0.005). Multivariate analysis demonstrated that PS, serum ProGRP, and nadir PSA held an independent predictive value for PFS (P < 0.05), and all correlated with bone-related factors. Serum ProGRP was the most significant predictor among pre-treatment factors in this model (P = 0.0094). The neuropeptide precursor ProGRP is a distinct serum marker that is useful to know the NE milieu and provides prognostic information in patients with advanced prostate cancer. Standard therapy for metastatic prostate cancer may make progress when further studies will clarify the causative link between serum ProGRP level and androgen-independent disease progression. Copyright 2003 Wiley-Liss, Inc.

Reducing Disparities in the Quality of Advance Care Planning for Older Adults

ClinicalTrials.gov

2018-05-07

Metastatic Cancer; Congestive Heart Failure; Chronic Obstructive Pulmonary Disease; Parkinson Disease; Interstitial Lung Disease; Amyotrophic Lateral Sclerosis; End Stage Liver Disease; End Stage Renal Disease; Diabetes Complications

Inhibition of NA+/H+ Exchanger 1 Attenuates Renal Dysfunction Induced by Advanced Glycation End Products in Rats

PubMed Central

Li, Peng; Chen, Geng-Rong; Wang, Fu; Xu, Ping; Liu, Li-Ying; Yin, Ya-Ling; Wang, Shuang-Xi

2016-01-01

It has been recognized that sodium hydrogen exchanger 1 (NHE1) is involved in the development of diabetic nephropathy. The role of NHE1 in kidney dysfunction induced by advanced glycation end products (AGEs) remains unknown. Renal damage was induced by AGEs via tail vein injections in rats. Function and morphology of kidney were determined. Compared to vehicle- or BSA-treated rats, AGEs caused abnormalities of kidney structures and functions in rats, accompanied with higher MDA level and lower GSH content. Gene expressions of NHE1 gene and TGF-β1 in the renal cortex and urine were also increased in AGEs-injected rats. Importantly, all these detrimental effects induced by AGEs were reversed by inhibition of NHE1 or suppression of oxidative stress. These pieces of data demonstrated that AGEs may activate NHE1 to induce renal damage, which is related to TGF-β1. PMID:26697498

[Multicentre randomized trial comparing triptorelin medical castration versus surgical castration in the treatment of locally advanced or metastatic prostate cancer].

PubMed

Botto, Henry; Rouprêt, Morgan; Mathieu, François; Richard, François

2007-04-01

To report the results of a trial comparing the efficacy of triptorelin and surgical castration in the treatment of locally advanced or metastatic prostate cancer. 80 patients with previously untreated locally advanced or metastatic prostate cancer prostate cancer were included in a one-year multicentre, randomized, prospective, open-label therapeutic trial. Patients either received a monthly injection of triptorelin (group 1; n = 40), or were treated by pulpectomy (group 2; n = 40). Patients were reviewed every 3 months, then every 6 months. The mean age of the patients was 71.22 +/- 8.25 years. At 1 month, 38 patients were castrated (plasma testosterone < 0.5 mg/ml) in the pulpectomy group versus 35 in the triptorelin group. The mean follow-up was 38.8 +/- 26 months in the triptorelin group and 36.3 +/- 25 months in the pulpectomy group. On multivariate analysis, age, impaired performance status and PAP level (> 3.2 ng/ml) were predictive factors of a poor outcome. The median survival was 37.5 +/- 9 months in the triptorelin group and 33 +/- 3 months in the pulpectomy group. At 3 years, no significant difference in specific survival was observed between the 2 groups. At 8 years of follow-up, 63 patients had died. This study demonstrates an equivalent specific survival between patients treated by triptorelin or surgical castration. Castration is rapidly obtained with triptorelin (< 2 months) and is maintained over time throughout the duration of treatment.

Beyond Seed and Soil: Understanding and Targeting Metastatic Prostate Cancer; Report From the 2016 Coffey-Holden Prostate Cancer Academy Meeting.

PubMed

Miyahira, Andrea K; Roychowdhury, Sameek; Goswami, Sangeeta; Ippolito, Joseph E; Priceman, Saul J; Pritchard, Colin C; Sfanos, Karen S; Subudhi, Sumit K; Simons, Jonathan W; Pienta, Kenneth J; Soule, Howard R

2017-02-01

The 2016 Coffey-Holden Prostate Cancer Academy (CHPCA) Meeting, "Beyond Seed and Soil: Understanding and Targeting Metastatic Prostate Cancer," was held from June 23 to June 26, 2016, in Coronado, California. For the 4th year in a row, the Prostate Cancer Foundation (PCF) hosted the CHPCA Meeting, a think tank-structured scientific conference, which focuses on a specific topic of critical unmet need on the biology and treatment of advanced prostate cancer. The 2016 CHPCA Meeting was attended by 71 investigators from prostate cancer and other fields, who discussed the biology, study methodologies, treatment strategies, and critical unmet needs concerning metastatic prostate cancer, with the ultimate goal of advancing strategies to treat and eliminate this disease. The major topics of discussion included: the molecular landscape and molecular heterogeneity of metastatic prostate cancer, the role of the metastatic microenvironment, optimizing immunotherapy in metastatic prostate cancer, learning from exceptional responders and non-responders, targeting DNA repair deficiency in advanced prostate cancer, developing and applying novel biomarkers and imaging techniques, and potential roles for the microbiome in prostate cancer. This article reviews the topics presented and discussions held at the CHPCA Meeting, with a focus on the unknowns and next steps needed to advance our understanding of the biology and most effective treatment strategies for metastatic prostate cancer. Prostate 77:123-144, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Interstitial lung disease during targeted therapy in metastatic renal cell carcinoma: a case series from three centres.

PubMed

Ivanyi, Philipp; Fuehner, Thomas; Adam, Meike; Eichelberg, Christian; Herrmann, Edwin; Merseburger, Axel Stuart; Ganser, Arnold; Grünwald, Viktor

2014-09-01

Interstitial lung disease (ILD) is an adverse event which occurs also during targeted treatment of patients with metastatic renal cell carcinoma (mRCC). Experiences on ILD-management in mRCC remain limited. mRCC patients treated with everolimus, temsirolimus, or sunitinib at three centres from January 2006 until December 2009 were analysed, retrospectively. Medical records and imaging studies, as well as clinical course, the incidence, diagnostic measures, treatment, and outcome of ILD were assessed. Twenty-six ILD patients (11 %) were identified out of 237 mRCC patients. Median treatment until ILD-diagnosis was 3.8 (range: 1-21.5) months. The ILD-frequency was 2.7 % (n = 6/226) during sunitinib therapy and 19.8 % (n = 20/101) during m-TOR-inhibitor treatment. Cough was the prevailing symptom (69.2 %, n = 18). Bronchoalveolar lavage reviled often lymphocytic (42.9 %, n = 6/14) or eosinophilic cellularity (28.6 %, n = 4/14). Dose reduction (42.3 %, n = 11), treatment interruption (46.2 %, n = 12) or termination (23.1 %, n = 6), and steroid application (34.6 %, n = 9) were common measures in ILD. Interestingly, eosinophilic ILD required pulsed steroids. Improvement occurred in 73.7 % of symptomatic patients. Continuation of targeted therapies was warranted in 65.4 % of ILD patients. No patient died from ILD. ILD during targeted mRCC treatment is common, and supportive measures should be adapted to the clinical course, and potentially in dependence of BAL findings. Re-exposure to targeted therapies appears feasible.

Is sunitinib-induced hypothyroidism a predictive clinical marker for better response in metastatic renal cell carcinoma patients?

PubMed

Bozkurt, Oktay; Karaca, Halit; Hacıbekiroglu, Ilhan; Kaplan, Muhammed Ali; Duzkopru, Yakup; Uysal, Mukremin; Berk, Veli; Inanc, Mevlude; Duran, Ayse Ocak; Ozaslan, Ersin; Ucar, Mahmut; Ozkan, Metin

2016-06-01

The main goal of this study was to examine whether the occurrence of hypothyroidism during sunitinib therapy in patients with metastatic renal cell carcinoma (mRCC) is associated with a better outcome. The study enrolled 81 patients with pathologically proven mRCC who were treated with sunitinib between March 2008 and June 2013.Thyroid function evaluation comprised (free-thyroxine) FT4 and thyroid-stimulating hormone (TSH) before treatment and at day 1 of each 6-week cycle. Survival analysis was performed using the Kaplan-Meier method, and the differences among the groups were determined using the log-rank test. Hypothyroidism occurred in 30 (37%) of 81 patients within a median 3 months (range 1-18) of treatment initiation. There was a statistically significant correlation between the occurrence of hypothyroidism during treatment and the rate of objective remission (ORR) (hypothyroid patients vs euthyroid patients: 46.7 vs 13.7%, respectively; P = 0.001). Median progression-free survival (PFS) was 10 (95% CI 6.13-13.8) months in the euthyroid patients, and 17 (95% CI 9.33-24.6) months in the hypothyroid patients (P = 0.001). The median overall survival (OS) was 39 (95% CI 25.4-52.5) months in the hypothyroid patients and 20 (95% CI 14.7-25.2) months in the euthyroid patients (P = 0.019). The occurrence of hypothyroidism during treatment in patients was significantly associated with longer PFS, OS and better ORR in the current study.

[Advanced Prostate Cancer Consensus Conference 2017 : Discussion of the recommendations for diagnosis and treatment of metastatic prostate cancer by a German panel of experts].

PubMed

Schostak, M; König, F; Bögemann, M; Goebell, P; Hammerer, P; Machtens, S; Schwentner, C; Thomas, C; von Amsberg, G; von Rundstedt, F-C; Heidenreich, A

2018-05-28

In March 2017 the 'Advanced Prostate Cancer Consensus Conference' (APCCC) took place in St. Gallen (Switzerland). The APCCC-panelists are internationally well known experts. With the actual data in mind they discussed treatment options for patients with advanced prostate cancer in order to update the international APCCC-recommendations from the previous meeting in 2015. Recently these consensus recommendations have been published in "European Urology".A group of German experts discussed this year APCCC-votes during the meeting and the recommendations that were concluded from the votes from the German perspective. Reasons for an additional German discussion are country-specific variations that may have influenced the APCCC-votes und recommendations. Due to the concept of the APCCC-meeting the wording of the questions could not always be as necessary.One focus of this year consensus discussion was the treatment of metastatic castration-naive prostate cancer (mCNPC). There are new data which may also influence the therapeutic situation of patients with metastatic castration-resistant prostate cancer (mCRPC). Further points of discussion were the impact of new imaging procedures in the clinical setting as well as the treatment of oligometastatic prostate cancer.

Metastatic renal cell carcinoma: CT-guided immunotherapy as a technically feasible and safe approach to delivery of gene therapy for treatment.

PubMed

Suh, Robert D; Goldin, Jonathan G; Wallace, Amanda B; Sheehan, Ramon E; Heinze, Stefan B; Gitlitz, Barbara J; Figlin, Robert A

2004-05-01

To assess the technical feasibility and safety of weekly outpatient percutaneous computed tomographic (CT)-guided intratumoral injections of interleukin-2 (IL-2) plasmid DNA in a wide variety of superficial and deep tumor sites. Twenty-nine patients with metastatic renal cell carcinoma and a total of 30 lesions measuring 1.0 cm(2) or greater in accessible thoracic (n = 15) or abdominal (n = 15) locations underwent up to three cycles of six weekly intratumoral IL-2 plasmid DNA injections. CT was used to guide needle placement and injection. After injection cycle 1, patients whose tumors demonstrated stable (< or =25% increase and < or =50% decrease in product of lesion diameters) or decreased size (>50% decrease in product of lesion diameters) advanced to injection cycle 2. Patients whose lesions decreased in size by more than 50% over the course of injection cycle 2 were eligible to begin injection cycle 3. An acceptable safety and technical feasibility profile for this technique was deemed to be (a) a safety and feasibility profile similar to that of single-needle biopsy and (b) an absence of serious adverse events (as defined in Title 21 of the Code of Federal Regulations) and/or unacceptable toxicities (as graded according to the National Cancer Institute Common Toxicity Criteria). A total of 284 intratumoral injections were performed, with a mean of 9.8 injections (range, 6-18 injections) received by each patient. Technical success (needle placement and injection of gene therapy agent) was achieved in all cases. Complications were experienced after 42 (14.8%) of the 284 injections. The most common complication was pneumothorax (at 32 [28.6%] of 112 intrathoracic injections), for which only one patient required catheter drainage. Complications occurred randomly throughout injection cycles and did not appear to increase as patients received more injections (P =.532). No patient experienced serious adverse events or unacceptable toxicities. Percutaneous CT

Icotinib plus gemcitabine for metastatic pancreatic cancer: A case report

PubMed Central

Zhao, Jing; Shen, Hong; Hu, Han-Guang; Huang, Jian-Jin

2015-01-01

A large majority of patients diagnosed with pancreatic cancer have advanced metastatic disease with unresectable malignancies. Despite treatment advances, the survival benefit from chemotherapeutic regimens and targeted drugs is limited. Moreover, their application is limited in China because of high toxicity and cost. Recently, inhibitors of epidermal growth factor receptor activity have shown promise for the treatment of solid cancers when used in combination with standard therapy. However, these drugs have not been evaluated extensively for the treatment of pancreatic cancer. Here, we report the treatment of a 64-year-old male with metastatic pancreatic cancer using a novel regimen of icotinib with gemcitabine. Marked shrinkage of the mass was observed after two treatment cycles, and partial remission was achieved. The abdominal pain was relieved. The adverse effects were tolerable and treatment cost was acceptable. This is the first reported case for the treatment of advanced pancreatic cancer with icotinib plus gemcitabine and demonstrates a promising therapeutic alternative. PMID:25805958

Icotinib plus gemcitabine for metastatic pancreatic cancer: a case report.

PubMed

Zhao, Jing; Shen, Hong; Hu, Han-Guang; Huang, Jian-Jin

2015-03-21

A large majority of patients diagnosed with pancreatic cancer have advanced metastatic disease with unresectable malignancies. Despite treatment advances, the survival benefit from chemotherapeutic regimens and targeted drugs is limited. Moreover, their application is limited in China because of high toxicity and cost. Recently, inhibitors of epidermal growth factor receptor activity have shown promise for the treatment of solid cancers when used in combination with standard therapy. However, these drugs have not been evaluated extensively for the treatment of pancreatic cancer. Here, we report the treatment of a 64-year-old male with metastatic pancreatic cancer using a novel regimen of icotinib with gemcitabine. Marked shrinkage of the mass was observed after two treatment cycles, and partial remission was achieved. The abdominal pain was relieved. The adverse effects were tolerable and treatment cost was acceptable. This is the first reported case for the treatment of advanced pancreatic cancer with icotinib plus gemcitabine and demonstrates a promising therapeutic alternative.

RAS testing in metastatic colorectal cancer: advances in Europe.

PubMed

Van Krieken, J Han J M; Rouleau, Etienne; Ligtenberg, Marjolijn J L; Normanno, Nicola; Patterson, Scott D; Jung, Andreas

2016-04-01

Personalized medicine shows promise for maximizing efficacy and minimizing toxicity of anti-cancer treatment. KRAS exon 2 mutations are predictive of resistance to epidermal growth factor receptor-directed monoclonal antibodies in patients with metastatic colorectal cancer. Recent studies have shown that broader RAS testing (KRAS and NRAS) is needed to select patients for treatment. While Sanger sequencing is still used, approaches based on various methodologies are available. Few CE-approved kits, however, detect the full spectrum of RAS mutations. More recently, "next-generation" sequencing has been developed for research use, including parallel semiconductor sequencing and reversible termination. These techniques have high technical sensitivities for detecting mutations, although the ideal threshold is currently unknown. Finally, liquid biopsy has the potential to become an additional tool to assess tumor-derived DNA. For accurate and timely RAS testing, appropriate sampling and prompt delivery of material is critical. Processes to ensure efficient turnaround from sample request to RAS evaluation must be implemented so that patients receive the most appropriate treatment. Given the variety of methodologies, external quality assurance programs are important to ensure a high standard of RAS testing. Here, we review technical and practical aspects of RAS testing for pathologists working with metastatic colorectal cancer tumor samples. The extension of markers from KRAS to RAS testing is the new paradigm for biomarker testing in colorectal cancer.

Downregulation of long non-coding RNA ENSG00000241684 is associated with poor prognosis in advanced clear cell renal cell carcinoma.

PubMed

Su, Hengchuan; Wang, Hongkai; Shi, Guohai; Zhang, Hailiang; Sun, Fukang; Ye, Dingwei

2018-06-01

In order to identify potential novel biomarkers of advanced clear cell renal cell carcinoma (ccRCC), we re-evaluated published long non-coding RNA (lncRNA) expression profiling data. The lncRNA expression profiles in ccRCC microarray dataset GSE47352 were analyzed and an independent cohort of 61 clinical samples including 21 advanced and 40 localized ccRCC patients was used to confirm the most statistically significant lncRNAs by real time PCR. Next, the relationships between the selected lncRNAs and ccRCC patients' clinicopathological features were investigated. The effects of LncRNAs on the invasion and proliferation of renal carcinoma cells were also investigated. The PCR results in a cohort of 21 advanced ccRCC and 40 localized ccRCC tissues were used for confirmation of the selected lncRNAs which were statistically most significant. The PCR results showed that the expression of three LncRNA (ENSG00000241684, ENSG00000231721 and NEAT1) were significantly downregulated in advanced ccRCC. Kaplan-Meier analysis revealed that reduced expression of LncRNA ENSG00000241684 and NEAT1 were significantly associated with poor overall survival. The univariate and multivariate Cox regression indicated LncRNA ENSG00000241684 had significant hazard ratios for predicting clinical outcome. LncRNA ENSG00000241684 expression was negatively correlated with pTNM stage. Overexpression of ENSG00000241684 significantly impaired cell proliferation and reduced the invasion ability in 786-O and ACHN cells. lncRNAs are involved in renal carcinogenesis and decreased lncRNA ENSG00000241684 expression may be an independent adverse prognostic factor in advanced ccRCC patients. Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Effects of statin therapy on clinical outcomes after acute myocardial infarction in patients with advanced renal dysfunction: A propensity score-matched analysis.

PubMed

Kim, Jin Sug; Kim, Weon; Park, Ji Yoon; Woo, Jong Shin; Lee, Tae Won; Ihm, Chun Gyoo; Kim, Yang Gyun; Moon, Ju-Young; Lee, Sang Ho; Jeong, Myung Ho; Jeong, Kyung Hwan

2017-01-01

Lipid lowering therapy is widely used for the prevention of cardiovascular complications after acute myocardial infarction (AMI). However, some studies show that this benefit is uncertain in patients with renal dysfunction, and the role of statins is based on the severity of renal dysfunction. In this study, we investigated the impact of statin therapy on major adverse cardiac events (MACEs) and all-cause mortality in patients with advanced renal dysfunction undergoing percutaneous coronary intervention (PCI) after AMI. This study was based on the Korea Acute Myocardial Infarction Registry database. We included 861 patients with advanced renal dysfunction from among 33,205 patients who underwent PCI after AMI between November 2005 and July 2012. Patients were divided into two groups: a statin group (n = 537) and a no-statin group (n = 324). We investigated the 12-month MACEs (cardiac death, myocardial infarction, repeated PCI or coronary artery bypass grafting) and all-cause mortality of each group. Subsequently, a propensity score-matched analysis was performed. In the total population studied, no significant differences were observed between the two groups with respect to the rate of recurrent MI, repeated PCI, coronary artery bypass grafting (CABG), or all-cause mortality. However, the cardiac death rate was significantly lower in the statin group (p = 0.009). Propensity score-matched analysis yielded 274 pairs demonstrating, results similar to those obtained from the total population. However, there was no significant difference in the cardiac death rate in the propensity score-matched population (p = 0.103). Cox-regression analysis revealed only left ventricular ejection fraction to be an independent predictor of 12-month MACEs (Hazard ratio [HR] of 0.979, 95% confidence interval [CI], 0962-0.996, p = 0.018). Statin therapy was not significantly associated with a reduction in the 12-month MACEs or all-cause mortality in patients with advanced renal dysfunction

Cytoreductive Surgery in the Management of Renal Tumours: Rationale, Current Evidence and Future Perspectives.

PubMed

Khochikar, Makarand V

2017-03-01

Renal cell carcinoma accounts for 3% of adult solid malignant tumours. Approximately 25% of the patients present with metastatic disease at presentation. In the era of immunotherapy (interferon alpha-2b and interleukin-2), studies showed significant survival benefit with cytoreductive nephrectomy (CRN) followed by interferon alpha-2b than interferon alpha 2-b alone. Introduction of targeted therapies (vascular endothelial growth factor receptor-tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors) in 2005 generated a great interest in the management of metastatic renal cell carcinoma (mRCC) as these drugs exhibited tumour shrinkage in the primary tumour as well as in the metastatic site/s. Though there is no level 1 evidence, many studies have shown the usefulness of cytoreductive nephrectomy along with targeted therapy as against to targeted therapy alone. This review is aimed at the rationale behind the cytoreductive nephrectomy in mRCC, the current evidence and what is in store for the future. A detailed search on the management of mRCC was carried out on MEDLINE, Embase, CANCERLIT and Cochrane Library databases using the key words "cytoreductive nephrectomy", "immunotherapy" and "targeted therapy" since 1980 till 2015. Original articles, review articles, monograms, book chapters on metastatic renal cancer and textbooks on urologic oncology, oncology and urology were reviewed. Various international guidelines on this issue were also studied. An identical search was performed using the American Society of Clinical Oncology Abstract database. Trials in the progress or recently completed that were relevant to this paper were identified through clinicaltrials.gov. The latest information for new articles ahead of publication was last accessed in November 2015. CRN has remained an integral part to the management of metastatic renal cell carcinoma mainly for the patients with good performance status, life expectancy of more than 12 months and in the

Hypertrophic osteopathy associated with renal pelvis transitional cell carcinoma in a dog

PubMed Central

Grillo, Thais P.; Brandão, Cláudia V.S.; Mamprim, Maria J.; de Jesus, Carlos M.N.; Santos, Taizha C.; Minto, Bruno W.

2007-01-01

A 6-year-old male, Belgian shepherd dog was presented with lethargy, oliguria, hematuria, and reluctance to move. The dog developed hypertrophic osteopathy secondary to renal pelvis transitional cell carcinoma. A nephrectomy was performed and after a year, the dog was completely asymptomatic, and no evidence of metastatic disease was present. PMID:17824162

Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial.

PubMed

Balar, Arjun V; Galsky, Matthew D; Rosenberg, Jonathan E; Powles, Thomas; Petrylak, Daniel P; Bellmunt, Joaquim; Loriot, Yohann; Necchi, Andrea; Hoffman-Censits, Jean; Perez-Gracia, Jose Luis; Dawson, Nancy A; van der Heijden, Michiel S; Dreicer, Robert; Srinivas, Sandy; Retz, Margitta M; Joseph, Richard W; Drakaki, Alexandra; Vaishampayan, Ulka N; Sridhar, Srikala S; Quinn, David I; Durán, Ignacio; Shaffer, David R; Eigl, Bernhard J; Grivas, Petros D; Yu, Evan Y; Li, Shi; Kadel, Edward E; Boyd, Zachary; Bourgon, Richard; Hegde, Priti S; Mariathasan, Sanjeev; Thåström, AnnChristine; Abidoye, Oyewale O; Fine, Gregg D; Bajorin, Dean F

2017-01-07

First-line chemotherapy for patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma is associated with short response duration, poor survival, and high toxicity. This study assessed atezolizumab (anti-programmed death-ligand 1 [PD-L1]) as treatment for metastatic urothelial cancer in cisplatin-ineligible patients. For this single-arm, multicentre, phase 2 study, in 47 academic medical centres and community oncology practices in seven countries in North America and Europe, we recruited previously untreated patients with locally advanced or metastatic urothelial cancer who were cisplatin ineligible. Patients were given 1200 mg intravenous atezolizumab every 21 days until progression. The primary endpoint was independently confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (central review), assessed in prespecified subgroups based on PD-L1 expression and in all patients. All participants who received one or more doses of atezolizumab were included in the primary and safety analyses. This study was registered with ClinicalTrials.gov, number NCT02108652. Between June 9, 2014, and March 30, 2015, we enrolled 123 patients, of whom 119 received one or more doses of atezolizumab. At 17·2 months' median follow-up, the objective response rate was 23% (95% CI 16 to 31), the complete response rate was 9% (n=11), and 19 of 27 responses were ongoing. Median response duration was not reached. Responses occurred across all PD-L1 and poor prognostic factor subgroups. Median progression-free survival was 2·7 months (2·1 to 4·2). Median overall survival was 15·9 months (10·4 to not estimable). Tumour mutation load was associated with response. Treatment-related adverse events that occurred in 10% or more of patients were fatigue (36 [30%] patients), diarrhoea (14 [12%] patients), and pruritus (13 [11%] patients). One treatment-related death (sepsis) occurred. Nine (8%) patients had an adverse event

A Decade of Experience in Developing Preclinical Models of Advanced- or Early-Stage Spontaneous Metastasis to Study Antiangiogenic Drugs, Metronomic Chemotherapy, and the Tumor Microenvironment.

PubMed

Kerbel, Robert S

2015-01-01

The clinical circumstance of treating spontaneous metastatic disease, after resection of primary tumors, whether advanced/overt or microscopic in nature, is seldom modeled in mice and may be a major factor in explaining the frequent discordance between preclinical and clinical therapeutic outcomes where the trend is "overprediction" of positive results in preclinical mouse model studies. To evaluate this hypothesis, a research program was initiated a decade ago to develop multiple models of metastasis in mice, using variants of human tumor cell lines selected in vivo for enhanced spontaneous metastatic aggressiveness after surgical resection of established orthotopic primary tumors. These models have included breast, renal, and colorectal carcinomas; ovarian cancer (but without prior surgery); and malignant melanoma. They have been used primarily for experimental therapeutic investigations involving various antiangiogenic drugs alone or with chemotherapy, especially "metronomic" low-dose chemotherapy. The various translational studies undertaken have revealed a number of clinically relevant findings. These include the following: (i) the potential of metronomic chemotherapy, especially when combined with a vascular endothelial growth factor pathway targeting drug to successfully treat advanced metastatic disease; (ii) the development of relapsed spontaneous brain metastases in mice with melanoma or breast cancer whose systemic metastatic disease is successfully controlled for a period with a given therapy; (iii) foreshadowing the failure of adjuvant antiangiogenic drug-based phase III trials; (iv) recapitulating the failure of oral antiangiogenic tyrosine kinase inhibitors plus standard chemotherapy in contrast to the modest successes of antiangiogenic antibodies plus chemotherapy in metastatic breast cancer; and (v) revealing "vessel co-option" and absence of angiogenesis as a determinant of intrinsic resistance or minimal responsiveness to antiangiogenic therapy

Therapeutic challenges in renal cell carcinoma

PubMed Central

Penticuff, Justin C; Kyprianou, Natasha

2015-01-01

Renal cell carcinoma (RCC) is a malignancy that in advanced disease, is highly resistant to systemic therapies. Elucidation of the angiogenesis pathways and their intrinsic signaling interactions with the genetic and metabolic disturbances within renal cell carcinoma variants has ushered in the era of “targeted therapies”. Advanced surgical interventions and novel drugs targeting VEGF and mTOR, have improved patient survival and prolonged clinically stable-disease states. This review discusses the current understanding of diagnostic challenges and the mechanism-based clinical evidence on therapeutic management of advanced RCC. PMID:26309897

Economic Evaluation of First-Line Treatments for Metastatic Renal Cell Carcinoma: A Cost-Effectiveness Analysis in A Health Resource–Limited Setting

PubMed Central

Wu, Bin; Dong, Baijun; Xu, Yuejuan; Zhang, Qiang; Shen, Jinfang; Chen, Huafeng; Xue, Wei

2012-01-01

Background To estimate, from the perspective of the Chinese healthcare system, the economic outcomes of five different first-line strategies among patients with metastatic renal cell carcinoma (mRCC). Methods and Findings A decision-analytic model was developed to simulate the lifetime disease course associated with renal cell carcinoma. The health and economic outcomes of five first-line strategies (interferon-alfa, interleukin-2, interleukin-2 plus interferon-alfa, sunitinib and bevacizumab plus interferon-alfa) were estimated and assessed by indirect comparison. The clinical and utility data were taken from published studies. The cost data were estimated from local charge data and current Chinese practices. Sensitivity analyses were used to explore the impact of uncertainty regarding the results. The impact of the sunitinib patient assistant program (SPAP) was evaluated via scenario analysis. The base-case analysis showed that the sunitinib strategy yielded the maximum health benefits: 2.71 life years and 1.40 quality-adjusted life-years (QALY). The marginal cost-effectiveness (cost per additional QALY) gained via the sunitinib strategy compared with the conventional strategy was $220,384 (without SPAP, interleukin-2 plus interferon-alfa and bevacizumab plus interferon-alfa were dominated) and $16,993 (with SPAP, interferon-alfa, interleukin-2 plus interferon-alfa and bevacizumab plus interferon-alfa were dominated). In general, the results were sensitive to the hazard ratio of progression-free survival. The probabilistic sensitivity analysis demonstrated that the sunitinib strategy with SPAP was the most cost-effective approach when the willingness-to-pay threshold was over $16,000. Conclusions Our analysis suggests that traditional cytokine therapy is the cost-effective option in the Chinese healthcare setting. In some relatively developed regions, sunitinib with SPAP may be a favorable cost-effective alternative for mRCC. PMID:22412884

Economic evaluation of first-line treatments for metastatic renal cell carcinoma: a cost-effectiveness analysis in a health resource-limited setting.

PubMed

Wu, Bin; Dong, Baijun; Xu, Yuejuan; Zhang, Qiang; Shen, Jinfang; Chen, Huafeng; Xue, Wei

2012-01-01

To estimate, from the perspective of the Chinese healthcare system, the economic outcomes of five different first-line strategies among patients with metastatic renal cell carcinoma (mRCC). A decision-analytic model was developed to simulate the lifetime disease course associated with renal cell carcinoma. The health and economic outcomes of five first-line strategies (interferon-alfa, interleukin-2, interleukin-2 plus interferon-alfa, sunitinib and bevacizumab plus interferon-alfa) were estimated and assessed by indirect comparison. The clinical and utility data were taken from published studies. The cost data were estimated from local charge data and current Chinese practices. Sensitivity analyses were used to explore the impact of uncertainty regarding the results. The impact of the sunitinib patient assistant program (SPAP) was evaluated via scenario analysis. The base-case analysis showed that the sunitinib strategy yielded the maximum health benefits: 2.71 life years and 1.40 quality-adjusted life-years (QALY). The marginal cost-effectiveness (cost per additional QALY) gained via the sunitinib strategy compared with the conventional strategy was $220,384 (without SPAP, interleukin-2 plus interferon-alfa and bevacizumab plus interferon-alfa were dominated) and $16,993 (with SPAP, interferon-alfa, interleukin-2 plus interferon-alfa and bevacizumab plus interferon-alfa were dominated). In general, the results were sensitive to the hazard ratio of progression-free survival. The probabilistic sensitivity analysis demonstrated that the sunitinib strategy with SPAP was the most cost-effective approach when the willingness-to-pay threshold was over $16,000. Our analysis suggests that traditional cytokine therapy is the cost-effective option in the Chinese healthcare setting. In some relatively developed regions, sunitinib with SPAP may be a favorable cost-effective alternative for mRCC.

Clinical outcomes in patients with metastatic renal cell carcinoma receiving everolimus or temsirolimus after sunitinib

PubMed Central

Iacovelli, Roberto; Cartenì, Giacomo; Milella, Michele; Berardi, Rossana; Di Lorenzo, Giuseppe; Verzoni, Elena; Rizzo, Mimma; Santoni, Matteo; Procopio, Giuseppe

2014-01-01

Introduction: There are little data on the clinical activity of temsirolimus (TM) and everolimus (EV) when used as second-line therapy after sunitinib (SU) in patients with metastatic renal cell carcinoma (mRCC). Methods: Patients with mRCC treated with EV or TM after SU were included in this retrospective analysis. Progression-free survival (PFS), time to sequence failure (TTSF) from the start of SU to disease progression with EV/TM and overall survival (OS) were estimated using Kaplan-Meier method and compared across groups using the log-rank test. Cox proportional hazards models were applied to investigate predictors of TTSF and OS. Results: In total, 89 patients (median age 60.0 years) were included. At baseline 43% were classified as MSKCC good-risk, 43% as intermediate-risk and 14% as poor-risk. Median OS was 36.3 months and median TTSF was 17.2 months. Sixty-five patients received SU-EV and 24 patients SU-TM. Median PFS after the second-line treatment was 4.3 months in the EV group and 3.5 months in the TM group (p = 0.63). Median TTSF was 17.0 and 18.9 months (p = 0.32) and the OS was 35.8 and 38.3 months (p = 0.73) with SU-EV and SU-TM, respectively. The prognostic role of initial MSKCC was confirmed by multivariable analysis (hazard ratio 1.76, 95% confidence interval 1.08–2.85. p = 0.023). Conclusions: This study did not show significant differences in terms of disease control and OS between EV and TM in the second-line setting. EV remains the preferred mTOR inhibitor for the treatment of mRCC patients resistant to prior tyrosine kinase inhibitor treatment. PMID:24678349

The normal and pathologic renal medulla: a comprehensive overview.

PubMed

López, José I; Larrinaga, Gorka; Kuroda, Naoto; Angulo, Javier C

2015-04-01

The renal medulla comprises an intricate system of tubules, blood vessels and interstitium that is not well understood by most general pathologists. We conducted an extensive review of the literature on the renal medulla, in both normal and pathologic conditions. We set out in detail the points of key interest to pathologists: normal and pathological development, physiology, microscopic anatomy, histology and immunohistochemistry; and the specific and most common other types of disease associated with this part of the kidney: developmental abnormalities, (multicystic dysplastic kidney, autosomal dominant and recessive polycystic kidney diseases, medullary cystic kidney disease), inflammatory conditions (xanthogranulomatous pyelonephritis, malakoplakia), hyperplasia and dysplasia, and neoplastic processes (oncocytoma, atypical oncocytic tumors, chromophobe cell carcinoma, collecting duct carcinoma, urothelial carcinoma, other carcinomas, renal medullary fibroma and metastatic tumors). This condensed overview of the origin, function and pathology of the renal medulla, both in terms of development, inflammation and neoplastic processes, should help focus the interest of clinical pathologists on this widely overlooked part of the kidney. Copyright © 2014 Elsevier GmbH. All rights reserved.

Preliminary results of M-VAC chemotherapy combined with mild hyperthermia, a new therapeutic strategy for advanced or metastatic transitional cell carcinoma of the urothelium.

PubMed

Yamada, Yoshiaki; Itoh, Youko; Aoki, Shigeyuki; Nakamura, Kogenta; Taki, Tomohiro; Naruse, Katsuya; Tobiume, Motoi; Zennami, Kenji; Katsuda, Remi; Kato, Yoshiharu; Watanabe, Masahito; Nishikawa, Genya; Minami, Miwako; Nakahira, Mariko; Ukai, Sayaka; Sawada, Masaki; Kitamura, Akiko; Honda, Nobuaki

2009-11-01

We evaluated the efficacy and safety of M-VAC chemotherapy combined with mild hyperthermia, a new therapeutic strategy for advanced metastatic transitional cell carcinoma of the urothelium. The subjects were 12 patients diagnosed with advanced metastatic transitional cell carcinoma of the urothelium. For mild hyperthermia, the patients' oral temperature was elevated to about 38 degrees C by heating for 20 min and retaining the heat for 20 min with a far-infrared heater. The antitumor effect was evaluated according to the RECIST, while adverse drug reactions were assessed based on the NCI-CTC. The antitumor effect was rated as partial remission (PR) in 10 of the 12 patients and stable disease in 2 patients, with an efficacy rate of 83% (10/12). All 10 patients who had achieved PR received three courses of treatment. Of the 12 patients, 5 died during the observation period, with survival for 9-23 months (mean: 15.6 months). Adverse drug reactions included myelosuppression in all patients (Grade 3 in 4 patients, Grade 4 in 8), and gastrointestinal toxicity, such as nausea or vomiting, which was mild (Grade 0 in 2 patients, Grade 1 in 8, Grade 2 in 1, Grade 3 in 1). The results of the present study suggest that M-VAC chemotherapy combined with mild hyperthermia, which potentiates the anticancer effect and reduces adverse drug reactions such as gastrointestinal symptoms, is a useful and safe method for the treatment of advanced transitional cell carcinoma of the urothelium.

Pemetrexed combined with paclitaxel in patients with advanced or metastatic non-small-cell lung cancer: a phase I-II trial.

PubMed

Stathopoulos, George P; Dimitroulis, John; Toubis, Michael; Katis, Costas; Karaindros, Dimitris; Stathopoulos, John; Koutandos, John

2007-07-01

Pemetrexed, a novel multi-targeted agent established for the treatment of mesothelioma, has been under investigation for other malignancies, and in recent years particularly for non-small-cell lung cancer (NSCLC). In the present trial we investigated pemetrexed in combination with paclitaxel as front-line treatment in advanced or metastatic NSCLC. Our objectives were to determine the response rate, median and overall survival and toxicity. From April 2005 until May 2006, 51 patients with advanced or metastatic NSCLC were enrolled and 48 were considered evaluable. There were 39 males and nine females, median age 62 years (range 37-81 years), one patient stage IIIA N(2), 23 patients, IIIB and 24, stage IV. All patients had a cytologically- or histologically-confirmed diagnosis. Pemetrexed was administered at a standard dose of 500mg/m(2) and paclitaxel at an escalating dose starting at 135mg/m(2), then 150mg/m(2) and ending at a dose of 175mg/m(2); the level was increased every three patients. Both agents were administered on day 1, repeated every 3 weeks for six courses. A 39.6% partial response rate was observed with a median survival of 14 months. Toxicity was mild with 8.3% grade 3 and 4 neutropenia and other very mild hematologic and non-hematologic adverse reactions. The combination of pemetrexed and paclitaxel at doses of 500mg/m(2) and 175mg/m(2), respectively, has been shown to be an effective combination with very limited toxicity.

Assessment of ethnic differences in sunitinib outcome between Caucasian and Asian patients with metastatic renal cell carcinoma: a meta-analysis.

PubMed

Liu, Xiaoyan; Fiocco, Marta; Swen, Jesse J; Guchelaar, Henk-Jan

2017-04-01

An increasing number of studies have reported ethnic differences in sunitinib outcome in metastatic renal cell carcinoma (mRCC) patients. However, a comprehensive analysis is still lacking. Therefore, we systematically collected available published data and performed a meta-analysis to compare sunitinib efficacy and toxicity in Asian and Caucasian mRCC patients. Data were extracted from published results from clinical trials, expanded access program and real-world clinical practice. Progression-free survival (or time to tumor progression), overall survival, objective response rate and adverse events were used as endpoints to evaluate the differences of sunitinib outcome between the two ethnicities. For adverse events, we focused the following clinically relevant side effects: diarrhea, fatigue, mucositis/stomatitis, hand-foot syndrome, hypertension, leukopenia, neutropenia and thrombocytopenia. A total of 33 publications including 9977 patients were available for meta-analysis. The efficacy of sunitinib in Asian patients was similar to that in Caucasian patients. However, Asian patients showed a higher incidence of all grades toxicity of hand-foot syndrome, > grade 2 fatigue, > grade 2 hand-foot syndrome and > grade 2 thrombocytopenia. Ethnic differences in adverse events of sunitinib in mRCC patients existed and dose adjustment in Asian patients may be considered.

Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100): an open-label, dose-finding and dose-expansion, phase 1b trial.

PubMed

Choueiri, Toni K; Larkin, James; Oya, Mototsugu; Thistlethwaite, Fiona; Martignoni, Marcella; Nathan, Paul; Powles, Thomas; McDermott, David; Robbins, Paul B; Chism, David D; Cho, Daniel; Atkins, Michael B; Gordon, Michael S; Gupta, Sumati; Uemura, Hirotsugu; Tomita, Yoshihiko; Compagnoni, Anna; Fowst, Camilla; di Pietro, Alessandra; Rini, Brian I

2018-04-01

The combination of an immune checkpoint inhibitor and a VEGF pathway inhibitor to treat patients with advanced renal-cell carcinoma might increase the clinical benefit of these drugs compared with their use alone. Here, we report preliminary results for the combination of avelumab, an IgG1 monoclonal antibody against the programmed cell death protein ligand PD-L1, and axitinib, a VEGF receptor inhibitor approved for second-line treatment of advanced renal-cell carcinoma, in treatment-naive patients with advanced renal-cell carcinoma. The JAVELIN Renal 100 study is an ongoing open-label, multicentre, dose-finding, and dose-expansion, phase 1b study, done in 14 centres in the USA, UK, and Japan. Eligible patients were aged 18 years or older (≥20 years in Japan) and had histologically or cytologically confirmed advanced renal-cell carcinoma with clear-cell component, life expectancy of at least 3 months, an Eastern Cooperative Oncology Group performance status of 1 or less, received no previous systemic treatment for advanced renal cell carcinoma, and had a resected primary tumour. Patients enrolled into the dose-finding phase received 5 mg axitinib orally twice daily for 7 days, followed by combination therapy with 10 mg/kg avelumab intravenously every 2 weeks and 5 mg axitinib orally twice daily. Based on the pharmacokinetic data from the dose-finding phase, ten additional patients were enrolled into the dose-expansion phase and assigned to this regimen. The other patients in the dose-expansion phase started taking combination therapy directly. The primary endpoint was dose-limiting toxicities in the first 4 weeks (two cycles) of treatment with avelumab plus axitinib. Safety and antitumour activity analyses were done in all patients who received at least one dose of avelumab or axitinib. This trial is registered with ClinicalTrials.gov, number NCT02493751. Between Oct 30, 2015, and Sept 30, 2016, we enrolled six patients into the dose-finding phase and 49 into the

Primary renal angiosarcoma with progressive clinical course despite surgical and adjuvant treatment: A case report

PubMed Central

CELEBI, FILIZ; PILANCI, KEZBAN NUR; SAGLAM, SEZER; BALCI, NUMAN CEM

2015-01-01

Angiosarcoma is an extremely rare, high-grade malignancy, which accounts for <2% of all soft-tissue sarcomas. Cases of primary renal angiosarcoma represent 1% of these. Angiosarcomas involving the kidney usually originate from metastatic skin lesions or primary visceral lesions and most often occur in the sixth and seventh decades of life. The present study describes a case of primary renal angiosarcoma that presented as a large right-sided renal mass with symptoms of flank pain. Despite surgical removal of the tumor, recurrent disease with associated lung metastases was identified at the surgical site following adjuvant chemotherapy. The patient succumbed to the disease 13 months after the diagnosis. PMID:25789072

An interdisciplinary consensus on the management of bone metastases from renal cell carcinoma.

PubMed

Grünwald, Viktor; Eberhardt, Berit; Bex, Axel; Flörcken, Anne; Gauler, Thomas; Derlin, Thorsten; Panzica, Martin; Dürr, Hans Roland; Grötz, Knut Achim; Giles, Rachel H; von Falck, Christian; Graser, Anno; Muacevic, Alexander; Staehler, Michael

2018-06-14

Bone is a major site of haematogenous tumour cell spread in renal cell carcinoma (RCC), and most patients with RCC will develop painful and functionally disabling bone metastases at advanced disease stages. The prognosis of these patients is generally poor and the treatment is, therefore, aimed at palliation. However, RCC-associated bone metastases can be curable in select patients. Current data support a multimodal management strategy that includes wide resection of lesions, radiotherapy, systemic therapy, and other local treatment options, which can improve quality of life and survival. Nevertheless, the optimal approach for metastatic bone disease in RCC has not yet been defined and practical recommendations are rare. To improve the management and outcomes of patients with RCC and bone metastases, the International Kidney Cancer Coalition and the interdisciplinary working group on renal tumours of the German Cancer Society convened a meeting of experts with a global perspective to perform an unstructured review and elaborate on current treatment strategies on the basis of published data and expertise. The panel formulated recommendations for the diagnosis and treatment of patients with RCC and metastasis to the bone. Furthermore, the experts summarized current challenges and unmet patient needs that should be addressed in the future.

Unusual Metastases in Renal Cell Carcinoma: A Single Institution Experience and Review of Literature

PubMed Central

Villarreal-Garza, Cynthia; Perez-Alvarez, Sandra I.; Gonzalez-Espinoza, Ivan R.; Leon-Rodriguez, Eucario

2010-01-01

Background To report location and management of atypical metastases from renal cell carcinoma (RCC) in the Instituto Nacional de Ciencias Medicas e Investigacion Salvador Zubiran (INCMNSZ) in Mexico City. Methods Between 1987 to 2009, 545 patients with RCC were retrospectively identified at the INCMNSZ. Patients with unusual metastases confirmed by histopathology were analyzed. Epidemiological, clinical, diagnosis, treatment and outcome data were reviewed. Results Sixty patients developed 98 unusual metastases secondary to RCC. The group was comprised of 35 men (58.3%), with a median age of 60 years at diagnosis. Metachronous unusual metastases with primary renal cancer were observed in 37 individuals (61.7%). Median time from primary RCC diagnosis to the first unusual metastasis was 16.5 months. Median survival from diagnosis of the first unusual metastasis to death was 5.0 months (CI 95%: 2.8-7.2 months). Patients with an initial solitary metastatic lesion in an unusual site (28.3%) had a better survival compared to patients who primarily presented with multiple metastases, 17.0 (CI 95%: 6.1-27.9) Vs 3.0 months (CI 95%: 0.9-5.1), p = 0.001. Unusual metastasis resection (21 patients) improved survival, 25.0 (CI 95%: 5.1-44.9) Vs 3.0 months (CI 95%: 0.8-5.2), p < 0.0001. No survival difference was observed between localization of unsual metastases (p = 0.72). Conclusions In patients with advanced RCC we suggest an individual diagnostic and surgical approach to achieve complete resection with disease-free margins, even in the presence of unusual metastatic sites, multifocality, or history of metastasectomy. These strategy might provide not only palliation for symptoms, but an opportunity for meaningful disease free and overall survival. PMID:29147198

Optimal Management of Metastatic Melanoma: Current Strategies and Future Directions

PubMed Central

Batus, Marta; Waheed, Salman; Ruby, Carl; Petersen, Lindsay; Bines, Steven D.; Kaufman, Howard L.

2013-01-01

Melanoma is increasing in incidence and remains a major public health threat. Although the disease may be curable when identified early, advanced melanoma is characterized by widespread metastatic disease and a median survival of less than 10 months. In recent years, however, major advances in our understanding of the molecular nature of melanoma and the interaction of melanoma cells with the immune system have resulted in several new therapeutic strategies that are showing significant clinical benefit. Current therapeutic approaches include surgical resection of metastatic disease, chemotherapy, immunotherapy, and targeted therapy. Dacarbazine, interleukin-2, ipilimumab, and vemurafenib are now approved for the treatment of advanced melanoma. In addition, new combination chemotherapy regimens, monoclonal antibodies blocking the programmed death-1 (PD-1)/PD-ligand 1 pathway, and targeted therapy against CKIT, mitogen-activated protein/extracellular signal-regulated kinase (MEK), and other putative signaling pathways in melanoma are beginning to show promise in early-phase clinical trials. Further research on these modalities alone and in combination will likely be the focus of future clinical investigation and may impact the outcomes for patients with advanced melanoma. PMID:23677693

Living Well? Strategies Used by Women Living With Metastatic Breast Cancer.

PubMed

Lewis, Sophie; Willis, Karen; Yee, Jasmine; Kilbreath, Sharon

2016-07-01

Metastatic breast cancer is a disease of changing status-once an imminent death sentence, now a chronic (albeit incurable) disease. Medical intervention advances mean women with metastatic breast cancer now have symptoms alleviated and, potentially, life extended. Living with this disease, however, requires more than a medical approach to symptoms. We were interested to know whether women manage, and if so, how, to "live well" with metastatic cancer. We conducted interviews with 18 women. Women differed in the approaches they used. Most common was the attempt to reestablish a sense of normality in their lives. However, a second group reevaluated and reprioritized their lives; and a third group was restricted in their capacity to live well because of symptoms. The findings provide the foundation for future research exploring normalization of experiences of metastatic cancer, and other chronic illnesses, where people are living with knowledge that they have contracted time. © The Author(s) 2015.

Consequences of advanced aging on renal function in chronic hyperandrogenemic female rat model: implications for aging women with polycystic ovary syndrome.

PubMed

Patil, Chetan N; Racusen, Lorraine C; Reckelhoff, Jane F

2017-11-01

Polycystic ovary syndrome (PCOS) is the most common endocrine and reproductive disorder in premenopausal women, characterized by hyperandrogenemia, metabolic syndrome, and inflammation. Women who had PCOS during their reproductive years remain hyperandrogenemic after menopause. The consequence of chronic hyperandrogenemia with advanced aging has not been studied to our knowledge. We have characterized a model of hyperandrogenemia in female rats and have aged them to 22-25 months to mimic advanced aging in hyperandrogenemic women, and tested the hypothesis that chronic exposure to hyperandrogenemia with aging has a deleterious effect on renal function. Female rats were chronically implanted with dihydrotestosterone pellets (DHT 7.5 mg/90 days) that were changed every 85 days or placebo pellets, and renal function was measured by clearance methods. Aging DHT-treated females had a threefold higher level of DHT with significantly higher body weight, mean arterial pressure, left kidney weight, proteinuria, and kidney injury molecule-1 (KIM-1), than did age-matched controls. In addition, DHT-treated-old females had a 60% reduction in glomerular filtration rate, 40% reduction in renal plasma flow, and significant reduction in urinary nitrate and nitrite excretion (UNOxV), an index of nitric oxide production. Morphological examination of kidneys showed that old DHT-treated females had significant focal segmental glomerulosclerosis, global sclerosis, and interstitial fibrosis compared to controls. Thus chronic hyperandrogenemia that persists into old age in females is associated with renal injury. These data suggest that women with chronic hyperandrogenemia such as in PCOS may be at increased risk for development of chronic kidney disease with advanced age. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Optimal management of renal cell carcinoma in the elderly: a review

PubMed Central

Quivy, Amandine; Daste, Amaury; Harbaoui, Asma; Duc, Sophie; Bernhard, Jean-Christophe; Gross-Goupil, Marine; Ravaud, Alain

2013-01-01

Both the aging population and the incidence of renal cell carcinoma (RCC) are growing, making the question of tumor management in the elderly a real challenge. Doctors should be aware of the importance of assessing this specific subpopulation. An aggressive therapeutic approach may be balanced by the benefit of the treatment — care or cure — and the life expectancy and willingness of the patient. The treatment for local disease can be surgery (radical or partial nephrectomy) or ablative therapies (radiofrequency, cryotherapy). Even if in most cases surgery is safe, complications such as alteration of renal function may occur, especially in the elderly, with physiological renal impairment at baseline. More recently, another option has been developed as an alternative: active surveillance. In the past decade, new drugs have been approved in the metastatic setting. All the phase 3 trials have included patients without a limit on age. Nevertheless, data concerning the elderly are still poor and concern only a very selective subpopulation. The toxicity profile of targeted agents may interfere with pre-existent comorbidities. Furthermore, the metabolism of several agents via cytochrome P450 can cause drug interaction. The importance of quality of life is a major factor with regard to management of therapy. Finally, to date, there is no recommendation of systematic a priori dose reduction in the elderly. In this review we describe the various possibilities of treatment for localized RCC or metastatic RCC in an aging population. PMID:23626463

Metastatic mucosal melanoma: imaging patterns of metastasis and recurrence.

PubMed

O'Regan, Kevin; Breen, Micheál; Ramaiya, Nikhil; Jagannathan, Jyothi; DiPiro, Pamela J; Hodi, F Stephen; Van den Abbeele, Annick D

2013-12-30

Mucosal melanoma is a rare but aggressive subtype of melanoma with unique clinicopathologic features. We hypothesize that mucosal melanoma shows predilection for separate and unique metastatic pathways. This was a retrospective analysis of 19 patients (5 men and 14 women; median age 60 years, range 38-76 years) with metastatic mucosal melanoma presenting to a tertiary oncology center between 2005 and 2010. We performed a review of medical records and histologic and imaging studies to evaluate the natural history, metastatic patterns and the role of imaging in the management of patients with advanced mucosal melanoma. At presentation, disease was confined to the primary site (58%, n = 11) or to the regional lymph nodes (32%, n = 6) in most patients. The most common site of metastasis was the lungs (89%, n = 16), followed by the liver (67%, n = 12) and peritoneum (44%, n = 8). Sinonasal melanoma preferentially spread to the liver (100%, n = 4), vaginal melanoma to the lungs (100%, n = 7) and anal melanoma to the inguinal lymph nodes (100%, n = 4). Pathways of metastatic spread in mucosal melanoma may differ from other forms of melanoma and between different primary sites of mucosal origin.

Phase Ib, Dose Escalation Study of Oral LDE225 in Combination With BKM120 in Patients With Advanced Solid Tumors

ClinicalTrials.gov

2016-02-18

Dose Escalation; Safety; Preliminary Efficacy; Advanced Solid Tumors; Metastatic Breast Cancer; Advanced Pancreatic Adenocarcinoma; Metastatic Colorectal Cancer; Recurrent Glioblastoma Multiforme; Gastric Cancer; Gastroesophageal Junction Cancer; Triple Negative Metastatic Breast Cancer; Hormone Receptor Positive (ER+/PR+, and Her2-) Metastatic Breast Cancer

Survival trends among patients with advanced renal cell carcinoma in the United States.

PubMed

Shah, Binay Kumar; Ghimire, Krishna Bilas

2015-01-01

Since the approval of sorafenib in December 2005, several targeted therapeutic agents have been approved by the FDA for the treatment of advanced renal cell carcinoma (RCC). This study was conducted to find out whether the improvements in survival of advanced RCC patients with targeted agents have translated into a survival benefit in a population-based cohort. We analyzed the SEER 18 (Surveillance, Epidemiology and End RESULTS) registry database to calculate the relative survival rates for advanced RCC patients during 2001-2009, 2001-2005, 2006-2007 and 2008-2009. We also evaluated the survival rates by age (<65 and ≥65 years) and sex. The total number of advanced RCC patients during 2001-2009, 2001-2005, 2006-2007 and 2008-2009 were 7,047, 4,059, 1,548 and 1,440, respectively. During 2001-2009, the 1- and 3-year relative survival rates were 26.7±0.6 and 10.0±0.4%, respectively. There was no significant difference in 1-year relative survival rates for patients diagnosed during 2006-2007 and 2008-2009 compared to those diagnosed during 2001-2005. Similarly, the 3-year survival rates for patients diagnosed during 2006-2007 were similar to those diagnosed during 2001-2005. This population-based study showed that there was no significant improvement in relative survival rates among advanced RCC patients in the era of targeted agents. © 2014 S. Karger AG, Basel.

Phase II Trial Of PS-341 (Bortezomib) In Patients With Previously Treated Advanced Urothelial Tract Transitional Cell Carcinoma

ClinicalTrials.gov

2013-06-04

Metastatic Transitional Cell Cancer of the Renal Pelvis and Ureter; Recurrent Bladder Cancer; Recurrent Transitional Cell Cancer of the Renal Pelvis and Ureter; Recurrent Urethral Cancer; Stage III Bladder Cancer; Stage III Urethral Cancer; Stage IV Bladder Cancer; Stage IV Urethral Cancer; Transitional Cell Carcinoma of the Bladder; Ureter Cancer

The contemporary role of ablative treatment approaches in the management of renal cell carcinoma (RCC): focus on radiofrequency ablation (RFA), high-intensity focused ultrasound (HIFU), and cryoablation.

PubMed

Klatte, Tobias; Kroeger, Nils; Zimmermann, Uwe; Burchardt, Martin; Belldegrun, Arie S; Pantuck, Allan J

2014-06-01

Currently, most of renal tumors are small, low grade, with a slow growth rate, a low metastatic potential, and with up to 30 % of these tumors being benign on the final pathology. Moreover, they are often diagnosed in elderly patients with preexisting medical comorbidities in whom the underlying medical conditions may pose a greater risk of death than the small renal mass. Concerns regarding overdiagnosis and overtreatment of patients with indolent small renal tumors have led to an increasing interest in minimally invasive, ablative as an alternative to extirpative interventions for selected patients. To provide an overview about the state of the art in radiofrequency ablation (RFA), high-intensity focused ultrasound, and cryoablation in the clinical management of renal cell carcinoma. A PubMed wide the literature search of was conducted. International consensus panels recommend ablative techniques in patients who are unfit for surgery, who are not considered candidates for or elect against elective surveillance, and who have small renal masses. The most often used techniques are cryoablation and RFA. These ablative techniques offer potentially curative outcomes while conferring several advantages over extirpative surgery, including improved patient procedural tolerance, faster recovery, preservation of renal function, and reduction in the risk of intraoperative and postsurgical complications. While it is likely that outcomes associated with ablative modalities will improve with further advances in technology, their application will expand to more elective indications as longer-term efficacy data become available. Ablative techniques pose a valid treatment option in selected patients.

Veliparib, Capecitabine, and Temozolomide in Patients With Advanced, Metastatic, and Recurrent Neuroendocrine Tumor

ClinicalTrials.gov

2017-09-26

Functional Pancreatic Neuroendocrine Tumor; Malignant Somatostatinoma; Merkel Cell Carcinoma; Metastatic Adrenal Gland Pheochromocytoma; Metastatic Carcinoid Tumor; Multiple Endocrine Neoplasia Type 1; Multiple Endocrine Neoplasia Type 2A; Multiple Endocrine Neoplasia Type 2B; Neuroendocrine Neoplasm; Non-Functional Pancreatic Neuroendocrine Tumor; Pancreatic Glucagonoma; Pancreatic Insulinoma; Recurrent Adrenal Cortex Carcinoma; Recurrent Adrenal Gland Pheochromocytoma; Recurrent Merkel Cell Carcinoma; Somatostatin-Producing Neuroendocrine Tumor; Stage III Adrenal Cortex Carcinoma; Stage III Thyroid Gland Medullary Carcinoma; Stage IIIA Merkel Cell Carcinoma; Stage IIIB Merkel Cell Carcinoma; Stage IV Adrenal Cortex Carcinoma; Stage IV Merkel Cell Carcinoma; Stage IVA Thyroid Gland Medullary Carcinoma; Stage IVB Thyroid Gland Medullary Carcinoma; Stage IVC Thyroid Gland Medullary Carcinoma; Thymic Carcinoid Tumor; VIP-Producing Neuroendocrine Tumor; Well Differentiated Adrenal Cortex Carcinoma; Zollinger Ellison Syndrome

Whole-body PET/CT evaluation of tumor perfusion using generator-based 62Cu-ethylglyoxal bis(thiosemicarbazonato)copper(II): validation by direct comparison to 15O-water in metastatic renal cell carcinoma.

PubMed

Fletcher, James W; Logan, Theodore F; Eitel, Jacob A; Mathias, Carla J; Ng, Yen; Lacy, Jeffrey L; Hutchins, Gary D; Green, Mark A

2015-01-01

This study was undertaken to demonstrate the feasibility of whole-body (62)Cu-ethylglyoxal bis(thiosemicarbazonato)copper(II) ((62)Cu-ETS) PET/CT tumor perfusion imaging in patients with metastatic renal carcinoma and to validate (62)Cu-ETS as a quantitative marker of tumor perfusion by direct comparison with (15)O-water perfusion imaging. PET/CT imaging of 10 subjects with stage IV renal cell cancer was performed after intravenous administration of (15)O-water (10-min dynamic list-mode study) with the heart and at least 1 tumor in the PET field of view, followed 10 min later by intravenous (62)Cu-ETS (6-min list-mode study). Whole-body (62)Cu imaging was then performed from 6 to 20 min at 2-3 min/bed position. Blood flow (K1) was quantified with both agents for normal and malignant tissues in the 21.7-cm dynamic field of view. The required arterial input functions were derived from the left atrium and, in the case of (62)Cu-ETS, corrected for partial decomposition of the agent by blood with data from an in vitro analysis using a sample of each patient's blood. This imaging protocol was repeated at an interval of 3-4 wk after initiation of a standard clinical treatment course of the antiangiogenic agent sunitinib. All subjects received the scheduled (62)Cu-ETS doses for the dynamic and subsequent whole-body PET/CT scans, but technical issues resulted in no baseline (15)O-water data for 2 subjects. Direct comparisons of the perfusion estimates for normal tissues and tumor metastases were made in 18 paired baseline and treatment studies (10 subjects; 8 baseline studies, 10 repeated studies during treatment). There was an excellent correlation between the blood flow estimates made with (62)Cu-ETS and (15)O-water for normal tissues (muscle, thyroid, myocardium) and malignant lesions (pulmonary nodules, bone lesions); the regression line was y = 0.85x + 0.15, R(2) = 0.83, for the 88 regions analyzed. (62)Cu-ETS provided high-quality whole-body PET/CT images, and (62)Cu

Heparan sulfate proteoglycans mediate renal carcinoma metastasis.

PubMed

Qazi, Henry; Shi, Zhong-Dong; Song, Jonathan W; Cancel, Limary M; Huang, Peigen; Zeng, Ye; Roberge, Sylvie; Munn, Lance L; Tarbell, John M

2016-12-15

The surface proteoglycan/glycoprotein layer (glycocalyx) on tumor cells has been associated with cellular functions that can potentially enable invasion and metastasis. In addition, aggressive tumor cells with high metastatic potential have enhanced invasion rates in response to interstitial flow stimuli in vitro. Our previous studies suggest that heparan sulfate (HS) in the glycocalyx plays an important role in this flow mediated mechanostransduction and upregulation of invasive and metastatic potential. In this study, highly metastatic renal cell carcinoma cells were genetically modified to suppress HS production by knocking down its synthetic enzyme NDST1. Using modified Boyden chamber and microfluidic assays, we show that flow-enhanced invasion is suppressed in HS deficient cells. To assess the ability of these cells to metastasize in vivo, parental or knockdown cells expressing fluorescence reporters were injected into kidney capsules in SCID mice. Histological analysis confirmed that there was a large reduction (95%) in metastasis to distant organs by tumors formed from the NDST1 knockdown cells compared to control cells with intact HS. The ability of these cells to invade surrounding tissue was also impaired. The substantial inhibition of metastasis and invasion upon reduction of HS suggests an active role for the tumor cell glycocalyx in tumor progression. © 2016 UICC.

Unusual late presentation of metastatic extrathoracic thymoma to gastrohepatic lymph node treated by surgical resection.

PubMed

Billè, Andrea; Sachidananda, Sandeep; Moreira, Andre L; Rizk, Nabil P

2017-02-01

In advanced stages, thymic tumors tend to spread locally. Distant metastatic disease is rare. We present the first report of single metastatic abdominal lymph node in a 37-year-old female patient and 5 years after an extrapleural pneumonectomy for stage IV thymoma followed by radiotherapy with no other evidence of abdominal disease successfully treated by robotic surgical resection.

Gemcitabine Hydrochloride and Cisplatin With or Without Bevacizumab in Treating Patients With Advanced Urinary Tract Cancer

ClinicalTrials.gov

2018-06-11

Bladder Urothelial Carcinoma; Distal Urethral Carcinoma; Infiltrating Bladder Urothelial Carcinoma Associated With Urethral Carcinoma; Metastatic Urothelial Carcinoma of the Renal Pelvis and Ureter; Proximal Urethral Carcinoma; Recurrent Bladder Carcinoma; Recurrent Prostate Carcinoma; Recurrent Urethral Carcinoma; Recurrent Urothelial Carcinoma of the Renal Pelvis and Ureter; Regional Urothelial Carcinoma of the Renal Pelvis and Ureter; Stage IV Bladder Cancer AJCC v7; Stage IV Prostate Cancer AJCC v7; Stage IV Urethral Cancer AJCC v7; Ureter Carcinoma

ABCG2 Polymorphism rs2231142 and hypothyroidism in metastatic renal cell carcinoma patients treated with sunitinib.

PubMed

Werbrouck, Emilie; Bastin, Julie; Lambrechts, Diether; Verbiest, Annelies; Van Brussel, Thomas; Lerut, Evelyne; Machiels, Jean-Pascal; Verschaeve, Vincent; Richard, Vincent; Debruyne, Philip R; Decallonne, Brigitte; Schöffski, Patrick; Bechter, Oliver; Wolter, Pascal; Beuselinck, Benoit

2018-05-23

Background and aim Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) cause significant adverse events including thyroid dysfunction, mainly hypothyroidism, in a considerable proportion of patients. In a series of metastatic renal cell carcinoma (mRCC) patients treated with sunitinib, we aimed to study the correlation between hypothyroidism and single nucleotide polymorphisms (SNPs) in genes involved in sunitinib pharmacokinetics and pharmacodynamics. Patients and methods We included 79 mRCC patients who started sunitinib between November 2005 and March 2016. Serum thyroid function markers were collected at start and during sunitinib therapy. Germ-line DNA genotyping for 16 SNPs in 8 candidate genes was performed. Endpoints were time to increase in thyroid stimulating hormone (TSH) and time to decrease in T4 or free T4 (FT4) on day 1 and day 28 of each sunitinib cycle. Results Patients with the ABCG2 rs2231142 CC-genotype had a significantly longer time-to-TSH-increase on day 1 (11 vs. 5 cycles; p = 0.0011), and time-to-T4/FT4-decrease on day 1 (not reached vs. 10 cycles; p = 0.013) and day 28 (28 vs. 7 cycles; p = 0.03) compared to CA-carriers. Patients with the CYP3A5 rs776746 GG-genotype had a significantly longer time-to-TSH-increase at day 1 compared to GA-patients: 11 vs. 5 cycles (p = 0.0071). Significant associations were also found between PDGFRA rs35597368 and rs1800812 and time-to-TSH-increase at day 28. Conclusion Polymorphism rs2231142 in the efflux pump ABCG2 is associated with hypothyroidism in mRCC patients treated with sunitinib.

Intravital imaging of tumor bioenergetics in metastatic and non-metastatic breast cancer

NASA Astrophysics Data System (ADS)

Rasul, Raisa; Harper, Mason; Rajaram, Narasimhan

2018-02-01

Early detection of metastatic cancer can reduce patient mortality and decrease cost of cancer treatment. However, current methods of prognosis or genetic screening are expensive and might not be applicable to all tumors. Although previous studies indicated that cancer cells are glycolytic, the link between metabolism and metastatic progression is not fully understood. To better understand the tumor bioenergetics, we investigated in vivo the vascular oxygenation, glucose intake, and optical redox ratio between a metastatic breast cancer cell line (4T1), a non-metastatic isogenic cell line (168FARN), and a non-metastatic derivative of 4T1 (TWIST gene knockout). The vascular oxygenation was measured by injecting 10,000 cells into mouse dorsal window chambers and acquiring and processing trans-illumination images of the tumor from 520 nm-620 nm light wavelength in 10 nm intervals. Glucose intake was measured by continuous fluorescent imaging of the glucose analog, 2-NBDG, for 90 minutes. Optical redox ratio was measured by intrinsic fluorescence imaging of electron carrying intermediates, NADH and FAD, where an increase in the ratio (FAD/FAD+NADH) meant increased oxidative phosphorylation. Our data show that the optical redox ratio and vascular oxygenation are higher and glucose intake is lower in metastatic tumors compared to non-metastatic tumors, suggesting that metastatic tumors display decreased glycolysis and increased oxidative phosphorylation. We observed a similar trend in vitro, where the redox ratio increased as the cell metastatic potential increased, indicating that metastatic cells can efficiently produce energy. These findings indicate that optical redox ratio can be a potential prognosis tool for detecting malignant tumors.

Robotic partial nephrectomy for renal cell carcinomas with venous tumor thrombus.

PubMed

Abaza, Ronney; Angell, Jordan

2013-06-01

To describe the first report of robotic partial nephrectomies (RPNs) for renal cell carcinoma (RCC) with venous tumor thrombus (VTT). Partial nephrectomy for RCC extending into the renal vein has been described in limited fashion, but such a complex procedure has not previously been reported in minimally-invasive fashion. We demonstrate the feasibility of robotic nephron-sparing surgery despite vein thrombi and the results of the initial four highly-selected patients to have undergone this novel procedure. Two patients underwent RPN for RCC with VTT involving intraparenchymal vein branches, and 2 others had VTT involving the main renal vein. Mean patient age was 65 years (range 50-74 years). Mean tumor size was 7.75 cm (range 4.3-12.8 cm) with mean RENAL (radius, exophytic/endophytic, nearness to collecting system, anterior/posterior, and location) nephrometry score of 9.75 (range 8-12). Mean warm ischemia time was 24.2 minutes (range 19-27 minutes) and mean estimated blood loss was 168.8 mL (range 100-300 mL). No patients required transfusion, and there were no intraoperative complications. No patients required conversion to open or standard laparoscopic surgery. All 4 patients were discharged home on the first postoperative day. A single postoperative complication occurred in 1 patient who was readmitted with an ileus that resolved spontaneously. All patients had negative surgical margins. Two patients developed metastatic disease on surveillance imaging. RPN in patients with VTT is safe and feasible in selected patients. Given the risk of metastatic disease in patients with pathologic stage T3a RCC, the role of nephron sparing requires further evaluation such that radical nephrectomy remains the standard of care. Copyright © 2013 Elsevier Inc. All rights reserved.

iTRAQ Quantitative Proteomic Comparison of Metastatic and Non-Metastatic Uveal Melanoma Tumors

PubMed Central

Crabb, John W.; Hu, Bo; Crabb, John S.; Triozzi, Pierre; Saunthararajah, Yogen; Singh, Arun D.

2015-01-01

Background Uveal melanoma is the most common malignancy of the adult eye. The overall mortality rate is high because this aggressive cancer often metastasizes before ophthalmic diagnosis. Quantitative proteomic analysis of primary metastasizing and non-metastasizing tumors was pursued for insights into mechanisms and biomarkers of uveal melanoma metastasis. Methods Eight metastatic and 7 non-metastatic human primary uveal melanoma tumors were analyzed by LC MS/MS iTRAQ technology with Bruch’s membrane/choroid complex from normal postmortem eyes as control tissue. Tryptic peptides from tumor and control proteins were labeled with iTRAQ tags, fractionated by cation exchange chromatography, and analyzed by LC MS/MS. Protein identification utilized the Mascot search engine and the human Uni-Prot/Swiss-Protein database with false discovery ≤ 1%; protein quantitation utilized the Mascot weighted average method. Proteins designated differentially expressed exhibited quantitative differences (p ≤ 0.05, t-test) in a training set of five metastatic and five non-metastatic tumors. Logistic regression models developed from the training set were used to classify the metastatic status of five independent tumors. Results Of 1644 proteins identified and quantified in 5 metastatic and 5 non-metastatic tumors, 12 proteins were found uniquely in ≥ 3 metastatic tumors, 28 were found significantly elevated and 30 significantly decreased only in metastatic tumors, and 31 were designated differentially expressed between metastatic and non-metastatic tumors. Logistic regression modeling of differentially expressed collagen alpha-3(VI) and heat shock protein beta-1 allowed correct prediction of metastasis status for each of five independent tumor specimens. Conclusions The present data provide new clues to molecular differences in metastatic and non-metastatic uveal melanoma tumors. While sample size is limited and validation required, the results support collagen alpha-3(VI) and

Renal cell carcinoma in the allograft: what is the role of polyomavirus?

PubMed

Neirynck, Valerie; Claes, Kathleen; Naesens, Maarten; De Wever, Liesbeth; Pirenne, Jacques; Kuypers, Dirk; Vanrenterghem, Yves; Poppel, Hendrik Van; Kabanda, Andre; Lerut, Evelyne

2012-07-01

BK virus (BKV) is known to cause subclinical infection in childhood. The virus remains latent in the human body, mainly in the urinary tract epithelium. After initiation of an immunosuppressive treatment, reactivation can occur in renal transplant recipients. BKV can cause hemorrhagic cystitis, ureteral stenosis and BKV nephropathy in immunocompromised patients. Furthermore, a number of case reports suggest an association between BKV infection and the development of urinary tract cancer. So far, an oncogenic potential of BKV has been observed in vitro and in animal models; however, its oncogenic capacity in humans remains unclear. We report the case of a 59-year-old patient who developed a poorly differentiated renal cell carcinoma in her renal allograft, with pulmonary and abdominal metastasis. Surgical removal of the allograft and cessation of the immunosuppressive therapy resulted in complete resolution of the metastatic disease.

Systematic review of renal carcinoma prognostic factors.

PubMed

Lorente, D; Trilla, E; Meseguer, A; Planas, J; Placer, J; Celma, A; Salvador, C; Regis, L; Morote, J

2017-05-01

The natural history of renal cell carcinoma is heterogeneous. Some scenarios can be found in terms of clinical presentation, clinical evolution or type of recurrence (local/metastatic). The aim of this publication is to analyze the most important prognostic factors published in the literature. A literature review ob published papers was performed using the Pubmed, from first Motzer's classification published in 1999 to 2015, according to PRISMA declaration. Search was done using the following keywords: kidney neoplasm, kidney cancer, renal cell carcinoma, prognostic factors, mortality, survival and disease progression. Papers were classified according to level of evidence, the number of patients included and the type of study performed. The evolution in the knowledge of molecular pathways related to renal oncogenesis and the new targeted therapies has left to remain obsolete the old prognostic models. It's necessary to perform a continuous review to actualize nomograms and to adapt them to the new scenarios. Is necessary to perform a proper external validation of existing prognostic factors using prospective and multicentric studies to add them into the daily urologist clinical practice. Copyright © 2016 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.

Metastatic mucosal melanoma: imaging patterns of metastasis and recurrence

PubMed Central

O’Regan, Kevin; Ramaiya, Nikhil; Jagannathan, Jyothi; DiPiro, Pamela J.; Stephen Hodi, F.; Van den Abbeele, Annick D.

2013-01-01

Abstract Purpose: Mucosal melanoma is a rare but aggressive subtype of melanoma with unique clinicopathologic features. We hypothesize that mucosal melanoma shows predilection for separate and unique metastatic pathways. Materials and methods: This was a retrospective analysis of 19 patients (5 men and 14 women; median age 60 years, range 38–76 years) with metastatic mucosal melanoma presenting to a tertiary oncology center between 2005 and 2010. We performed a review of medical records and histologic and imaging studies to evaluate the natural history, metastatic patterns and the role of imaging in the management of patients with advanced mucosal melanoma. Results: At presentation, disease was confined to the primary site (58%, n = 11) or to the regional lymph nodes (32%, n = 6) in most patients. The most common site of metastasis was the lungs (89%, n = 16), followed by the liver (67%, n = 12) and peritoneum (44%, n = 8). Sinonasal melanoma preferentially spread to the liver (100%, n = 4), vaginal melanoma to the lungs (100%, n = 7) and anal melanoma to the inguinal lymph nodes (100%, n = 4). Conclusion: Pathways of metastatic spread in mucosal melanoma may differ from other forms of melanoma and between different primary sites of mucosal origin. PMID:24434078

Everolimus Plus Exemestane in Advanced Breast Cancer: Safety Results of the BALLET Study on Patients Previously Treated Without and with Chemotherapy in the Metastatic Setting.

PubMed

Generali, Daniele; Montemurro, Filippo; Bordonaro, Roberto; Mafodda, Antonino; Romito, Sante; Michelotti, Andrea; Piovano, Pierluigi; Ionta, Maria Teresa; Bighin, Claudia; Sartori, Donata; Frassoldati, Antonio; Cazzaniga, Marina Elena; Riccardi, Ferdinando; Testore, Franco; Vici, Patrizia; Barone, Carlo Antonio; Schirone, Alessio; Piacentini, Federico; Nolè, Franco; Molino, Annamaria; Latini, Luciano; Simoncini, Edda Lucia; Roila, Fausto; Cognetti, Francesco; Nuzzo, Francesco; Foglietta, Jennifer; Minisini, Alessandro Marco; Goffredo, Francesca; Portera, Giuseppe; Ascione, Gilda; Mariani, Gabriella

2017-06-01

The BALLET study was an open-label, multicenter, expanded access study designed to allow treatment with everolimus plus exemestane in postmenopausal women with hormone receptor-positive metastatic breast cancer progressed following prior endocrine therapy. A post hoc analysis to evaluate if previous chemotherapy in the metastatic setting affects the safety profile of the combination regimen of everolimus and exemestane was conducted on the Italian subset, as it represented the major part of the patients enrolled (54%). One thousand one hundred and fifty-one Italian patients were included in the present post hoc analysis, which focused on two sets of patients: patients who never received chemotherapy in the metastatic setting (36.1%) and patients who received at least one chemotherapy treatment in the metastatic setting (63.9%). One thousand one hundred and sixteen patients (97.0%) prematurely discontinued the study drug, and the main reasons reported were disease progression (39.1%), local reimbursement of everolimus (31.1%), and adverse events (AEs) (16.1%). The median duration of study treatment exposure was 139.5 days for exemestane and 135.0 days for everolimus. At least one AE was experienced by 92.5% of patients. The incidence of everolimus-related AEs was higher (83.9%) when compared with those that occurred with exemestane (29.1%), and the most commonly reported everolimus-related AE was stomatitis (51.3%). However, no significant difference in terms of safety related to the combination occurred between patients without and with chemotherapy in the metastatic setting. Real-life data of the Italian patients BALLET-related cohort were an adequate setting to state that previous chemotherapy did not affect the safety profile of the combination regimen of everolimus and exemestane. With the advent of new targeted agents for advanced or metastatic breast cancer, multiple lines of therapy may be possible, and components of the combined regimens can overlap from

Active smoking may negatively affect response rate, progression-free survival, and overall survival of patients with metastatic renal cell carcinoma treated with sunitinib.

PubMed

Keizman, Daniel; Gottfried, Maya; Ish-Shalom, Maya; Maimon, Natalie; Peer, Avivit; Neumann, Avivit; Hammers, Hans; Eisenberger, Mario A; Sinibaldi, Victoria; Pili, Roberto; Hayat, Henry; Kovel, Svetlana; Sella, Avishay; Boursi, Ben; Weitzen, Rony; Mermershtain, Wilmosh; Rouvinov, Keren; Berger, Raanan; Carducci, Michael A

2014-01-01

Obesity, smoking, hypertension, and diabetes are risk factors for renal cell carcinoma development. Their presence has been associated with a worse outcome in various cancers. We sought to determine their association with outcome of sunitinib treatment in metastatic renal cell carcinoma (mRCC). An international multicenter retrospective study of sunitinib-treated mRCC patients was performed. Multivariate analyses were performed to determine the association between outcome and the pretreatment status of smoking, body mass index, hypertension, diabetes, and other known prognostic factors. Between 2004 and 2013, 278 mRCC patients were treated with sunitinib: 59 were active smokers, 67 were obese, 73 were diabetic, and 165 had pretreatment hypertension. Median progression-free survival (PFS) was 9 months, and overall survival (OS) was 22 months. Factors associated with PFS were smoking status (past and active smokers: hazard ratio [HR]: 1.17, p = .39; never smokers: HR: 2.94, p < .0001), non-clear cell histology (HR: 1.62, p = .011), pretreatment neutrophil-to-lymphocyte ratio >3 (HR: 3.51, p < .0001), use of angiotensin system inhibitors (HR: 0.63, p = .01), sunitinib dose reduction or treatment interruption (HR: 0.72, p = .045), and Heng risk (good and intermediate risk: HR: 1.07, p = .77; poor risk: HR: 1.87, p = .046). Factors associated with OS were smoking status (past and active smokers: HR: 1.25, p = .29; never smokers: HR: 2.7, p < .0001), pretreatment neutrophil-to-lymphocyte ratio >3 (HR: 2.95, p < .0001), and sunitinib-induced hypertension (HR: 0.57, p = .002). Active smoking may negatively affect the PFS and OS of sunitinib-treated mRCC. Clinicians should consider advising patients to quit smoking at initiation of sunitinib treatment for mRCC.

Budget impact of everolimus for the treatment of progressive, well-differentiated, non-functional neuroendocrine tumors of gastrointestinal or lung origin that are advanced or metastatic.

PubMed

Rose, Darya B; Nellesen, Dave; Neary, Maureen P; Cai, Beilei

2017-04-01

Advanced neuroendocrine tumors (NETs) are a rare malignancy with considerable need for effective therapies. Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) in 2016 for treatment of adults with progressive, well-differentiated, non-functional NETs of gastrointestinal (GI) or lung origin that are unresectable, locally advanced, or metastatic. To assess the 3-year budget impact for a typical US health plan following availability of everolimus for treatment of GI and lung NETs. Methods An economic model was developed that considered two perspectives: an entire health plan and a pharmacy budget. The total budget impact included costs of drug therapies, administration, hospitalizations, physician visits, monitoring, and adverse events (AEs). The pharmacy model only considered drug costs. In a US health plan with 1 million members, the model estimated 66 patients with well-differentiated, non-functional, and advanced or metastatic GI NETs and 20 with lung NETs undergoing treatment each year. Total budget impact in the first through third year after FDA approval ranged from $0.0568-$0.1443 per member per month (PMPM) for GI NETs and from $0.0181-$0.0355 PMPM for lung NETs. The total budget impact was lower than the pharmacy budget impact because it included cost offsets from administration and AE management for everolimus compared with alternative therapies (e.g. chemotherapies). Because GI and lung NETs are rare diseases with limited published data, several assumptions were made that may influence interpretation of results. The budget impact for everolimus was minimal in this rare disease area with a high unmet need, largely due to low disease prevalence. These results should be considered in the context of significant clinical benefits potentially provided by everolimus, including significantly longer progression-free survival (PFS) for advanced GI and lung NET

Planning for Advanced Cancer

Cancer.gov

Find out what issues need to be addressed when dealing with an advanced or metastatic cancer diagnosis. Completing advance directives, looking at health insurance, organizing records and documents, and looking at the meanings in your life are some of the things to think about.

Renal autotransplantation: current perspectives.

PubMed

Stewart, B H; Banowsky, L H; Hewitt, C B; Straffon, R A

1977-09-01

Autotransplantation, with or without an extracorporeal renal operation, has been done 39 times in 37 patients. Indications for the procedure included several ureteral injury in 4 patients, failed supravesical diversion in 2, renal carcinoma in a solitary kidney in 1, renovascular hypertension in 1 and donor arterial reconstruction before renal transplantation in 29. Success was obtained in all but 2 procedures, both of which involved previously operated kidneys with severe inflammation and adhesions involving the renal pelvis and pedicle. Based on our experience and a review of currently available literature we believe that renal autotransplantation and extracorporeal reconstruction can provide the best solution for patients with severe renovascular and ureteral disease not correctable by conventional operative techniques. The technique can be of particular value in removing centrally located tumors in solitary kidneys and in preparing donor kidneys with abnormal arteries for renal transplantation. The role of autotransplantation in the management of advanced renal trauma and calculus disease is less clear. A long-term comparison of patients treated by extracorporeal nephrolithotomy versus conventional lithotomy techniques will be necessary before a conclusion is reached in these disease categories.

Renal autotransplantation: current perspectives.

PubMed

Stewart, B H; Banowsky, L H; Hewitt, C B; Straffon, R A

1976-01-01

Autotransplantation, with or without an extracorporeal renal operation, has been done 39 times in 37 patients. Indications for the procedure included severe ureteral injury in 4 patients, failed supravesical diversion in 2, renal carcinoma in a solitary kidney in 1, renovascular hypertension in 1 and donor arterial reconstruction before renal transplantation in 29. Success was obtained in all but 2 procedures, both of which involved previously operated kidneys with severe inflammation and adhesions involving the renal pelvis and pedicle. Based on our experience and a review of currently available literature we believe that renal autotransplantation and extracorporeal reconstruction can provide the best solution for patients with severe renovascular and ureteral disease not correctable by conventional operative techniques. The technique can be of particular value in removing centrally located tumors in solitary kidneys and in preparing donor kidneys with abnormal arteries for renal transplantation. The role of autotransplantation in the management of advanced renal trauma and calculus disease is less clear. A long-term comparison of patients treated by extracorporeal nephrolithotomy versus conventional lithotomy techniques will be necessary before a conclusion is reached in these disease categories.

Disseminated alveolar echinococcosis resembling metastatic malignancy: a case report.

PubMed

Caire Nail, Laura; Rodríguez Reimundes, Ezequiel; Weibel Galluzzo, Christelle; Lebowitz, Dan; Ibrahim, Yasmine Lucile; Lobrinus, Johannes Alexander; Chappuis, François

2017-04-18

Alveolar echinococcosis is a potentially lethal zoonosis caused by larval forms of the tapeworm Echinococcus multilocularis. Humans are aberrant intermediate hosts who become infected by ingestion of egg-contaminated food or water or via physical contact with domestic or wild animals that carry the parasite in their small intestine. In humans, the disease usually affects the liver and can spread to other organs causing metastatic infiltration. In this report, we describe an advanced presentation of human alveolar echinococcosis mimicking metastatic malignancy. A 62-year-old white woman was evaluated for fever, jaundice, and abdominal pain, associated with significant weight loss. She lived in a rural area in Switzerland and used to eat wild forest fruits and mushrooms. She owned cats that used to hunt rodents. On physical examination, she appeared severely ill with cachexia, altered mental status, jaundice, and massive hepatomegaly. Laboratory tests showed cholestasis with preserved liver function. An abdominal computed tomography scan showed an enlarged liver with a huge cystic mass in the right lobe extending into the left lobe, infiltrating her hepatic hilum, causing intrahepatic bile duct dilation and occlusion of her right portal vein. A chest computed tomography scan showed multiple calcified bilateral pulmonary nodules. Her clinical and radiological presentation resembled an advanced neoplastic disease. Serologic tests for Echinococcus multilocularis were positive. The diagnosis of alveolar echinococcosis was established on her past history of exposure, imaging, and serology results. Clinical presentation and radiologic imaging findings of disseminated alveolar echinococcosis can mimic metastatic malignancy, and diagnosis can be challenging in atypically advanced cases. As the incidence of human alveolar echinococcosis appears to be increasing in Europe and Switzerland, physicians should be aware of alveolar echinococcosis, its epidemiology, and its clinical

Metastatic spinal cord compression from basal cell carcinoma of the skin treated with surgical decompression and vismodegib: case report and review of Hedgehog signalling pathway inhibition in advanced basal cell carcinoma.

PubMed

McGrane, J; Carswell, S; Talbot, T

2017-01-01

We report a case of a 66-year-old man with locally advanced and metastatic basal cell carcinoma (BCC) causing spinal cord compression, which was treated with spinal surgery and subsequent vismodegib. The patient presented with a large fungating chest wall lesion and a metastasis in T8 that was causing cord compression. He had neurosurgical decompression of the T8 lesion and fixation of the spine. Punch biopsy from the fungating chest wall lesion showed a BCC with some malignant squamous differentiation (basosquamous). Histopathological examination of the metastatic lesion in T8 at the time of surgical decompression identified features identical to the punch biopsy. The patient was referred to the oncology clinic for adjuvant treatment. In light of his metastatic disease and the large area over his chest wall that could not fully be covered by radiotherapy, he was treated with the novel oral Hedgehog signalling pathway (HHSP) inhibitor vismodegib, which led to marked improvement. © 2016 British Association of Dermatologists.

Reduction of severe mitral regurgitation with the MitraClip system improves renal function in two patients presenting with acute kidney injury and progressive renal failure due to cardio renal syndrome.

PubMed

Asdonk, T; Nickenig, G; Hammerstingl, C

2014-10-01

Mitral regurgitation (MR) is a frequent valve disorder in elderly patients, often accompanied by multiple comorbidities such as renal impairment. In these patients percutaneous mitral valve (MV) repair has become an established treatment option but the role of MR on renal dysfunction is not yet well defined. We here report on two cases presenting with severe MR and progressive renal failure caused by cardio renal syndrome, in which percutaneous MV treatment with the MitraClip system significantly improved renal function. These findings suggest that interventional MV repair can prevent progression of renal deterioration in patients suffering from combined advanced heart and renal failure. Further clinical studies are necessary to support our finding and to answer the question whether optimizing renal function by implantation of the MitraClip device is also of prognostic relevance in these patients. © 2014 Wiley Periodicals, Inc.

Tumor attributes predicting cutaneous metastatic destiny: a report of two interesting cases.

PubMed

Gurumurthi, Ravichandran; Thirumalai, Raja; Easow, Jose M; Mohan, Subhashini

2014-07-01

Cutaneous metastases are the result of complex interaction between the tumor cells ("seed") and the host environment ("soil"). Metastases to the skin can be an early sign of internal malignancy or represent recurrence of the primary tumor and portends a poorer prognosis. Invasion and metastasis are the hallmarks of on cogenesis. Skin is the largest organ in the body, but the incidence of metastases is low. With advances in molecular biology, factors responsible for the initiation and perpetuation of metastatic tumor cells at distant sites are being elucidated. The concept of "pre-metastatic niche" and interaction between various chemokines has given a new outlook in understanding the organ specificity of metastatic tumor cells. We present two cases of cutaneous metastases with interesting clinical findings correlating with its biologic subtypes.

Quality of Life Outcomes for Cabozantinib Versus Everolimus in Patients With Metastatic Renal Cell Carcinoma: METEOR Phase III Randomized Trial.

PubMed

Cella, David; Escudier, Bernard; Tannir, Nizar M; Powles, Thomas; Donskov, Frede; Peltola, Katriina; Schmidinger, Manuela; Heng, Daniel Y C; Mainwaring, Paul N; Hammers, Hans J; Lee, Jae Lyun; Roth, Bruce J; Marteau, Florence; Williams, Paul; Baer, John; Mangeshkar, Milan; Scheffold, Christian; Hutson, Thomas E; Pal, Sumanta; Motzer, Robert J; Choueiri, Toni K

2018-03-10

Purpose In the phase III METEOR trial ( ClinicalTrials.gov identifier: NCT01865747), 658 previously treated patients with advanced renal cell carcinoma were randomly assigned 1:1 to receive cabozantinib or everolimus. The cabozantinib arm had improved progression-free survival, overall survival, and objective response rate compared with everolimus. Changes in quality of life (QoL), an exploratory end point, are reported here. Patients and Methods Patients completed the 19-item Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19) and the five-level EuroQol (EQ-5D-5L) questionnaires at baseline and throughout the study. The nine-item FKSI-Disease-Related Symptoms (FKSI-DRS), a subset of FKSI-19, was also investigated. Data were summarized descriptively and by repeated-measures analysis (for which a clinically relevant difference was an effect size ≥ 0.3). Time to deterioration (TTD) was defined as the earlier of date of death, radiographic progressive disease, or ≥ 4-point decrease from baseline in FKSI-DRS. Results The QoL questionnaire completion rates remained ≥ 75% through week 48 in each arm. There was no difference over time for FKSI-19 Total, FKSI-DRS, or EQ-5D data between the cabozantinib and everolimus arms. Among the individual FKSI-19 items, cabozantinib was associated with worse diarrhea and nausea; everolimus was associated with worse shortness of breath. These differences are consistent with the adverse event profile of each drug. Cabozantinib improved TTD overall, with a marked improvement in patients with bone metastases at baseline. Conclusion In patients with advanced renal cell carcinoma, relative to everolimus, cabozantinib generally maintained QoL to a similar extent. Compared with everolimus, cabozantinib extended TTD overall and markedly improved TTD in patients with bone metastases.

Advances in the Urinary Exosomes in Renal Diseases.

PubMed

Chen, Pei-Pei; Qin, Yan; Li, Xue-Mei

2016-08-01

Cells secrete around 30- 100 nm membrane-enclosed vesicles that are released into the extracellular spaceis termed exosomes(EXs). EXs widely present in body fluids and incorporated proteins,nucleic acids that reflect the physiological state of their cells of origin and they may play an important role in cell-to-cell communication in various physiological and disease processes. In this article we review the recent basic and clinical studies in urinary EXs in renal diseases,focusing on their biological characteristics and potential roles as new biological markers,intervention treatment goals,and targeted therapy vectors in renal diseases.However,some issues still exist;in particular,the clinical application of EXs as a liquid biopsy technique warrants further investigations.

Effect of taurine on advanced glycation end products-induced hypertrophy in renal tubular epithelial cells

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

Huang, J.-S.; Chuang, L.-Y.; Guh, J.-Y.

2008-12-01

Mounting evidence indicates that advanced glycation end products (AGE) play a major role in the development of diabetic nephropathy (DN). Taurine is a well documented antioxidant agent. To explore whether taurine was linked to altered AGE-mediated renal tubulointerstitial fibrosis in DN, we examined the molecular mechanisms of taurine responsible for inhibition of AGE-induced hypertrophy in renal tubular epithelial cells. We found that AGE (but not non-glycated BSA) caused inhibition of cellular mitogenesis rather than cell death by either necrosis or apoptosis. There were no changes in caspase 3 activity, bcl-2 protein expression, and mitochondrial cytochrome c release in BSA, AGE,more » or the antioxidant taurine treatments in these cells. AGE-induced the Raf-1/extracellular signal-regulated kinase (ERK) activation was markedly blocked by taurine. Furthermore, taurine, the Raf-1 kinase inhibitor GW5074, and the ERK kinase inhibitor PD98059 may have the ability to induce cellular proliferation and cell cycle progression from AGE-treated cells. The ability of taurine, GW5074, or PD98059 to inhibit AGE-induced hypertrophy was verified by the observation that it significantly decreased cell size, cellular hypertrophy index, and protein levels of RAGE, p27{sup Kip1}, collagen IV, and fibronectin. The results obtained in this study suggest that taurine may serve as the potential anti-fibrotic activity in DN through mechanism dependent of its Raf-1/ERK inactivation in AGE-induced hypertrophy in renal tubular epithelial cells.« less

17β-Hydroxywithanolides as Sensitizers of Renal Carcinoma Cells to Tumor Necrosis Factor-α Related Apoptosis Inducing Ligand (TRAIL) Mediated Apoptosis: Structure-Activity Relationships.

PubMed

Xu, Ya-Ming; Brooks, Alan D; Wijeratne, E M Kithsiri; Henrich, Curtis J; Tewary, Poonam; Sayers, Thomas J; Gunatilaka, A A Leslie

2017-04-13

Renal cell carcinoma (RCC) is a cancer with poor prognosis, and the 5-year survival rate of patients with metastatic RCC is 5-10%. Consequently, treatment of metastatic RCC represents an unmet clinical need. Screening of a 50 000-member library of natural and synthetic compounds for sensitizers of RCC cells to TRAIL-mediated apoptosis led to identification of the 17β-hydroxywithanolide (17-BHW), withanolide E (1), as a promising lead. To explore structure-activity relationships, we obtained natural and semisynthetic withanolides 1, 2a, 2c, and 3-36 and compared their ability to sensitize TRAIL-mediated apoptosis in a panel of renal carcinoma cells. Our findings revealed that 17-BHWs with a α-oriented side chain are superior to known TRAIL-sensitizing withanolides belonging to withaferin A class with a β-oriented side chain and demonstrated that the 17-BHW scaffold can be modified to enhance sensitization of RCCs to TRAIL-mediated apoptosis, thereby assisting development of natural-product-inspired drugs to treat metastatic RCC.

Regression of albuminuria and hypertension and arrest of severe renal injury by a losartan-hydrochlorothiazide association in a model of very advanced nephropathy.

PubMed

Arias, Simone Costa Alarcon; Valente, Carla Perez; Machado, Flavia Gomes; Fanelli, Camilla; Origassa, Clarice Silvia Taemi; de Brito, Thales; Camara, Niels Olsen Saraiva; Malheiros, Denise Maria Avancini Costa; Zatz, Roberto; Fujihara, Clarice Kazue

2013-01-01

Treatments that effectively prevent chronic kidney disease (CKD) when initiated early often yield disappointing results when started at more advanced phases. We examined the long-term evolution of renal injury in the 5/6 nephrectomy model (Nx) and the effect of an association between an AT-1 receptor blocker, losartan (L), and hydrochlorothiazide (H), shown previously to be effective when started one month after Nx. Adult male Munich-Wistar rats underwent Nx, being divided into four groups: Nx+V, no treatment; Nx+L, receiving L monotherapy; Nx+LH, receiving the L+H association (LH), and Nx+AHHz, treated with the calcium channel blocker, amlodipine, the vascular relaxant, hydralazine, and H. This latter group served to assess the effect of lowering blood pressure (BP). Rats undergoing sham nephrectomy (S) were also studied. In a first protocol, treatments were initiated 60 days after Nx, when CKD is at a relatively early stage. In a second protocol, treatments were started 120 days after Nx, when glomerulosclerosis and interstitial fibrosis are already advanced. In both protocols, L treatment promoted only partial renoprotection, whereas LH brought BP, albuminuria, tubulointerstitial cell proliferation and plasma aldosterone below pretreatment levels, and completely detained progression of renal injury. Despite normalizing BP, the AHHz association failed to prevent renal damage, indicating that the renoprotective effect of LH was not due to a systemic hemodynamic action. These findings are inconsistent with the contention that thiazides are innocuous in advanced CKD. In Nx, LH promotes effective renoprotection even at advanced stages by mechanisms that may involve anti-inflammatory and intrarenal hemodynamic effects, but seem not to require BP normalization.

Therapeutic vaccines in renal cell carcinoma.

PubMed

Schwaab, Thomas; Ernstoff, Marc S

2011-07-01

Metastatic renal cell carcinoma (mRCC) is a lethal disease. The advent of tyrosine kinase inhibitors (TKIs) has changed the disease process, yet the majority of patients will develop treatment-resistant disease. IL-2 based immunotherapy in mRCC is the only US FDA-approved treatment with curative results. Immunotherapeutic vaccine approaches to mRCC have been under investigation for several decades with mixed results. The recent FDA-approval of the first cellular immunotherapy in prostate cancer (Provenge(®)) has reinvigorated the search for similar vaccines approaches in mRCC. This review introduces the concepts and different features required for a successful anticancer vaccine approach.

Sixth BHD Symposium and First International Upstate Kidney Cancer Symposium: latest scientific and clinical discoveries.

PubMed

Bratslavsky, Gennady; Woodford, Mark R; Daneshvar, Michael; Mollapour, Mehdi

2016-03-29

The Sixth BHD Symposium and First International Upstate Kidney Cancer Symposium concluded in September 2015, in Syracuse, NY, USA. The program highlighted recent findings in a variety of areas, including drug development, therapeutics and surgical management of patients with BHD and multi-focal renal tumors, as well as multidisciplinary approaches for patients with localized, locally advanced and metastatic renal cell carcinoma.

Resilience and hope during advanced disease: a pilot study with metastatic colorectal cancer patients.

PubMed

Solano, Joao Paulo Consentino; da Silva, Amanda Gomes; Soares, Ivan Agurtov; Ashmawi, Hazem Adel; Vieira, Joaquim Edson

2016-08-02

The balance between hope-hopelessness plays an important role in the way terminally ill patients report quality of life, and personal resilience may be related to hope at the end of life. The objective of this study was to explore associations between personal resilience, hope, and other possible predictors of hope in advanced cancer patients. A cross-sectional pilot study was carried out with metastatic colorectal cancer patients in a tertiary hospital. The patients answered the Connor-Davidson Resilience Scale, Herth Hope Index, Barthel Index, an instrument addressing family and social support, visual-numeric scales for pain and suffering, a two-item screening for depression, socio-demographic and socio-economic information about the family. Forty-four patients were interviewed (mean age 56 years; range 29-86). A strong correlation was noted between resilience and hope (0.63; p < 0.05). No correlation was found between hope and independence for activities of daily living, support from family and community, and pain and suffering levels. Of the 44 patients, 20 presented with depressive symptoms. These depressive patients had lower resilience (p = 0.005) and hope (p = 0.003), and higher scores of suffering (p < 0.001). The association between resilience and hope kept stable after adjusting for age, gender, and presence of depression (p < 0.001). Given that resilience is a dynamic, changeable path that can improve hope, resilience-fostering interventions should be most valued in palliative care settings and should be commenced as soon as possible with cancer patients. Patients with advanced stages of non-malignant conditions would also probably benefit from such interventions.

Modern Pathologic Diagnosis of Renal Oncocytoma.

PubMed

Wobker, Sara E; Williamson, Sean R

2017-01-01

Oncocytoma is a well-defined benign renal tumor, with classic gross and histologic features, including a tan or mahogany-colored mass with central scar, microscopic nested architecture, bland cytology, and round, regular nuclei with prominent central nucleoli. As a result of variations in this classic appearance, difficulty in standardizing diagnostic criteria, and entities that mimic oncocytoma, such as eosinophilic variant chromophobe renal cell carcinoma and succinate dehydrogenase-deficient renal cell carcinoma, pathologic diagnosis remains a challenge. This review addresses the current state of pathologic diagnosis of oncocytoma, with emphasis on modern diagnostic markers, areas of controversy, and emerging techniques for less invasive diagnosis, including renal mass biopsy and advanced imaging.

A PHASE II STUDY OF GEMCITABINE AND CAPECITABINE IN PATIENTS WITH ADVANCED RENAL CELL CANCER (RCC): SOUTHWEST ONCOLOGY GROUP STUDY S0312

PubMed Central

Van Veldhuizen, Peter J.; Hussey, Michael; Lara, Primo N.; Mack, Philip C.; Gandour-Edwards, Regina; Clark, Joseph I.; Lange, Marianne K.; Crawford, E. David

2010-01-01

Background Gemcitabine plus capecitabine has modest efficacy in patients with advanced RCC but has considerable toxicity. We evaluated the efficacy and toxicity of a modified dose-schedule of this doublet in patients with advanced unresectable or metastatic RCC. Methods Chemotherapy-naïve patients were treated with gemcitabine at 900mg/m2 on days 1,8,15 and capecitabine at 625mg/m2 twice daily on days 1 through 21, every 28 days. Eligible patients must have adequate performance status and end-organ function. The primary endpoint was tumor response rate (RR). No further evaluation of this regimen would be pursued if the RR was ≤ 5%. In an exploratory manner using archival specimens, we also evaluated potential markers of prognosis and treatment response including thymidylate synthase (TS) gene polymorphisms and tumor expression of p53, PTEN, pAKT, pmTOR, and ERCC1. Results Of 43 patients registered, 1 was ineligible and 2 were not analyzable. There was 1 confirmed complete response (CR) and three unconfirmed partial responses (PR), for an overall response rate of 10% (95% CI: 3, 24). Nineteen patients (48%) had stable disease (SD). The six-month freedom-from-treatment-failure and overall survival rates were 20% (95% CI: 8, 32) and 75% (95% CI: 62, 88), respectively. Median survival time was 23 months (95% CI: 10, 37). One patient each experienced Grade 4 neutropenia, fatigue, thrombocytopenia and hemolysis with renal failure. The most common Grade 3 toxicities were neutropenia (12 patients), fatigue (5), and leucopenia (4). Patients with a best response of stable disease or better were more likely to have a decrease in expression of PTEN and an increased expression of pmTOR. Conclusions Gemcitabine plus capecitabine at this reduced dose-schedule benefits a small percentage of patients with RCC with an acceptable toxicity profile. The combination of gemcitabine and capecitabine may serve as a base regimen for combination therapy with targeted agents in select RCC

Comprehensive analysis and validation of contemporary survival prognosticators in Korean patients with metastatic renal cell carcinoma treated with targeted therapy: prognostic impact of pretreatment neutrophil-to-lymphocyte ratio.

PubMed

Koo, Kyo Chul; Lee, Kwang Suk; Cho, Kang Su; Rha, Koon Ho; Hong, Sung Joon; Chung, Byung Ha

2016-06-01

In line with the era of targeted therapy (TT), an increasing number of prognosticators are becoming available for patients with metastatic renal cell carcinoma (mRCC). Here, potential prognosticators of cancer-specific survival (CSS) were identified based on the contemporary literature and were comprehensively validated in an independent cohort of patients treated for mRCC. Data were collected from 478 patients treated with TT for mRCC between January 1999 and July 2013 at a single institution. The analysis included 25 clinicopathological covariates that included both traditional and contemporary prognosticators. Multivariate Cox regression models were used to quantify the effect of covariates on CSS. Median survival from the initial diagnosis of metastasis was 24.5 (IQR, 11.5-55.7) months. There were 303 (63.4 %) cancer-specific deaths, yielding a 2-year CSS rate of 62.5 %. Low Karnofsky performance status (KPS), hypercalcemia, neutrophil-to-lymphocyte ratio (NLR), the number of metastatic sites (≥2), and the presence of brain metastases were independent adverse prognosticators of CSS. The C-index of the model was 0.78. Patients with at least one adverse prognosticator demonstrated lower 2-year CSS rates compared to those with no prognosticators (53.9 vs. 70.6 %; log rank p < 0.001). Together with traditional prognosticators such as KPS, hypercalcemia, and the number and location of metastases, the NLR was an independent predictor of CSS in patients with mRCC treated with TT. Our findings could be useful for guiding clinical decision making including stratification of patients for TT and inclusion in clinical trials.

Technological advances in renal replacement therapy: five years and beyond.

PubMed

Rastogi, Anjay; Nissenson, Allen R

2009-12-01

The worldwide epidemic of chronic kidney disease shows no signs of abating in the near future. Current dialysis forms of renal replacement therapy (RRT), even though successful in sustaining life and improving quality of life somewhat for patients with ESRD, have many limitations that result in still unacceptably high morbidity and mortality. Transplantation is an excellent option but is limited by the scarcity of organs. An ideal form of RRT would mimic the functions of natural kidneys and be transparent to the patient, as well as affordable to society. Recent advances in technology, although generally in early stages of development, might achieve these goals. The application of nanotechnology, microfluidics, bioreactors with kidney cells, and miniaturized sorbent systems to regenerate dialysate makes clinical reality seem closer than ever before. Finally, stem cells hold much promise, both for kidney disease and as a source of tissues and organs. In summary, nephrology is at an exciting crossroad with the application of innovative and novel technologies to RRT that hold considerable promise for the near future.

Sapanisertib in Treating Patients With Locally Advanced or Metastatic Bladder Cancer With TSC1 and/or TSC2 Mutations

ClinicalTrials.gov

2018-05-02

Metastatic Transitional Cell Carcinoma; Metastatic Urothelial Carcinoma; Recurrent Bladder Carcinoma; Stage III Bladder Urothelial Carcinoma AJCC v6 and v7; Stage IV Bladder Urothelial Carcinoma AJCC v7; TSC1 Gene Mutation; TSC2 Gene Mutation

Microproteinuria during Opisthorchis viverrini Infection: A Biomarker for Advanced Renal and Hepatobiliary Pathologies from Chronic Opisthorchiasis

PubMed Central

Saichua, Prasert; Sithithaworn, Paiboon; Jariwala, Amar R.; Deimert, David J.; Sithithaworn, Jiraporn; Sripa, Banchob; Laha, Thewarach; Mairiang, Eimorn; Pairojkul, Chawalit; Periago, Maria Victoria; Khuntikeo, Narong; Mulvenna, Jason; Bethony, Jeffrey M.

2013-01-01

Approximately 680 million people are at risk of infection with Opisthorchis viverrini (OV) and Clonorchis sinensis, with an estimated 10 million infected with OV in Southeast Asia alone. While opisthorchiasis is associated with hepatobiliary pathologies, such as advanced periductal fibrosis (APF) and cholangiocarcinoma (CCA), animal models of OV infection show that immune-complex glomerulonephritis is an important renal pathology that develops simultaneously with hepatobiliary pathologies. A cardinal sign of immune-complex glomerulonephritis is the urinary excretion of immunoglobulin G (IgG) (microproteinuria). In community-based studies in OV endemic areas along the Chi River in northeastern Thailand, we observed that over half of the participants had urine IgG against a crude OV antigen extract (OV antigen). We also observed that elevated levels of urine IgG to OV antigen were not associated with the intensity of OV infection, but were likely the result of immune-complex glomerulonephritis as seen in animal models of OV infection. Moreover, we observed that urine IgG to OV antigen was excreted at concentrations 21 times higher in individuals with APF and 158 times higher in individuals with CCA than controls. We also observed that elevated urine IgG to OV antigen could identify APF+ and CCA+ individuals from non-cases. Finally, individuals with urine IgG to OV antigen had a greater risk of APF as determined by Odds Ratios (OR = 6.69; 95%CI: 2.87, 15.58) and a greater risk of CCA (OR = 71.13; 95%CI: 15.13, 334.0) than individuals with no detectable level of urine IgG to OV antigen. Herein, we show for the first time the extensive burden of renal pathology in OV endemic areas and that a urine biomarker could serve to estimate risk for both renal and hepatobiliary pathologies during OV infection, i.e., serve as a “syndromic biomarker” of the advanced pathologies from opisthorchiasis. PMID:23717698

Clinically Non-Metastatic Renal Cell Carcinoma With Sarcomatoid Dedifferentiation: Natural History and Outcomes after Surgical Resection with Curative Intent

PubMed Central

Merrill, Megan M.; Wood, Christopher G.; Tannir, Nizar M.; Slack, Rebecca S.; Babaian, Kara N.; Jonasch, Eric; Pagliaro, Lance C.; Compton, Zachary; Tamboli, Pheroze; Sircar, Kanishka; Pisters, Louis L.; Matin, Surena F.; Karam, Jose A.

2015-01-01

Purpose Renal cell carcinoma with sarcomatoid dedifferentiation (sRCC) is an aggressive malignancy associated with a poor prognosis. While existing literature focuses on patients presenting with metastatic disease, characteristics and outcomes for patients with localized disease are not well described. We aimed to evaluate post-nephrectomy characteristics, outcomes, and predictors of survival in patients with sRCC who presented with clinically localized disease. Patients and Methods An IRB-approved review from 1986–2011 identified 77 patients who presented with clinically localized disease, underwent nephrectomy and had sRCC in their primary kidney tumor. Clinical and pathologic variables were captured for each patient. Overall survival (OS) and recurrence-free survival (RFS) were calculated for all patients and those who had no evidence of disease (NED) following nephrectomy, respectively. Comparisons were made with categorical groupings in proportional hazards regression models for univariable and multivariable analyses. Results OS for the entire cohort (N=77) at 2 years was 50%. A total of 56 (77%) patients of the 73 who were NED following nephrectomy experienced a recurrence, with a median time to recurrence of 26.2 months. On multivariable analysis, tumor stage, pathologically positive lymph nodes, and year of nephrectomy were significant predictors of both OS and RFS. Limitations include the retrospective nature of this study and relatively small sample size. Conclusions Long-term survival for patients with sRCC, even in clinically localized disease is poor. Aggressive surveillance of those who are NED following nephrectomy is essential and further prospective studies evaluating the benefit of adjuvant systemic therapies in this cohort are warranted. PMID:25700975

Histotripsy and metastasis: Assessment in a renal VX-2 rabbit tumor model

NASA Astrophysics Data System (ADS)

Styn, Nicholas R.; Hall, Timothy L.; Fowlkes, J. Brian; Cain, Charles A.; Roberts, William W.

2012-10-01

Histotripsy is a non-invasive, pulsed ultrasound technology where controlled cavitation is used to homogenize targeted tissue. We sought to assess the possibility that histotripsy may increase metastatic spread of tumor by quantifying the number of lung metastasis apparent after histotripsy treatment of aggressive renal VX-2 tumor compared to nontreated controls. VX-2 tumor was implanted in the left kidneys of 28 New Zealand White rabbits. Twenty rabbits were treated with histotripsy (day 13 after implantation) while 8 served as controls. All rabbits underwent left nephrectomy (day 14) and then were euthanized (day 19). This study was powered to detect a doubling in metastatic rate. Homogenized tumor was seen in all treated nephrectomy specimens. Whole-mount, coronal lung sections were viewed to calculate number and density of metastases. Viable tumor was present in all 28 lungs examined. Histology confirmed fractionation of tumor in all treatment rabbits. There was not a statistical difference in total lung metastases (88.7 vs. 72.5; p=0.29) or metastatic density (8.9 vs. 7.0 mets/cm2; p=0.22) between treated and control rabbits. Further investigation is planned to validate these results in the VX-2 model and to assess metastatic rates in less aggressive tumors treated with histotripsy.

Comparative proteomic investigation of metastatic and non-metastatic osteosarcoma cells of human and canine origin

PubMed Central

Roy, Jahnabi; Wycislo, Kathryn L.; Pondenis, Holly; Fan, Timothy M.

2017-01-01

Osteosarcoma is the most common bone cancer in dogs and people. In order to improve clinical outcomes, it is necessary to identify proteins that are differentially expressed by metastatic cells. Membrane bound proteins are responsible for multiple pro-metastatic functions. Therefore characterizing the differential expression of membranous proteins between metastatic and non-metastatic clonal variants will allow the discovery of druggable targets and consequently improve treatment methodology. The objective of this investigation was to systemically identify the membrane-associated proteomics of metastatic and non-metastatic variants of human and canine origin. Two clonal variants of divergent in vivo metastatic potential from human and canine origins were used. The plasma membranes were isolated and peptide fingerprinting was used to identify differentially expressed proteins. Selected proteins were further validated using western blotting, flow cytometry, confocal microscopy and immunohistochemistry. Over 500 proteins were identified for each cell line with nearly 40% of the proteins differentially regulated. Conserved between both species, metastatic variants demonstrated significant differences in expression of membrane proteins that are responsible for pro-metastatic functions. Additionally, CD147, CD44 and vimentin were validated using various biochemical techniques. Taken together, through a comparative proteomic approach we have identified several differentially expressed cell membrane proteins that will help in the development of future therapeutics. PMID:28910304

Comparative proteomic investigation of metastatic and non-metastatic osteosarcoma cells of human and canine origin.

PubMed

Roy, Jahnabi; Wycislo, Kathryn L; Pondenis, Holly; Fan, Timothy M; Das, Aditi

2017-01-01

Osteosarcoma is the most common bone cancer in dogs and people. In order to improve clinical outcomes, it is necessary to identify proteins that are differentially expressed by metastatic cells. Membrane bound proteins are responsible for multiple pro-metastatic functions. Therefore characterizing the differential expression of membranous proteins between metastatic and non-metastatic clonal variants will allow the discovery of druggable targets and consequently improve treatment methodology. The objective of this investigation was to systemically identify the membrane-associated proteomics of metastatic and non-metastatic variants of human and canine origin. Two clonal variants of divergent in vivo metastatic potential from human and canine origins were used. The plasma membranes were isolated and peptide fingerprinting was used to identify differentially expressed proteins. Selected proteins were further validated using western blotting, flow cytometry, confocal microscopy and immunohistochemistry. Over 500 proteins were identified for each cell line with nearly 40% of the proteins differentially regulated. Conserved between both species, metastatic variants demonstrated significant differences in expression of membrane proteins that are responsible for pro-metastatic functions. Additionally, CD147, CD44 and vimentin were validated using various biochemical techniques. Taken together, through a comparative proteomic approach we have identified several differentially expressed cell membrane proteins that will help in the development of future therapeutics.

Significance of Age in Japanese Patients Receiving Sunitinib as First-line Systemic Therapy for Metastatic Renal Cell Carcinoma: Comparative Assessment of Efficacy and Safety between Patients Aged <75 and ≥75 Years.

PubMed

Miyake, Hideaki; Aki, Ryota; Matsushita, Yuto; Tamura, Keita; Motoyama, Daisuke; Ito, Toshiki; Sugiyama, Takayuki; Otsuka, Atsushi

2018-06-01

To date, it has not been well characterized whether sunitinib is effective in elderly patients with metastatic renal cell carcinoma (mRCC). The objective of this study was to investigate the impact of age on clinical outcomes of mRCC patients receiving sunitinib. The efficacy and safety of first-line sunitinib in 154 consecutive mRCC patients were retrospectively compared between patients aged <75 (n=125) and ≥75 (n=29) years. There were no significant differences in the major clinicopathological characteristics between younger and older patients; however, the reduction of the initial dose of sunitinib was significantly more frequent in older than younger patients. No significant difference in response rate, clinical benefit rate or proportion of patients going on to receive second-line therapy was noted between these two groups. Furthermore, there was no significant difference in progression-free survival (PFS) or overall survival (OS) between the two groups, and no significant impact of age on PFS or OS was documented by the Cox proportional hazards regression analyses. Of several adverse events, only anemia and fatigue were significantly more frequently observed in older than younger patients. Although there was no significant difference in the incidence of dose reduction or discontinuation of sunitinib between the two groups, the interruption of sunitinib was more frequently required in older than younger patients. These findings suggest that advanced age alone should not be regarded as a contraindication to the introduction of sunitinib as first-line systemic therapy for mRCC patients. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Phase II trial of interleukin 2, interferon alpha, and 5-fluorouracil in metastatic renal cell cancer: a cytokine working group study.

PubMed

Dutcher, J P; Logan, T; Gordon, M; Sosman, J; Weiss, G; Margolin, K; Plasse, T; Mier, J; Lotze, M; Clark, J; Atkins, M

2000-09-01

The purpose of this study was to evaluate the potential efficacy of alternating two outpatient regimens for the treatment of metastatic renal cell cancer. These regimens consisted of 4 weeks of recombinant interleukin 2 (rIL-2) plus IFN-alpha2B followed by 4 weeks of 5-fluorouracil plus IFN-alpha2B. Fifty patients meeting eligibility criteria of previous Cytokine Working Group studies were treated on an outpatient basis. Patients received s.c. rIL-2 (Proleukin; Chiron, Emeryville, CA) during weeks 1-4 of the 8-week regimen. During weeks 1 and 4, the dosage for rIL-2 was 10 MIU/m2 twice daily on days 3-5, and the dosage for IFN-alpha2B (Intron; Schering Plough, Kenilworth, NJ) was 6 MIU/m2 on day 1. During weeks 2 and 3, the dosage for rIL-2 was 5 MIU/m2 on days 1, 3, and 5, and the dosage for IFN-alpha2B was 6 MIU/m2 on days 1, 3, 5. During weeks 5-8, 5-fluorouracil (750 mg/m2) was administered once weekly by i.v. infusion, and IFN-alpha2B (9 MIU/mZ) was administered as a s.c. injection three times weekly. Throughout the treatment, an assessment of quality of life was made and a symptom-distress scale was evaluated. There were two patients with complete responses (CRs) and seven with partial responses (PRs) for an objective response rate of 18% (95% confidence interval, 10-25). The median response duration was 8 months (range, 3-51+ months). The CRs lasted 5 months and 51+ months and the PRs ranged from 3+ to 18 months. After completing at least one course of treatment, eight patients (three with PR, one with minor response, four with stable disease) became CRs after surgery for remaining metastatic disease. Six remain alive at 43+ to 53+ months, and 5 remain disease-free since surgery. The median survival of the study group is 17.5 months, with a maximal follow-up of 53+ months. The range in survival is 1-53+ months. Toxicity was primarily constitutional. and treatment modifications were designed to maintain toxicity at grade 2/3. The most common toxicities during

High Expression of KCa3.1 in Patients with Clear Cell Renal Carcinoma Predicts High Metastatic Risk and Poor Survival

PubMed Central

Rabjerg, Maj; Oliván-Viguera, Aida; Hansen, Lars Koch; Jensen, Line; Sevelsted-Møller, Linda; Walter, Steen; Jensen, Boye L.; Marcussen, Niels; Köhler, Ralf

2015-01-01

Background Ca2+-activated K+ channels have been implicated in cancer cell growth, metastasis, and tumor angiogenesis. Here we hypothesized that high mRNA and protein expression of the intermediate-conductance Ca2+-activated K+ channel, KCa3.1, is a molecular marker of clear cell Renal Cell Carcinoma (ccRCC) and metastatic potential and survival. Methodology/Principal Findings We analyzed channel expression by qRT-PCR, immunohistochemistry, and patch-clamp in ccRCC and benign oncocytoma specimens, in primary ccRCC and oncocytoma cell lines, as well as in two ccRCC cell lines (Caki-1 and Caki-2). CcRCC specimens contained 12-fold higher mRNA levels of KCa3.1 than oncocytoma specimens. The large-conductance channel, KCa1.1, was 3-fold more highly expressed in ccRCC than in oncocytoma. KCa3.1 mRNA expression in ccRCC was 2-fold higher than in the healthy cortex of the same kidney. Disease specific survival trended towards reduction in the subgroup of high-KCa3.1-expressing tumors (p<0.08 vs. low-KCa3.1-expressing tumors). Progression-free survival (time to metastasis/recurrence) was reduced significantly in the subgroup of high-KCa3.1-expressing tumors (p<0.02, vs. low-KCa3.1-expressing tumors). Immunohistochemistry revealed high protein expression of KCa3.1 in tumor vessels of ccRCC and oncocytoma and in a subset of ccRCC cells. Oncocytoma cells were devoid of KCa3.1 protein. In a primary ccRCC cell line and Caki-1/2-ccRCC cells, we found KCa3.1-protein as well as TRAM-34-sensitive KCa3.1-currents in a subset of cells. Furthermore, Caki-1/2-ccRCC cells displayed functional Paxilline-sensitive KCa1.1 currents. Neither KCa3.1 nor KCa1.1 were found in a primary oncocytoma cell line. Yet KCa-blockers, like TRAM-34 (KCa3.1) and Paxilline (KCa1.1), had no appreciable effects on Caki-1 proliferation in-vitro. Conclusions/Significance Our study demonstrated expression of KCa3.1 in ccRCC but not in benign oncocytoma. Moreover, high KCa3.1-mRNA expression levels were indicative

High expression of KCa3.1 in patients with clear cell renal carcinoma predicts high metastatic risk and poor survival.

PubMed

Rabjerg, Maj; Oliván-Viguera, Aida; Hansen, Lars Koch; Jensen, Line; Sevelsted-Møller, Linda; Walter, Steen; Jensen, Boye L; Marcussen, Niels; Köhler, Ralf

2015-01-01

Ca2+-activated K+ channels have been implicated in cancer cell growth, metastasis, and tumor angiogenesis. Here we hypothesized that high mRNA and protein expression of the intermediate-conductance Ca2+-activated K+ channel, KCa3.1, is a molecular marker of clear cell Renal Cell Carcinoma (ccRCC) and metastatic potential and survival. We analyzed channel expression by qRT-PCR, immunohistochemistry, and patch-clamp in ccRCC and benign oncocytoma specimens, in primary ccRCC and oncocytoma cell lines, as well as in two ccRCC cell lines (Caki-1 and Caki-2). CcRCC specimens contained 12-fold higher mRNA levels of KCa3.1 than oncocytoma specimens. The large-conductance channel, KCa1.1, was 3-fold more highly expressed in ccRCC than in oncocytoma. KCa3.1 mRNA expression in ccRCC was 2-fold higher than in the healthy cortex of the same kidney. Disease specific survival trended towards reduction in the subgroup of high-KCa3.1-expressing tumors (p<0.08 vs. low-KCa3.1-expressing tumors). Progression-free survival (time to metastasis/recurrence) was reduced significantly in the subgroup of high-KCa3.1-expressing tumors (p<0.02, vs. low-KCa3.1-expressing tumors). Immunohistochemistry revealed high protein expression of KCa3.1 in tumor vessels of ccRCC and oncocytoma and in a subset of ccRCC cells. Oncocytoma cells were devoid of KCa3.1 protein. In a primary ccRCC cell line and Caki-1/2-ccRCC cells, we found KCa3.1-protein as well as TRAM-34-sensitive KCa3.1-currents in a subset of cells. Furthermore, Caki-1/2-ccRCC cells displayed functional Paxilline-sensitive KCa1.1 currents. Neither KCa3.1 nor KCa1.1 were found in a primary oncocytoma cell line. Yet KCa-blockers, like TRAM-34 (KCa3.1) and Paxilline (KCa1.1), had no appreciable effects on Caki-1 proliferation in-vitro. Our study demonstrated expression of KCa3.1 in ccRCC but not in benign oncocytoma. Moreover, high KCa3.1-mRNA expression levels were indicative of low disease specific survival of ccRCC patients, short

Advanced Prostate Cancer

MedlinePlus

... to learn about these types of treatments. This article is for men with metastatic and castrate-resistant ... Related Resources Urology 101 Fact Sheet UrologyHealth extra® Articles What is Advanced Prostate Cancer? Keeping Your Bones ...

Meridional lenticular astigmatism associated with bilateral concurrent uveal metastases in renal cell carcinoma.

PubMed

Priluck, Joshua C; Grover, Sandeep; Chalam, Kv

2012-01-01

To demonstrate a case illustrating meridional lenticular astigmatism as a result of renal cell carcinoma uveal metastases. Case report with images. Clinical findings and diagnostic testing of a patient with acquired meridional lenticular astigmatism are described. The refraction revealed best-corrected visual acuity of 20/20-1 OD (-2.50 + 0.25 × 090) and 20/50 OS (-8.25 + 3.25 × 075). Bilateral concurrent renal cell carcinoma metastases to the choroid and ciliary body are demonstrated by utilizing ultrasonography, ultrawidefield fluorescein angiography, and unique spectral-domain optical coherence tomography. Metastatic disease should be included in the differential of acquired astigmatism. Spectral-domain optical coherence tomography, ultrawidefield fluorescein angiography, and ultrasonography have roles in delineating choroidal metastases.

Overall Survival Analysis From a Randomized Phase II Study of Axitinib With or Without Dose Titration in First-Line Metastatic Renal Cell Carcinoma.

PubMed

Rini, Brian I; Tomita, Yoshihiko; Melichar, Bohuslav; Ueda, Takeshi; Grünwald, Viktor; Fishman, Mayer N; Uemura, Hirotsugu; Oya, Mototsugu; Bair, Angel H; Andrews, Glen I; Rosbrook, Brad; Jonasch, Eric

2016-12-01

In a randomized phase II trial in metastatic renal cell carcinoma (mRCC), objective response rate was significantly higher with axitinib versus placebo titration (54% vs. 34%; 1-sided P = .019). Treatment-naive patients with mRCC (n = 213) received axitinib 5 mg twice per day (b.i.d.) for 4 weeks. Patients meeting dose titration criteria were randomized to receive axitinib 5 mg b.i.d. with axitinib or placebo titration (n = 56 each); 91 patients ineligible for randomization continued axitinib 5 mg b.i.d.; 10 discontinued before randomization. Median overall survival (95% confidence interval [CI]) was 42.7 months (24.7-not estimable) with axitinib titration versus 30.4 months (23.7-45.0) with placebo titration (stratified hazard ratio, 0.785; 95% CI, 0.485-1.272; 1-sided P = .162), and 41.6 months (95% CI, 33.0-not estimable) in nonrandomized patients. Safety data were consistent with previous reports. Median overall survival was numerically longer in patients with first-line mRCC who received axitinib versus placebo titration. No new safety signal was observed after long-term axitinib treatment in first-line mRCC. Copyright © 2016 Elsevier Inc. All rights reserved.

Innovations in imaging modalities for recurrent and metastatic prostate cancer: a systematic review.

PubMed

Albisinni, Simone; Aoun, Fouad; Marcelis, Quentin; Jungels, Claude; Al Hajj Obeid, Walid; Zanaty, Marc; Tubaro, Andrea; Roumeguere, Thierry; DE Nunzio, Cosimo

2018-01-31

The last decade has witnessed tremendous changes in the management of advanced and metastatic castration resistant prostate cancer (mCRPC). In the current systematic review, we analyze novel imaging techniques in the setting of recurrent and metastatic PCa, exploring available data and highlighting future exams which could enter clinical practice in the upcoming years. The National Library of Medicine Database was searched for relevant articles published between January 2012 and August 2017. A wide search was performed including the combination of following words: "Prostate" AND "Cancer" AND ("Metastatic" OR "Recurrent") AND "imaging" AND ("MRI" OR "PET"). The selection procedure followed the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) principles and is presented using a PRISMA flow chart. Novel imaging techniques, as multiparametric MRI, whole-body MRI and Choline and PSMA PET imaging techniques are currently revolutioning the treatment planning in patients with advanced and metastatic PCa, allowing a better characterization of the disease. Multiparametric MRI performs well in the detection of local recurrences, with sensitivity rates of 67-98% and overall diagnostic accuracy of 83-93%, depending on the type of magnetic field strength (1.5 vs 3T). Whole body MRI instead shows a high specificity (>95%) for bone metastases. PET imaging, and in particular PSMA PET/CT, showed promising results in the detection of both local and distant recurrences, even for low PSA values (<0.5ng/ml). Sensitivity varies from 77-98% depending on PSA value and PSA velocity. Whole body-MRI, NaF PET, Choline-PET/CT and PSMA PET/CT are flourishing techniques which find great application in the field of recurrent and metastatic PCa, in the effort to reduce treatment of "PSA only" and rather focus our therapies on clinical tumor entities. Standardization is urgently needed to allow adequate comparison of results and diffusion on a large scale.

Immunotherapy of patients with metastatic melanoma.

PubMed

Yu, Zhe; Si, Lu

2017-04-01

Malignant melanoma (MM) is the primary cause of skin cancer related death and the incidence is increasing in the past years. Advanced MM still has a poor prognosis, but in recent years, the development of immunotherapy has changed its poor prognosis. Immune checkpoints show the revolutionary treatment of metastatic melanoma. Ipilimumab and pembrolizumab, monoclonal antibodies against the CTLA-4 and PD-1 respectively, have been shown to prolong overall survival (OS) in patients with advanced melanoma. The combination immunotherapy seems to be superior to monotherapy. In this review, recently immunotherapy clinical trial results are presented. The combination of immunotherapy provides new options for the treatment of MM patients. However, further studies are necessary to answer such question as optimal treatment, combination of immunotherapies, crowd selection and risk balance in patients with melanoma.

MicroRNAs Associated with Von Hippel-Lindau Pathway in Renal Cell Carcinoma: A Comprehensive Review.

PubMed

Schanza, Lisa-Maria; Seles, Maximilian; Stotz, Michael; Fosselteder, Johannes; Hutterer, Georg C; Pichler, Martin; Stiegelbauer, Verena

2017-11-22

Renal cell carcinoma (RCC) are the most common renal neoplasia and can be divided into three main histologic subtypes, among which clear cell RCC is by far the most common form of kidney cancer. Despite substantial advances over the last decade in the understanding of RCC biology, surgical treatments, and targeted and immuno-therapies in the metastatic setting, the prognosis for advanced RCC patients remains poor. One of the major problems with RCC treatment strategies is inherent or acquired resistance towards therapeutic agents over time. The discovery of microRNAs (miRNAs), a class of small, non-coding, single-stranded RNAs that play a crucial role in post-transcriptional regulation, has added new dimensions to the development of novel diagnostic and treatment tools. Because of an association between Von Hippel-Lindau (VHL) genes with chromosomal loss in 3p25-26 and clear cell RCC, miRNAs have attracted considerable scientific interest over the last years. The loss of VHL function leads to constitutional activation of the hypoxia inducible factor (HIF) pathway and to consequent expression of numerous angiogenic and carcinogenic factors. Since miRNAs represent key players of carcinogenesis, tumor cell invasion, angiogenesis, as well as in development of metastases in RCC, they might serve as potential therapeutic targets. Several miRNAs are already known to be dysregulated in RCC and have been linked to biological processes involved in tumor angiogenesis and response to anti-cancer therapies. This review summarizes the role of different miRNAs in RCC angiogenesis and their association with the VHL gene, highlighting their potential role as novel drug targets.

Metastatic colorectal cancer responsive to regorafenib for 2 years: a case report.

PubMed

Yoshino, Kenji; Manaka, Dai; Kudo, Ryo; Kanai, Shunpei; Mitsuoka, Eisei; Kanto, Satoshi; Hamasu, Shinya; Konishi, Sayuri; Nishitai, Ryuta

2017-08-18

Regorafenib is an oral multikinase inhibitor that has been demonstrated as clinically effective in patients with metastatic colorectal cancer in phase III studies. Although disease control was achieved in 40% of the pretreated patients with metastatic colorectal cancer in the pivotal studies, radiological response has rarely been reported. Severe adverse events associated with regorafenib are known to occur during the first and second courses of treatment. We present a case of a 62-year-old Japanese patient whose metastatic colorectal cancer has been responding to treatment with regorafenib for 2 years. A 54-year-old Japanese man visited our institute exhibiting general malaise, and he was diagnosed with ascending colon cancer in April 2006. He underwent right hemicolectomy, and the final staging was T3N0M0, stage II. After 19 months, pulmonary metastasis and anastomotic recurrences were detected, and a series of operations were performed to resect both metastatic lesions. After that, liver metastasis, a duodenal metastasis with right renal invasion, right adrenal metastasis, and para-aortic lymph node metastases were observed during follow-up, and chemotherapy and resection were performed. The patient had metastatic para-aortic lymph nodes after the fifth tumor resection and underwent multiple lines of chemotherapy in April 2014. Regorafenib monotherapy was started at 80 mg/day. Then, regorafenib was increased to 120 mg/day in the second cycle. Regorafenib monotherapy led to 60% tumor shrinkage within the initial 2 months, and the tumor further decreased in size over 4 months until it became unrecognizable on imaging studies. The clinical effects of regorafenib monotherapy have shown a partial response according to Response Evaluation Criteria in Solid Tumors criteria. No severe adverse events were observed, except for mild fatigue and hand-foot syndrome. The patient has received 24 courses of regorafenib over 2 years without exhibiting tumor progression. To the

Differential Expression of Ccn4 and Other Genes Between Metastatic and Non-metastatic EL4 Mouse Lymphoma Cells

PubMed Central

S. CHAHAL, MANPREET; TERESA KU, H.; ZHANG, ZHIHONG; M. LEGASPI, CHRISTIAN; LUO, ANGELA; M. HOPKINS, MANDI; E. MEIER, KATHRYN

2016-01-01

Background: Previous work characterized variants of the EL4 murine lymphoma cell line. Some are non-metastatic, and others metastatic, in syngenic mice. In addition, metastatic EL4 cells were stably transfected with phospholipase D2 (PLD2), which further enhanced metastasis. Materials and Methods: Microarray analyses of mRNA expression was performed for non-metastatic, metastatic, and PLD2-expressing metastatic EL4 cells. Results: Many differences were observed between non-metastatic and metastatic cell lines. One of the most striking new findings was up-regulation of mRNA for the matricellular protein WNT1-inducible signaling pathway protein 1 (CCN4) in metastatic cells; increased protein expression was verified by immunoblotting and immunocytochemistry. Other differentially expressed genes included those for reproductive homeobox 5 (Rhox5; increased in metastatic) and cystatin 7 (Cst7; decreased in metastatic). Differences between PLD2-expressing and parental cell lines were limited but included the signaling proteins Ras guanyl releasing protein 1 (RGS18; increased with PLD2) and suppressor of cytokine signaling 2 (SOCS2; decreased with PLD2). Conclusion: The results provide insights into signaling pathways potentially involved in conferring metastatic ability on lymphoma cells. PMID:27807066

Altered Redox Status Accompanies Progression to Metastatic Human Bladder Cancer

PubMed Central

Hempel, Nadine; Ye, Hanqing; Abessia, Bryan; Mian, Badar; Melendez, J. Andres

2009-01-01

The role of reactive oxygen species (ROS) in bladder cancer progression remains an unexplored field. Expression levels of enzymes regulating ROS levels are often altered in cancer. Search of publicly available micro-array data reveals that expression of mitochondrial manganese superoxide dismutase (Sod2), responsible for the conversion of superoxide (O2-.) to hydrogen peroxide (H2O2), is consistently increased in high grade and advanced stage bladder tumors. Here we aim to identify the role of Sod2 expression and ROS in bladder cancer. Using an in vitro human bladder tumor model we monitored the redox state of both non-metastatic (253J) and highly metastatic (253J B-V) bladder tumor cell lines. 253J B-V cells displayed significantly higher Sod2 protein and activity levels compared to their parental 253J cell line. The increase in Sod2 expression was accompanied by a significant decrease in catalase activity, resulting in a net increase in H2O2 production in the 253J B-V line. Expression of pro-metastatic and –angiogenic factors, matrix metalloproteinase 9 (MMP-9) and vascular endothelial derived growth factor (VEGF), respectively, were similarly upregulated in the metastatic line. Expression of both MMP-9 and VEGF were shown to be H2O2-dependent, as removal of H2O2 by overexpression of catalase attenuated their expression. Similarly, expression of catalase effectively reduced the clonogenic activity of 253J B-V cells. These findings indicate that metastatic bladder cancer cells display an altered antioxidant expression profile, resulting in a net increase in ROS production, which leads to the induction of redox-sensitive pro-tumorigenic and pro-metastatic genes such as VEGF and MMP-9. PMID:18930813

Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane.

PubMed

Kaufman, Peter A; Awada, Ahmad; Twelves, Chris; Yelle, Louise; Perez, Edith A; Velikova, Galina; Olivo, Martin S; He, Yi; Dutcus, Corina E; Cortes, Javier

2015-02-20

This phase III randomized trial (ClinicalTrials.gov identifier: NCT00337103) compared eribulin with capecitabine in patients with locally advanced or metastatic breast cancer (MBC). Women with MBC who had received prior anthracycline- and taxane-based therapy were randomly assigned to receive eribulin or capecitabine as their first-, second-, or third-line chemotherapy for advanced/metastatic disease. Stratification factors were human epidermal growth factor receptor-2 (HER2) status and geographic region. Coprimary end points were overall survival (OS) and progression-free survival (PFS). Median OS times for eribulin (n = 554) and capecitabine (n = 548) were 15.9 and 14.5 months, respectively (hazard ratio [HR], 0.88; 95% CI, 0.77 to 1.00; P = .056). Median PFS times for eribulin and capecitabine were 4.1 and 4.2 months, respectively (HR, 1.08; 95% CI, 0.93 to 1.25; P = .30). Objective response rates were 11.0% for eribulin and 11.5% for capecitabine. Global health status and overall quality-of-life scores over time were similar in the treatment arms. Both treatments had manageable safety profiles consistent with their known adverse effects; most adverse events were grade 1 or 2. In this phase III study, eribulin was not shown to be superior to capecitabine with regard to OS or PFS.

Successful treatment by pembrolizumab in a patient with end-stage renal disease with advanced non-small cell lung cancer and high PD-L1 expression.

PubMed

Ishizuka, Shiho; Sakata, Shinya; Yoshida, Chieko; Takaki, Akira; Saeki, Sho; Nakamura, Kazuyoshi; Fujii, Kazuhiko

2018-05-10

We report a 66-year-old Japanese male with end-stage renal disease (ESRD) and advanced non-small cell lung cancer (NSCLC) who was on hemodialysis. The patient harbored high programmed death ligand 1 (PD-L1) expression and was successfully treated with pembrolizumab. Laboratory examination upon diagnosis showed elevated serum creatinine (6.58 mg/dL). We administered pembrolizumab (200 mg/body) and repeated every 3 weeks. His renal dysfunction gradually progressed, hemodialysis was initiated after eight courses of pembrolizumab, and the antitumor effect was maintained at five months after hemodialysis initiation. Therefore, pembrolizumab can be administered for patients with ESRD and advanced NSCLC, who harbor high PD-L1 expression, during preparation for hemodialysis. Copyright © 2018 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

Metastatic human hepatocellular carcinoma models in nude mice and cell line with metastatic potential

PubMed Central

Tang, Zhao-You; Sun, Fan-Xian; Tian, Jian; Ye, Sheng-Long; Liu, Yin-Kun; Liu, Kang-Da; Xue, Qiong; Chen, Jie; Xia, Jing-Lin; Qin, Lun-Xiu; Sun, Hui-Chuan; Wang, Lu; Zhou, Jian; Li, Yan; Ma, Zeng-Chen; Zhou, Xin-Da; Wu, Zhi-Quan; Lin, Zhi-Ying; Yang, Bing-Hui

2001-01-01

Metastatic human HCC model is needed for the studies on mechanism and interven tion of metastatic recurrence. By using orthotopic implantation of histologically intact tissues of 30 surgical specimens, a patient-like metastatic model of hu man HCC in nude mice (LCI-D20) and a low metastatic model of human HCC in nude mice (LCI-D35) have been established. All mice with transplanted LCI-D20 tumors exhibited extremely high metastatic ability including spontaneous metasta sis to liver, lungs, lymph nodes and peritoneal seeding. Remarkable difference was also found in expression of some of the invasiveness related genes and growth factors between the LCI-D20 and LCI-D35 tumors. PAI-1 increased gradually following tumor progression in LCI-D20 model, and correlated with tumor size and AFP level. Phasic expression of tissue intercellular adhesio nmolecule-1 in this model was also observed. Using corneal micropocket model, it was demonstrated that the vascular response induced by LCI-D20 tumor was stronger than that induced by LCI-D35 tumor. Similar report on metastatic human HCC model in nude mice and human HCC cell line with metastatic potential was rarely found in the literature. This LCI-D20 model has been widely used for the studies on intervention of metastasis, including anti-angiogenesis, antisense approach, metallopro teinase inhibitor, differentiation inducer, etc. It is concluded that the establ ishment of metastatic human HCC model in nude mice and human HCC cell line with metastatic potential will provide important models for the in vivo and in vitro study of HCC invasiveness, angiogenesis as well as intervention of HCC recurrence. PMID:11819839

Axitinib after Sunitinib in Metastatic Renal Cancer: Preliminary Results from Italian "Real-World" SAX Study.

PubMed

D'Aniello, Carmine; Vitale, Maria G; Farnesi, Azzurra; Calvetti, Lorenzo; Laterza, Maria M; Cavaliere, Carla; Della Pepa, Chiara; Conteduca, Vincenza; Crispo, Anna; De Vita, Ferdinando; Grillone, Francesco; Ricevuto, Enrico; De Tursi, Michele; De Vivo, Rocco; Di Napoli, Marilena; Cecere, Sabrina C; Iovane, Gelsomina; Amore, Alfonso; Piscitelli, Raffaele; Quarto, Giuseppe; Pisconti, Salvatore; Ciliberto, Gennaro; Maiolino, Piera; Muto, Paolo; Perdonà, Sisto; Berretta, Massimiliano; Naglieri, Emanuele; Galli, Luca; Cartenì, Giacomo; De Giorgi, Ugo; Pignata, Sandro; Facchini, Gaetano; Rossetti, Sabrina

2016-01-01

Axitinib is an oral angiogenesis inhibitor, currently approved for treatment of metastatic renal cell carcinoma (mRCC) after failure of prior treatment with Sunitinib or cytokine. The present study is an Italian Multi-Institutional Retrospective Analysis that evaluated the outcomes of Axitinib, in second-line treatment of mRCC. The medical records of 62 patients treated with Axitinib, were retrospectively reviewed. The Progression Free Survival (PFS), the Overall Survival (OS), the Objective Response Rate (ORR), the Disease Control Rate (DCR), and the safety profile of axitinib and sunitinib-axitinib sequence, were the primary endpoint. The mPFS was 5.83 months (95% CI 3.93-7.73 months). When patients was stratified by Heng score, mPFS was 5.73, 5.83, 10.03 months according to poor, intermediate, and favorable risk group, respectively. The mOS from the start of axitinib was 13.3 months (95% CI 8.6-17.9 months); the observed ORR and DCR were 25 and 71%, respectively. When stratified patients by subgroups defined by duration of prior therapy with Sunitinib (≤ vs. >median duration), there was a statistically significant difference in mPFS with 8.9 (95% CI 4.39-13.40 months) vs. 5.46 months (95% CI 4.04-6.88 months) for patients with a median duration of Sunitinib >13.2 months. DCR and ORR to previous Sunitinib treatment was associated with longer statistically mPFS, 7.23 (95% CI 3.95-10.51 months, p = 0.01) and 8.67 (95% CI 4.0-13.33 months, p = 0.008) vs. 2.97 (95% CI 0.65-5.27 months, p = 0.01) and 2.97 months (95% CI 0.66-5.28 months, p = 0.01), respectively. Overall Axitinib at standard schedule of 5 mg bid, was well-tolerated. The most common adverse events of all grades were fatig (25.6%), hypertension (22.6%), gastro-intestinal disorders (25.9%), and hypothyroidism (16.1%). The sequence Sunitinib-Axitinib was well-tolerated without worsening in side effects, with a median OS of 34.7 months (95% CI 18.4-51.0 months). Our results are consistent with the

Stable and high expression of Galectin-8 tightly controls metastatic progression of prostate cancer

PubMed Central

Gentilini, Lucas Daniel; Pérez, Ignacio González; Kotler, Monica Lidia; Chauchereau, Anne; Laderach, Diego Jose; Compagno, Daniel

2017-01-01

Two decades ago, Galectin-8 was described as a prostate carcinoma biomarker since it is only expressed in the neoplastic prostate, but not in the healthy tissue. To date, no biological function has been attributed to Galectin-8 that could explain this differential expression. In this study we silenced Galectin-8 in two human prostate cancer cell lines, PC3 and IGR-CaP1, and designed a pre-clinical experimental model that allows monitoring the pathology from its early steps to the long-term metastatic stages. We show for the first time that the natural and conserved expression of Gal-8 in tumour cells is responsible for the metastatic evolution of prostate cancer. In fact, Gal-8 controls the rearrangement of the cytoskeleton and E-Cadherin expression, with a major impact on anoikis and homotypic aggregation of tumour cells, both being essential processes for the survival of circulating tumour cells during metastasis. While localized prostate cancer can be cured, metastatic and advanced disease remains a significant therapeutic challenge, urging for the identification of prognostic markers of the metastatic process. Collectively, our results highlight Galectin-8 as a potential target for anti-metastatic therapy against prostate cancer. PMID:28591719

Differential Expression of Ccn4 and Other Genes Between Metastatic and Non-metastatic EL4 Mouse Lymphoma Cells.

PubMed

Chahal, Manpreet S; Ku, H Teresa; Zhang, Zhihong; Legaspi, Christian M; Luo, Angela; Hopkins, Mandi M; Meier, Kathryn E

Previous work characterized variants of the EL4 murine lymphoma cell line. Some are non-metastatic, and others metastatic, in syngenic mice. In addition, metastatic EL4 cells were stably transfected with phospholipase D2 (PLD2), which further enhanced metastasis. Microarray analyses of mRNA expression was performed for non-metastatic, metastatic, and PLD2-expressing metastatic EL4 cells. Many differences were observed between non-metastatic and metastatic cell lines. One of the most striking new findings was up-regulation of mRNA for the matricellular protein WNT1-inducible signaling pathway protein 1 (CCN4) in metastatic cells; increased protein expression was verified by immunoblotting and immunocytochemistry. Other differentially expressed genes included those for reproductive homeobox 5 (Rhox5; increased in metastatic) and cystatin 7 (Cst7; decreased in metastatic). Differences between PLD2-expressing and parental cell lines were limited but included the signaling proteins Ras guanyl releasing protein 1 (RGS18; increased with PLD2) and suppressor of cytokine signaling 2 (SOCS2; decreased with PLD2). The results provide insights into signaling pathways potentially involved in conferring metastatic ability on lymphoma cells. Copyright© 2016, International Institute of Anticancer Research (Dr. John G. Delinasios), All rights reserved.

Treatment of NRAS-mutated advanced or metastatic melanoma: rationale, current trials and evidence to date

PubMed Central

Boespflug, Amélie; Caramel, Julie; Dalle, Stephane; Thomas, Luc

2017-01-01

The disease course of BRAF (v-raf murine sarcoma viral oncogene homolog B1)-mutant melanoma has been drastically improved by the arrival of targeted therapies. NRAS (neuroblastoma RAS viral oncogene homolog)-mutated melanoma represents 15–25% of all metastatic melanoma patients. It currently does not have an approved targeted therapy. Metastatic patients receive immune-based therapies as first-line treatments, then cytotoxic chemotherapy like carboplatin/paclitaxel (C/P), dacarbazine (DTIC) or temozolomide (TMZ) as a second-line treatment. We will review current preclinical and clinical developments in NRAS-mutated melanoma, and analyze ongoing clinical trials that are evaluating the benefit of different targeted and immune-based therapies, either tested as single agents or in combination, in NRAS-mutant melanoma. PMID:28717400

The Clinical Activity of PD-1/PD-L1 inhibitors in Metastatic Non-Clear Cell Renal Cell Carcinoma.

PubMed

McKay, Rana R; Bossé, Dominick; Xie, Wanling; Wankowicz, Stephanie A M; Flaifel, Abdallah; Brandao, Raphael; Lalani, Aly-Khan; Martini, Dylan J; Wei, Xiao X; Braun, David A; Van Allen, Eliezer M; Castellano, Daniel; de Velasco, Guillermo; Wells, J Connor; Heng, Daniel Y C; Fay, Andre P; Schutz, Fabio A; Hsu, JoAnn; Pal, Sumanta Kumar; Lee, Jae-Lyun; Hsieh, James; Harshman, Lauren C; Signoretti, Sabina; Motzer, Robert J; Feldman, Darren R; Choueiri, Toni K

2018-05-10

Programmed death 1 (PD-1) and PD ligand 1 (PD-L1) inhibitors have shown activity in metastatic clear cell renal cell carcinoma (ccRCC). Data on the activity of these agents in patients with non-clear cell RCC (nccRCC) or patients with sarcomatoid/rhabdoid differentiation is limited. In this multicenter analysis, we explored the efficacy of PD-1/PD-L1 inhibitors in patients with nccRCC or sarcomatoid/rhabdoid differentiation. Baseline and follow-up demographic, clinical, treatment, and radiographic data were collected. The primary endpoint was objective response rate. Secondary endpoints include time-to-treatment failure (TTF), overall survival (OS), and biomarker correlates. Forty-three patients were included: papillary (n = 14; 33%), chromophobe (n = 10; 23%), unclassified (n = 9; 21%), translocation (n = 3; 7%), and ccRCC with sarcomatoid differentiation (n = 7, 16%). Of those 43 patients, 11 patients (26%) had sarcomatoid and/or rhabdoid differentiation (n = 7 with ccRCC; n = 4 nccRCC). Overall, eight patients (19%) objectively responded, including four patients (13%) who received PD-1/PD-L1 monotherapy. Responses were observed in patients with ccRCC with sarcomatoid and/or rhabdoid differentiation (n = 3/7, 43%), translocation RCC (n = 1/3, 33%), and papillary RCC (n = 4/14, 29%). The median TTF was 4.0 months (95% confidence interval (CI) 2.8, 5.5) and median OS was 12.9 months (95% CI 7.4, not reached). No specific genomic alteration was associated with clinical benefit. Modest antitumor activity for PD-1/PD-L1 blocking agents was observed in some patients with nccRCC. Further prospective studies are warranted to investigate the efficacy of PD-1/PD-L1 blockade in this heterogeneous patient population. Copyright ©2018, American Association for Cancer Research.

Identification of Metastatic Tumor Stem Cell

DTIC Science & Technology

2010-09-01

addition to a tumor stem cell , an existence of a metastatic stem cell is predicted. Despite the critical importance of the concept, this idea has not been...isolating stem cell population from a unique set of breast tumor cell lines and by examining their metastatic behavior in an animal model. The overall...will (i) isolate stem - cell population from non-metastatic and metastatic cells of a pair of syngenic breast tumor cell lines, and test their metastatic

Oncology Gold Standard™ practical consensus recommendations 2016 for treatment of advanced clear cell renal cell carcinoma.

PubMed

Batra, U; Parikh, P M; Prabhash, K; Tongaonkar, H B; Chibber, P; Dabkara, D; Deshmukh, C; Ghadyalpatil, N; Hingmire, S; Joshi, A; Raghunath, S K; Rajappa, S; Rajendranath, R; Rawal, S K; Singh, Manisha; Singh, R; Somashekhar, S P; Sood, R

2016-01-01

The Oncology Gold Standard (OGS) Expert Group on renal cell carcinoma (RCC) developed the consensus statement to provide community oncologists practical guidelines on the management of advanced clear cell (cc) RCC using published evidence, practical experience of experts in real life management, and results of a nationwide survey involving 144 health-care professionals. Six broad question categories containing 33 unique questions cover major situations in the routine management of RCC. This document serves as a ready guide for the standard of care to optimize outcome. The table of "Take Home Messages" at the end is a convenient tool for busy practitioners.

A blastema-predominant canine renal nephroblastoma with gingival metastasis: case report and literature review.

PubMed

Chen, Bo; Li, Wen-Ta; Wang, Fun-In

2018-05-01

Nephroblastomas are uncommon embryonal tumors in dogs. We report herein a blastema-predominant nephroblastoma with gingival metastasis in an 8-y-old Miniature Pinscher dog. Histologically, the mass was composed mainly of blastemal elements with minor epithelial and mesenchymal differentiation. Metastatic masses in the gingiva had histologic and immunohistochemical features similar to those of the primary renal nephroblastoma. Neoplastic cells were extensively positive for both vimentin and PAX8, and scattered positive for cytokeratin. Using the clinical staging of human Wilms tumor, we staged our case as stage IV with <4 mo of survival time. We summarized previous studies of canine renal and spinal nephroblastomas, and analyzed the correlations among clinical staging, histologic classification, and mean survival time of dogs with renal nephroblastomas. Clinical staging was significantly correlated with survival time, as shown in humans. In dogs, however, additional factors can potentially influence the outcome of treatment and disease development.

Effects of statin therapy on cerebrovascular and renal outcomes in patients with predialysis advanced chronic kidney disease and dyslipidemia.

PubMed

Chung, Chang-Min; Lin, Ming-Shyan; Hsu, Jen-Te; Hsiao, Ju-Feng; Chang, Shih-Tai; Pan, Kuo-Li; Lin, Chun-Liang; Lin, Yu-Sheng

Treatment with statin may be beneficial for patients with chronic kidney disease (CKD). However, the debate over the clinical importance of statin in patients with predialysis advanced CKD remains unresolved. The objective of the article was to evaluate the effect of statin on mortality, cerebrovascular, and renal outcomes in patients with predialysis advanced CKD and dyslipidemia. Data on predialysis advanced CKD patients were retrieved from the National Health Insurance Research Database based on the guidelines for prescribing regular erythropoietin-stimulating agent in CKD patients. Patients with dyslipidemia were further selected and divided into 2 groups by their statin use after the prescribed erythropoietin-stimulating agent. All-cause mortality and cerebrovascular and renal outcomes were analyzed after propensity score matching. There were 2016 and 14,412 patients in the statin and nonstatin groups. Their average follow-up periods were 3.7 and 3.0 years, respectively. After 1:2 propensity score matching, the annual all-cause mortality rate was higher in the nonstatin than in the statin group (143.99 vs 109.50 per 1000 person-years; P < .001; hazard ratio: 0.73; 95% confidence interval: 0.68-080). The annual risk of ischemic stroke (P = .186) and intracranial hemorrhage (P = .322) were not significantly different between the 2 groups. The nonstatin group had a higher risk of dialysis than the statin group (1269.45 vs 1095.00 per 1000 person-years; P = .002). Adverse events were not significant between the 2 groups. Statins may reduce the all-cause mortality and reduced the risk of dialysis in patients with predialysis advanced CKD and dyslipidemia. However, statins have no impact on ischemic-hemorrhage stroke. Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Systemic therapy in muscle-invasive and metastatic bladder cancer: current trends and future promises.

PubMed

Aragon-Ching, Jeanny B; Trump, Donald L

2016-09-01

Bladder urothelial cancers remain an important urologic cancer with limited treatment options in the locally advanced and metastatic setting. While neoadjuvant chemotherapy for locally advanced muscle-invasive cancers has shown overall survival benefit, clinical uptake in practice have lagged behind. Controversies surrounding adjuvant chemotherapy use are also ongoing. Systemic therapies for metastatic bladder cancer have largely used platinum-based therapies without effective standard second-line therapy options for those who fail, although vinflunine is approved in Europe as a second-line therapy based on a Phase III trial, and most recently, atezolizumab, a checkpoint inhibitor, was approved by the US FDA. Given increasing recognition of mutational signatures expressed in urothelial carcinomas, several promising agents with use of VEGF-targeted therapies, HER2-directed agents and immunotherapies with PD-1/PD-L1 antibodies in various settings are discussed herein.

CPI-006 Alone and in Combination With CPI-444 and With Pembrolizumab for Patients With Advanced Cancers

ClinicalTrials.gov

2018-03-27

Non-Small Cell Lung Cancer; Renal Cell Cancer; Colorectal Cancer; Triple Negative Breast Cancer; Cervical Cancer; Ovarian Cancer; Pancreatic Cancer; Endometrial Cancer; Sarcoma; Squamous Cell Carcinoma of the Head and Neck; Bladder Cancer; Metastatic Castration Resistant Prostate Cancer

Meridional lenticular astigmatism associated with bilateral concurrent uveal metastases in renal cell carcinoma

PubMed Central

Priluck, Joshua C; Grover, Sandeep; Chalam, KV

2012-01-01

Purpose To demonstrate a case illustrating meridional lenticular astigmatism as a result of renal cell carcinoma uveal metastases. Methods Case report with images. Results Clinical findings and diagnostic testing of a patient with acquired meridional lenticular astigmatism are described. The refraction revealed best-corrected visual acuity of 20/20–1 OD (−2.50 + 0.25 × 090) and 20/50 OS (−8.25 + 3.25 × 075). Bilateral concurrent renal cell carcinoma metastases to the choroid and ciliary body are demonstrated by utilizing ultrasonography, ultrawidefield fluorescein angiography, and unique spectral-domain optical coherence tomography. Conclusions Metastatic disease should be included in the differential of acquired astigmatism. Spectral-domain optical coherence tomography, ultrawidefield fluorescein angiography, and ultrasonography have roles in delineating choroidal metastases. PMID:23152663

Biopsy confirmation of metastatic sites in breast cancer patients: clinical impact and future perspectives

PubMed Central

2014-01-01

Determination of hormone receptor (estrogen receptor and progesterone receptor) and human epidermal growth factor receptor 2 status in the primary tumor is clinically relevant to define breast cancer subtypes, clinical outcome, and the choice of therapy. Retrospective and prospective studies suggest that there is substantial discordance in receptor status between primary and recurrent breast cancer. Despite this evidence and current recommendations, the acquisition of tissue from metastatic deposits is not routine practice. As a consequence, therapeutic decisions for treatment in the metastatic setting are based on the features of the primary tumor. Reasons for this attitude include the invasiveness of the procedure and the unreliable outcome of biopsy, in particular for biopsies of lesions at complex visceral sites. Improvements in interventional radiology techniques mean that most metastatic sites are now accessible by minimally invasive methods, including surgery. In our opinion, since biopsies are diagnostic and changes in biological features between the primary and secondary tumors can occur, the routine biopsy of metastatic disease needs to be performed. In this review, we discuss the rationale for biopsy of suspected breast cancer metastases, review issues and caveats surrounding discordance of biomarker status between primary and metastatic tumors, and provide insights for deciding when to perform biopsy of suspected metastases and which one (s) to biopsy. We also speculate on the future translational implications for biopsy of suspected metastatic lesions in the context of clinical trials and the establishment of bio-banks of biopsy material taken from metastatic sites. We believe that such bio-banks will be important for exploring mechanisms of metastasis. In the future, advances in targeted therapy will depend on the availability of metastatic tissue. PMID:25032257

Phase II trial evaluating the feasibility of interdigitating folfox with chemoradiotherapy in locally advanced and metastatic rectal cancer.

PubMed

Michael, M; Chander, S; McKendrick, J; MacKay, J R; Steel, M; Hicks, R; Heriot, A; Leong, T; Cooray, P; Jefford, M; Zalcberg, J; Bressel, M; McClure, B; Ngan, S Y

2014-11-11

Patients (pts) with metastatic rectal cancer and symptomatic primary, require local and systemic control. Chemotherapy used during chemoradiotherapy (CRT) is adequate for radiosensitisation, but suboptimal for systemic control. The aim of this phase II study was to assess tolerability, local/systemic benefits, of a novel regimen delivering interdigitating intensive chemotherapy with radical CRT. Eligible pts had untreated synchronous symptomatic primary/metastatic rectal cancer. A total of 12 weeks of treatment with split-course pelvic CRT (total 50.4 Gy with concurrent oxaliplatin and 5-FU infusion) alternating with FOLFOX chemotherapy. All pts staged with CT, MRI and FDG-PET pre and post treatment. Twenty-six pts were treated. Rectal primary MRI stage: T3 81% and T4 15%. Liver metastases in 81%. Twenty-four pts (92%) completed the 12-week regimen. All patients received planned RT dose, and for both agents over 88% of patients achieved a relative dose intensity of >75%. Grade 3 toxicities: neutropenia 23%, diarrhoea 15%, and radiation skin reaction 12%. Grade 4 toxicity: neutropenia 15%. FDG-PET metabolic response rate for rectal primary 96%, and for metastatic disease 60%. Delivery of interdigitating chemotherapy with radical CRT was feasible to treat both primary and metastatic rectal cancer. High completion and response rates were encouraging.

Actomyosin tension as a determinant of metastatic cancer mechanical tropism

NASA Astrophysics Data System (ADS)

McGrail, Daniel J.; Kieu, Quang Minh N.; Iandoli, Jason A.; Dawson, Michelle R.

2015-04-01

Despite major advances in the characterization of molecular regulators of cancer growth and metastasis, patient survival rates have largely stagnated. Recent studies have shown that mechanical cues from the extracellular matrix can drive the transition to a malignant phenotype. Moreover, it is also known that the metastatic process, which results in over 90% of cancer-related deaths, is governed by intracellular mechanical forces. To better understand these processes, we identified metastatic tumor cells originating from different locations which undergo inverse responses to altered matrix elasticity: MDA-MB-231 breast cancer cells that prefer rigid matrices and SKOV-3 ovarian cancer cells that prefer compliant matrices as characterized by parameters such as tumor cell proliferation, chemoresistance, and migration. Transcriptomic analysis revealed higher expression of genes associated with cytoskeletal tension and contractility in cells that prefer stiff environments, both when comparing MDA-MB-231 to SKOV-3 cells as well as when comparing bone-metastatic to lung-metastatic MDA-MB-231 subclones. Using small molecule inhibitors, we found that blocking the activity of these pathways mitigated rigidity-dependent behavior in both cell lines. Probing the physical forces exerted by cells on the underlying substrates revealed that though force magnitude may not directly correlate with functional outcomes, other parameters such as force polarization do correlate directly with cell motility. Finally, this biophysical analysis demonstrates that intrinsic levels of cell contractility determine the matrix rigidity for maximal cell function, possibly influencing tissue sites for metastatic cancer cell engraftment during dissemination. By increasing our understanding of the physical interactions of cancer cells with their microenvironment, these studies may help develop novel therapeutic strategies.

Comprehensive Genomic Profiling Aids in Distinguishing Metastatic Recurrence from Second Primary Cancers

PubMed Central

Weinberg, Benjamin A.; Gowen, Kyle; Lee, Thomas K.; Ou, Sai‐Hong Ignatius; Bristow, Robert; Krill, Lauren; Almira‐Suarez, M. Isabel; Ali, Siraj M.; Miller, Vincent A.; Liu, Stephen V.

2017-01-01

Abstract Background. Metastatic recurrence after treatment for locoregional cancer is a major cause of morbidity and cancer‐specific mortality. Distinguishing metastatic recurrence from the development of a second primary cancer has important prognostic and therapeutic value and represents a difficult clinical scenario. Advances beyond histopathological comparison are needed. We sought to interrogate the ability of comprehensive genomic profiling (CGP) to aid in distinguishing between these clinical scenarios. Materials and Methods. We identified three prospective cases of recurrent tumors in patients previously treated for localized cancers in which histologic analyses suggested subsequent development of a distinct second primary. Paired samples from the original primary and recurrent tumor were subjected to hybrid capture next‐generation sequencing‐based CGP to identify base pair substitutions, insertions, deletions, copy number alterations (CNA), and chromosomal rearrangements. Genomic profiles between paired samples were compared using previously established statistical clonality assessment software to gauge relatedness beyond global CGP similarities. Results. A high degree of similarity was observed among genomic profiles from morphologically distinct primary and recurrent tumors. Genomic information suggested reclassification as recurrent metastatic disease, and patients received therapy for metastatic disease based on the molecular determination. Conclusions. Our cases demonstrate an important adjunct role for CGP technologies in separating metastatic recurrence from development of a second primary cancer. Larger series are needed to confirm our observations, but comparative CGP may be considered in patients for whom distinguishing metastatic recurrence from a second primary would alter the therapeutic approach. Implications for Practice. Distinguishing a metastatic recurrence from a second primary cancer can represent a difficult clinicopathologic

Analysis of Why the Renal Dialysis Unit is Losing Money

DTIC Science & Technology

1997-06-30

urinary obstruction, severe hypertension, diabetes mellitus, gout, and polycystic kidney disease. Patients with advanced chronic renal failure develop...failure. An excess amount of potassium in the body, also termed hyperkalemia , occurs in chronic renal failure because of inadequate renal excretion...Patients with hyperkalemia can develop skeletal muscle paralysis, but the most dangerous effect of hyperkalemia is the effect it has on the heart

Emerging growth factor receptor antagonists for the treatment of renal cell carcinoma.

PubMed

Zahoor, Haris; Rini, Brian I

2016-12-01

The landscape of systemic treatment for metastatic renal cell carcinoma (RCC) has dramatically changed with the introduction of targeted agents including vascular endothelial growth factor (VEGF) inhibitors. Recently, multiple new agents including growth factor receptor antagonists and a checkpoint inhibitor were approved for the treatment of refractory metastatic RCC based on encouraging benefit shown in clinical trials. Areas covered: The background and biological rationale of existing treatment options including a brief discussion of clinical trials which led to their approval, is presented. This is followed by reviewing the limitations of these therapeutic options, medical need to develop new treatments and major goals of ongoing research. We then discuss two recently approved growth factor receptor antagonists i.e. cabozantinib and lenvatinib, and a recently approved checkpoint inhibitor, nivolumab, and issues pertaining to drug development, and future directions in treatment of metastatic RCC. Expert opinion: Recently approved growth factor receptor antagonists have shown encouraging survival benefit but associated drug toxicity is a major issue. Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, has similarly shown survival benefit and is well tolerated. With multiple options now available in this patient population, the right sequence of these agents remains to be determined.

Renal Manifestation of Birt-Hogg-Dubé Syndrome Depicted by 18F-fludeoxyglucose Positron Emission Tomography/Computed Tomography in a Patient with Hurtle Cell Thyroid Malignancy.

PubMed

Panagiotidis, Emmanouil; Seshadri, Nagabhushan; Vinjamuri, Sobhan

2018-01-01

Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant genetic disorder characterized by small papular skin lesions (fibrofolliculomas) causing susceptibility to kidney cancer, renal and pulmonary cysts, spontaneous pneumothoraces, and several noncutaneous tumors. We report a case of a 67-year-old woman, with a previous history of right hemithyroidectomy for adenomatous lesion. She presented with a swelling in the right thyroid bed that on subsequent biopsy revealed features of metastatic carcinoma. 18F-fludeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) performed for the detection of primary malignancy showed increased high-grade metabolic activity in the right supraclavicular soft tissue mass extending into the superior mediastinum. Moreover, on low-dose CT, there have been bilateral renal interpolar cortical lesions with mild metabolic activity. Given the fact that the right neck mass was highly unlikely to represent renal metastases in the absence of widespread metastatic disease, surgical excision of the right neck mass was performed. The histology of the mass was in keeping with hurtle cell thyroid carcinoma. In regard to renal lesions, bilateral partial nephrectomy was performed, which was consistent with chromophobe renal cell carcinoma, raising the suspicion of BHD that was confirmed by the subsequent genetic evaluation. It is well established that 18F-FDG PET/CT study is not an optimal modality for evaluation of renal lesions. However, careful assessment of the CT features in conjunction with the associated metabolic activity of the 18F-FDG PET component increases the diagnostic accuracy of PET/CT.

Pregnancy in women with renal disease. Yes or no?

PubMed Central

Edipidis, K

2011-01-01

Women with renal disease who conceive and continue pregnancy, are at significant risk for adverse maternal and fetal outcomes. Although advances in antenatal and neonatal care continue to improve these outcomes, the risks remain proportionate to the degree of underlying renal dysfunction. The aim of this article, is to examine the impact of varying degrees of renal insufficiency on pregnancy outcome, in women with chronic renal disease and to provide if possible, useful conclusions whether and when, a woman with Chronic Kidney Disease (CKD), should decide to get pregnant. This article, reviews briefly the normal physiological changes of renal function during pregnancy, and make an attempt to clarify the nature and severity of the risks, in the settings of chronic renal insufficiency and end stage renal disease, including dialysis patients and transplant recipients. PMID:21897751

Development of Bell's Palsy After Treatment With Ipilimumab and Nivolumab for Metastatic Melanoma: A Case Report.

PubMed

Zecchini, Julia M; Kim, Sara; Yum, Kendra; Friedlander, Philip

2018-01-01

Ipilimumab is a human monoclonal antibody that targets cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), and it is FDA approved for the treatment of unresectable or metastatic melanoma. Immune-related adverse events (irAEs) of gastrointestinal, dermatologic, and endocrine origin are commonly seen, ranging between 18% and 44%, with immune checkpoint inhibitors (anti-CTLA-4 and anti-PD-1/PD-L1). Rare irAEs include neurological, renal, and hematologic toxicities. Bell's palsy is a form of neurological toxicity that presents as an idiopathic paralysis of the muscles on one side of the face. We report a case of Bell's palsy in a 45-year-old male patient who received 1 dose of both ipilimumab and nivolumab for the treatment of metastatic melanoma. After the resolution of symptoms, ipilimumab was permanently discontinued and single-agent nivolumab administered. The patient has remained free of neurological symptoms. This case suggests that Bell's palsy is an irAE induced by ipilimumab.

Markers of systemic inflammation predict survival in patients with advanced renal cell cancer.

PubMed

Fox, P; Hudson, M; Brown, C; Lord, S; Gebski, V; De Souza, P; Lee, C K

2013-07-09

The host inflammatory response has a vital role in carcinogenesis and tumour progression. We examined the prognostic value of inflammatory markers (albumin, white-cell count and its components, and platelets) in pre-treated patients with advanced renal cell carcinoma (RCC). Using data from a randomised trial, multivariable proportional hazards models were generated to examine the impact of inflammatory markers and established prognostic factors (performance status, calcium, and haemoglobin) on overall survival (OS). We evaluated a new prognostic classification incorporating additional information from inflammatory markers. Of the 416 patients, 362 were included in the analysis. Elevated neutrophil counts, elevated platelet counts, and a high neutrophil-lymphocyte ratio were significant independent predictors for shorter OS in a model with established prognostic factors. The addition of inflammatory markers improves the discriminatory value of the prognostic classification as compared with established factors alone (C-statistic 0.673 vs 0.654, P=0.002 for the difference), with 25.8% (P=0.004) of patients more appropriately classified using the new classification. Markers of systemic inflammation contribute significantly to prognostic classification in addition to established factors for pre-treated patients with advanced RCC. Upon validation of these data in independent studies, stratification of patients using these markers in future clinical trials is recommended.

Pharmacokinetic drug evaluation of atezolizumab for the treatment of locally advanced or metastatic urothelial carcinoma.

PubMed

Patel, Rutveej; Bock, Megan; Polotti, Charles F; Elsamra, Sammy

2017-02-01

Muscle invasive bladder cancer (MIBC) is difficult to manage for patients who progress during or after initial chemotherapy regimens. Current regimens offer low response rates with high toxicities. The advent of immune checkpoint inhibitors may represent a new opportunity for effective management of these patients. Areas covered: Atezolizumab is an engineered humanized monoclonal immunoglobulin G1 antibody that binds selectively to PD-L1 and prevents its interaction with PD-1 and B7-1. It is administered intravenously and is given every 3 weeks as long as there is no evidence of tumor progression. Phase I trials confirmed antitumor activity of atezolizumab in patients with advanced or metastatic urothelial carcinoma. Phase II trials showed an improved response rate and a longer durable response than current conventional therapy. Phase III trials are currently underway with an estimated accrual end date of 2017. Expert opinion: MIBC is a high-risk disease, and after progression on current chemotherapy regimens, second-line treatments leave much to be desired. Emerging evidence of efficacy and safety and a recent accelerated approval by the FDA presents atezolizumab as a promising treatment option. Current clinical challenges include the details of disease progression and determining where immune checkpoint inhibition will reside in the treatment algorithm.

Oncology Nursing Support for Safe and Effective Use of Eribulin in Metastatic Breast Cancer

PubMed Central

Donovan, Diana; Urquhart, Laura; Hopkins, Una; Knight, Sandra; Moore, Laura

2014-01-01

Nurse practitioners play important roles in breast cancer prevention, early detection, therapeutic efficacy, and surveillance. Assessment of a patient’s health status is part of the nine nurse practitioner core competencies updated in 2012 by the National Organization of Nurse Practitioner Faculties. Although adverse events are common in treatment for metastatic breast cancer (MBC), proactive management strategies can limit the number and/or severity of adverse events. Additionally, knowledge of common metastatic sites and clinical signs/symptoms of recurrence provides one of the first-line strategies for successful treatment. We review five case studies of women with MBC who were managed successfully with eribulin mesylate in late lines of therapy after at least two chemotherapeutic regimens for advanced breast cancer that included both an anthracycline and a taxane in either the adjuvant or metastatic setting. PMID:24855406

Phase III Open-Label Randomized Study of Eribulin Mesylate Versus Capecitabine in Patients With Locally Advanced or Metastatic Breast Cancer Previously Treated With an Anthracycline and a Taxane

PubMed Central

Kaufman, Peter A.; Awada, Ahmad; Twelves, Chris; Yelle, Louise; Perez, Edith A.; Velikova, Galina; Olivo, Martin S.; He, Yi; Dutcus, Corina E.; Cortes, Javier

2015-01-01

Purpose This phase III randomized trial (ClinicalTrials.gov identifier: NCT00337103) compared eribulin with capecitabine in patients with locally advanced or metastatic breast cancer (MBC). Patients and Methods Women with MBC who had received prior anthracycline- and taxane-based therapy were randomly assigned to receive eribulin or capecitabine as their first-, second-, or third-line chemotherapy for advanced/metastatic disease. Stratification factors were human epidermal growth factor receptor-2 (HER2) status and geographic region. Coprimary end points were overall survival (OS) and progression-free survival (PFS). Results Median OS times for eribulin (n = 554) and capecitabine (n = 548) were 15.9 and 14.5 months, respectively (hazard ratio [HR], 0.88; 95% CI, 0.77 to 1.00; P = .056). Median PFS times for eribulin and capecitabine were 4.1 and 4.2 months, respectively (HR, 1.08; 95% CI, 0.93 to 1.25; P = .30). Objective response rates were 11.0% for eribulin and 11.5% for capecitabine. Global health status and overall quality-of-life scores over time were similar in the treatment arms. Both treatments had manageable safety profiles consistent with their known adverse effects; most adverse events were grade 1 or 2. Conclusion In this phase III study, eribulin was not shown to be superior to capecitabine with regard to OS or PFS. PMID:25605862

Metastatic melanoma - a review of current and future drugs.

PubMed

Velho, Tiago Rodrigues

2012-11-19

Melanoma is one of the most aggressive cancers, and it is estimated that 76,250 men and women will be diagnosed with melanoma of the skin in the USA in 2012. Over the last few decades many drugs have been developed but only in 2011 have new drugs demonstrated an impact on survival in metastatic melanoma. A systematic search of literature was conducted, and studies providing data on the effectiveness of current and/or future drugs used in the treatment of metastatic melanoma were selected for review. This review discusses the advantages and limitations of these agents, evaluating past, current and future clinical trials designed to overcome such limitations. To date, there are four drugs approved by the Food and Drug Administration for melanoma (dacarbazine, interleukin-2, ipilimumab and vemurafenib). Despite efforts to develop new drugs, few of them have demonstrated any clinical benefits. Approved in 1975, dacarbazine remains the gold standard in chemotherapy, although ipilimumab and vemurafenib have raised many hopes in the last few years. Combining dacarbazine or other chemotherapy agents with new pharmacological agents may be a new way to achieve better clinical responses in patients with metastatic melanoma. Advances in the molecular knowledge of melanoma have led to major improvements in the treatment of patients with metastatic melanoma, providing new targets and insights. However, heterogeneity amongst study populations, different approaches to treatment and the different melanoma types and localisations included in the trials makes their comparison difficult. New studies focusing on drugs developed in recent decades are warranted.

[Case report of rare co-occurrence of renal cell carcinoma and crossed renal dystopia (L-shaped kidney)].

PubMed

Bakov, V N; Los, M S

2017-10-01

L-shaped kidney refers to a rare anomaly of the relative kidney positioning. Due to low prevalence, the literature on the co-occurrence of this anomaly with malignancy is lacking. And, if the diagnosis of a renal anomaly does not present difficulties, if a tumor is detected in such a kidney, even MSCT does not always help differentiate a pelvic tumor from a tumor of the renal parenchyma spreading to the pelvicalyceal system. This has important implications for choosing an appropriate surgical strategy. A feature of the presented clinical observation is the co-occurrence of the rare anomaly of kidney position and locally advanced renal cell carcinoma spreading to the renal pelvis. Due to the massive spread of the tumor, an organ-sparing surgery was not feasible. Due to the suspicion of tumor spread to the renal pelvis, the patient underwent nephrureterectomy of the L-shaped kidney. Introduction to renoprival state with transfer to chronic hemodialysis became the only option to maintain homeostasis and extend the patients life. Histological examination revealed clear cell renal cell carcinoma with invasion of the pelvis and renal capsule, with no clear demarcation between the fused kidneys.

Management of metastatic colorectal cancer patients: guidelines of the Italian Medical Oncology Association (AIOM)

PubMed Central

Salvatore, Lisa; Aprile, Giuseppe; Arnoldi, Ermenegildo; Aschele, Carlo; Carnaghi, Carlo; Cosimelli, Maurizio; Maiello, Evaristo; Normanno, Nicola; Sciallero, Stefania; Valvo, Francesca; Beretta, Giordano D

2017-01-01

In the past 15 years, the outcome for patients with metastatic colorectal cancer has substantially improved owing to the availability of new cytotoxic and biological agents along with many significant advances in molecular selection, the use of personalised therapy and locoregional treatment, a more widespread sharing of specific professional experiences (multidisciplinary teams with oncologists, surgeons, radiotherapists, radiologists, biologists and pathologists), and the adoption of patient-centred healthcare strategies. The Italian Medical Oncology Association (AIOM) has developed evidence-based recommendations to help oncologists and all professionals involved in the management of patients with metastatic colorectal cancer in their daily clinical practice. PMID:28761730

Management of metastatic colorectal cancer patients: guidelines of the Italian Medical Oncology Association (AIOM).

PubMed

Salvatore, Lisa; Aprile, Giuseppe; Arnoldi, Ermenegildo; Aschele, Carlo; Carnaghi, Carlo; Cosimelli, Maurizio; Maiello, Evaristo; Normanno, Nicola; Sciallero, Stefania; Valvo, Francesca; Beretta, Giordano D

2017-01-01

In the past 15 years, the outcome for patients with metastatic colorectal cancer has substantially improved owing to the availability of new cytotoxic and biological agents along with many significant advances in molecular selection, the use of personalised therapy and locoregional treatment, a more widespread sharing of specific professional experiences (multidisciplinary teams with oncologists, surgeons, radiotherapists, radiologists, biologists and pathologists), and the adoption of patient-centred healthcare strategies. The Italian Medical Oncology Association (AIOM) has developed evidence-based recommendations to help oncologists and all professionals involved in the management of patients with metastatic colorectal cancer in their daily clinical practice.

Avelumab for the treatment of metastatic Merkel cell carcinoma.

PubMed

Cordes, L M; Gulley, J L

2017-07-01

Avelumab is a promising new therapeutic agent for patients with metastatic Merkel cell carcinoma, a rare and aggressive type of neuroendocrine tumor of the skin. Until the recent approval of avelumab (Bavencio), no therapies were approved by the U.S. Food and Drug Administration for the treatment of metastatic Merkel cell carcinoma. In a recent trial, avelumab, an anti-programmed death ligand-1 antibody, demonstrated an objective response in 28 of 88 patients (31.8% [95.9% CI, 21.9-43.1]) with advanced, chemotherapy-refractory Merkel cell carcinoma. Overall, avelumab was well tolerated at a dose of 10 mg/kg administered intravenously every 2 weeks. Serious treatment-related adverse events were reported in 5 patients (6%), but no grade 4 adverse events or treatment-related deaths were reported. Preliminary data evaluating avelumab in chemotherapy-naive patients is also encouraging. Copyright 2017 Clarivate Analytics.

Atezolizumab as first-line therapy in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial

PubMed Central

Balar, Arjun V; Galsky, Matthew D; Rosenberg, Jonathan E; Powles, Thomas; Petrylak, Daniel P; Bellmunt, Joaquim; Loriot, Yohann; Necchi, Andrea; Hoffman-Censits, Jean; Perez-Gracia, Jose Luis; Dawson, Nancy A; van der Heijden, Michiel S; Dreicer, Robert; Srinivas, Sandy; Retz, Margitta M; Joseph, Richard W; Drakaki, Alexandra; Vaishampayan, Ulka N; Sridhar, Srikala S; Quinn, David I; Durán, Ignacio; Shaffer, David R; Eigl, Bernhard J; Grivas, Petros D; Yu, Evan Y; Li, Shi; Kadel, Edward E; Boyd, Zachary; Bourgon, Richard; Hegde, Priti S; Mariathasan, Sanjeev; Thåström, AnnChristine; Abidoye, Oyewale O; Fine, Gregg D; Bajorin, Dean F

2017-01-01

Summary Background First-line chemotherapy for patients with cisplatin-ineligible locally-advanced or metastatic urothelial carcinoma (mUC) is associated with short response duration, poor survival, and high toxicity. This multicenter, 2-cohort phase 2 study evaluated atezolizumab (anti–programmed death-ligand 1 [PD-L1]) as treatment for mUC in this setting, as well as in later lines. Methods In a cohort of previously untreated patients who were cisplatin ineligible, atezolizumab was given 1200 mg every 3 weeks until progression. The primary endpoint was independently confirmed objective response rate per Response Evaluation Criteria In Solid Tumors v1.1 (central review), evaluated in pre-specified subgroups based on PD-L1 expression and in all patients. Secondary endpoints included response duration, progression-free survival, overall survival, and safety. Exploratory analyses included biomarker correlates of response and survival. This study is registered with ClinicalTrials.gov, number NCT02108652. Findings Of 119 patients who received atezolizumab in the first-line setting, 83 (70%) had baseline renal impairment, and 24 (20%) had Eastern Cooperative Oncology Group performance status 2. At 17·2 months’ median follow-up, the objective response rate was 23% (95% CI 16–31), the complete response rate was 9%, and 19 of 27 responses were ongoing. Median response duration was not reached. Responses occurred across all PD-L1 and poor prognostic factor subgroups. Median progression-free survival was 2·7 months. Median overall survival was 15·9 months. Tumour mutation load was associated with response. Treatment-related adverse events ≥10% were fatigue, diarrhoea, and pruritus. One treatment-related death (sepsis) occurred. Nine patients (8%) had an adverse event leading to treatment discontinuation. Immune-mediated events occurred in 14 (12%) patients. Interpretation Atezolizumab demonstrated encouraging durable response rates, survival, and tolerability

Oncology Gold Standard™ practical consensus recommendations 2016 for treatment of advanced clear cell renal cell carcinoma

PubMed Central

Batra, U; Parikh, PM; Prabhash, K; Tongaonkar, HB; Chibber, P; Dabkara, D; Deshmukh, C; Ghadyalpatil, N; Hingmire, S; Joshi, A; Raghunath, SK; Rajappa, S; Rajendranath, R; Rawal, SK; Singh, Manisha; Singh, R; Somashekhar, SP; Sood, R

2016-01-01

The Oncology Gold Standard (OGS) Expert Group on renal cell carcinoma (RCC) developed the consensus statement to provide community oncologists practical guidelines on the management of advanced clear cell (cc) RCC using published evidence, practical experience of experts in real life management, and results of a nationwide survey involving 144 health-care professionals. Six broad question categories containing 33 unique questions cover major situations in the routine management of RCC. This document serves as a ready guide for the standard of care to optimize outcome. The table of “Take Home Messages” at the end is a convenient tool for busy practitioners. PMID:28032079

Adriamycin and cis-platinum as first-line treatment in unresectable locally advanced or metastatic adult soft-tissue sarcomas.

PubMed

Kalofonos, Haralabos P; Bafaloukos, Dimitrios; Kourelis, Theodoros G; Karamouzis, Michalis V; Megas, Panagiotis; Iconomou, Grigorios; Tsiata, Ekaterini; Dimitropoulos, Dimitrios; Kosmidis, Paris; Lampiris, E

2004-06-01

Standard chemotherapy in advanced adult soft-tissue sarcomas (STS) has not yet been established. We evaluated the efficacy and toxicity of the combination of adriamycin (ADR) and cis-platinum (CDDP) as first-line treatment in nonoperable locally advanced or metastatic adult STS. Thirty patients were treated with CDDP 100 mg/m2 on day 1 and ADR 75 mg/m2 equally divided on days 1 to 3, every 3 weeks for 6 cycles. Patients were evaluated for response, toxicity, and survival, while resectability of residual disease was also assessed after the third cycle and the end of chemotherapy. No complete response was observed. Five patients (16.7%, 95% CI: 2.5%-31%) achieved partial response, 16 patients (53.3%, 95% CI: 34%-72%) had stable disease and 9 patients (30%, 95% CI: 13%-47%) had progressive disease. The overall median survival was 11.5 months (range, 4-96 months), and the median time to disease progression was 6 months (range, 0-96 months). Furthermore, two patients with PR and six patients with stable disease underwent further surgery followed by radiotherapy in four of them. At present, 5 patients remain free of relapse for 96, 90, 72, 60, and 48 months, respectively. Treatment-related toxicity was acceptable, with moderate myelosuppression and alopecia as the main adverse events. The ADR/CDDP regimen was well tolerated, but it did not achieve a high response rate. However, patients with resectable disease after chemotherapy achieved long-term survival. Further studies are needed to evaluate the role of combined-modality treatments in the management of patients with advanced STS.

Theranostics Targeting Metastatic Breast Cancer

DTIC Science & Technology

2017-10-01

AWARD NUMBER: W81XWH-15-1-0389 TITLE: Theranostics Targeting Metastatic Breast Cancer PRINCIPAL INVESTIGATOR: Kevin Burgess CONTRACTING...ADDRESS. 1. REPORT DATE October 2017 2. REPORT TYPE Annual 3. DATES COVERED 4. TITLE AND SUBTITLE Theranostics Targeting Metastatic Breast Cancer 5a...safe and effective interventions; (ii) elimination of mortality associated with metastatic breast cancer ; and, (iii) distinguishing aggressive breast

Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America.

PubMed

Stadler, Walter M; Figlin, Robert A; McDermott, David F; Dutcher, Janice P; Knox, Jennifer J; Miller, Wilson H; Hainsworth, John D; Henderson, Charles A; George, Jeffrey R; Hajdenberg, Julio; Kindwall-Keller, Tamila L; Ernstoff, Marc S; Drabkin, Harry A; Curti, Brendan D; Chu, Luis; Ryan, Christopher W; Hotte, Sebastien J; Xia, Chenghua; Cupit, Lisa; Bukowski, Ronald M

2010-03-01

The Advanced Renal Cell Carcinoma Sorafenib (ARCCS) program made sorafenib available to patients with advanced renal cell carcinoma (RCC) before regulatory approval. In this nonrandomized, open-label expanded access program, 2504 patients from the United States and Canada were treated with oral sorafenib 400 mg twice daily. Safety and efficacy were explored overall and in subgroups of patients including those with no prior therapy, nonclear cell (nonclear cell) RCC, brain metastases, prior bevacizumab treatment, and elderly patients. Sorafenib was approved for RCC 6 months after study initiation, at which time patients with no prior therapy or with nonclear cell RCC could enroll in an extension protocol for continued assessment for a period of 6 months. The most common grade > or =2 drug-related adverse events were hand-foot skin reaction (18%), rash (14%), hypertension (12%), and fatigue (11%). In the 1891 patients evaluable for response, complete response was observed in 1 patient, partial response in 67 patients (4%), and stable disease for at least 8 weeks in 1511 patients (80%). Median progression-free survival in the extension population was 36 weeks (95% confidence interval [CI], 33-45 weeks; censorship rate, 56%); median overall survival in the entire population was 50 weeks (95% CI, 46-52 weeks; censorship rate, 63%). The efficacy and safety results were similar across the subgroups. Sorafenib 400 mg twice daily demonstrated activity and a clinically acceptable toxicity profile in all patient subsets enrolled in the ARCCS expanded access program (clinicaltrials.gov identifier: NCT00111020).

Current management of advanced and castration resistant prostate cancer.

PubMed

Gomella, Leonard G; Petrylak, Daniel P; Shayegan, Bobby

2014-04-01

Newer approaches to the management of advanced prostate cancer have rapidly evolved. While basic androgen deprivation remains as the first line in newly diagnosed hormone naïve metastatic prostate cancer, the agents used and strategies followed have undergone significant changes. Numerous new agents such as sipuleucel-T, abiraterone, enzalutamide, cabazitaxel and radium 223 have all been approved since 2010 to treat metastatic castration resistant prostate cancer (CRPC). New imaging techniques to detect advanced disease such as F-18 PET, 11 C-choline PET and other modalities are becoming available. The concepts of "bone health" and the management of side effects related to androgen deprivation therapy are also gaining attention as men are being treated with longer courses of androgen deprivation. Understanding the theory behind these new agents and management approaches while focusing on the practical clinical considerations are essential to improve outcomes in advanced prostate cancer. A review of the current state of the art in the management of advanced and castration resistant prostate cancer presented in this Canadian Journal of Urology International supplement was performed. Key findings are summarized and presented along with critical updates based on recent publications and meeting presentations. Key concepts identified in the management of advanced prostate cancer included the new understanding of prostate cancer based on translational discoveries, applications of various hormonally based strategies in advanced disease including traditional and recently approved agents. The use of new imaging modalities to identify metastatic disease, immunotherapy approaches and discussions of sequencing and which new agents are likely to be available in the future in the management of CRPC were identified. Bone targeted strategies are also addressed in the setting of androgen deprivation and metastatic disease. The management of men with advanced prostate cancer has

The Effect of Patient and Surgical Characteristics on Renal Function After Partial Nephrectomy.

PubMed

Winer, Andrew G; Zabor, Emily C; Vacchio, Michael J; Hakimi, A Ari; Russo, Paul; Coleman, Jonathan A; Jaimes, Edgar A

2018-06-01

The purpose of the study was to identify patient and disease characteristics that have an adverse effect on renal function after partial nephrectomy. We conducted a retrospective review of 387 patients who underwent partial nephrectomy for renal tumors between 2006 and 2014. A line plot with a locally weighted scatterplot smoothing was generated to visually assess renal function over time. Univariable and multivariable longitudinal regression analyses incorporated a random intercept and slope to evaluate the association between patient and disease characteristics with renal function after surgery. Median age was 60 years and most patients were male (255 patients [65.9%]) and white (343 patients [88.6%]). In univariable analysis, advanced age at surgery, larger tumor size, male sex, longer ischemia time, history of smoking, and hypertension were significantly associated with lower preoperative estimated glomerular filtration rate (eGFR). In multivariable analysis, independent predictors of reduced renal function after surgery included advanced age, lower preoperative eGFR, and longer ischemia time. Length of time from surgery was strongly associated with improvement in renal function among all patients. Independent predictors of postoperative decline in renal function include advanced age, lower preoperative eGFR, and longer ischemia time. A substantial number of subjects had recovery in renal function over time after surgery, which continued past the 12-month mark. These findings suggest that patients who undergo partial nephrectomy can experience long-term improvement in renal function. This improvement is most pronounced among younger patients with higher preoperative eGFR. Copyright © 2017 Elsevier Inc. All rights reserved.

Advanced Glycation End-Products Induce Connective Tissue Growth Factor-Mediated Renal Fibrosis Predominantly through Transforming Growth Factor β-Independent Pathway

PubMed Central

Zhou, Guihua; Li, Cai; Cai, Lu

2004-01-01

Advanced glycation end-products (AGEs) play a critical role in diabetic nephropathy by stimulating extracellular matrix (ECM) synthesis. Connective tissue growth factor (CTGF) is a potent inducer of ECM synthesis and increases in the diabetic kidneys. To determine the critical role of CTGF in AGE-induced ECM accumulation leading to diabetic nephropathy, rats were given AGEs by intravenous injection for 6 weeks. AGE treatment induced a significant renal ECM accumulation, as shown by increases in periodic acid-Schiff-positive materials, fibronectin, and type IV collagen (Col IV) accumulation in glomeruli, and a mild renal dysfunction, as shown by increases in urinary volume and protein content. AGE treatment also caused significant increases in renal CTGF and transforming growth factor (TGF)-β1 mRNA and protein expression. Direct exposure of rat mesangial cells to AGEs in vitro significantly induced increases in fibronectin and Col IV production, which could be completely prevented by pretreatment with anti-CTGF antibody. AGE treatment also significantly increased both TGF-β1 and CTGF mRNA expression; however, inhibition of TGF-β1 mRNA expression by shRNA or neutralization of TGF-β1 protein by anti-TGF-β1 antibody did not significantly prevent AGE-increased expression of CTGF mRNA and protein. These results suggest that AGE-induced CTGF expression, predominantly through a TGF-β1-independent pathway, plays a critical role in renal ECM accumulation leading to diabetic nephropathy. PMID:15579446

Treatment of caval vein thrombosis associated with renal tumors.

PubMed

Jiménez-Romero, Carlos; Conde, María; de la Rosa, Federico; Manrique, Alejandro; Calvo, Jorge; Caso, Óscar; Muñoz, Carlos; Marcacuzco, Alberto; Justo, Iago

2017-03-01

Renal carcinoma represents 3% of all solid tumors and is associated with renal or inferior caval vein (IVC) thrombosis between 2-10% of patients, extending to right atrial in 1% of cases. This is a retrospective study that comprises 5 patients who underwent nephrectomy and thrombectomy by laparotomy because of renal tumor with IVC thrombosis level iii. Four patients were males and one was female, and the mean age was 57,2 years (range: 32-72). Most important clinical findings were hematuria, weight loss, weakness, anorexia, and pulmonary embolism. Diagnostic confirmation was performed by CT scanner. Metastatic disease was diagnosed before surgery in 3 patients. Suprahepatic caval vein and hepatic hilium (Pringle's maneouver) were clamped in 4 patients, and ligation of infrarrenal caval vein was carry out in one patient. Five patients developed mild complications (Clavien I/II). No patient died and the mean hospital stay was 8,6 days. All patients were treated with chemotherapy, and 3 died because distant metastasis, but 2 are alive, without recurrence, at 5 and 60 months, respectively. Nephrectomy and thrombectomy in renal tumors with caval thrombosis can be curative in absence of metastasis or, at less, can increase survival or quality of live. Then these patients must be treated in liver transplant units because major surgical and anesthesiologic expertise. Adjuvant treatment with tyrosin kinase inhibitors must be validate in the future with wider experiences. Copyright © 2017 AEC. Publicado por Elsevier España, S.L.U. All rights reserved.

Stereotactic radiation therapy in the strategy of treatment of metastatic renal cell carcinoma: A study of the Getug group.

PubMed

Meyer, Emmanuel; Pasquier, David; Bernadou, Guillemette; Calais, Gilles; Maroun, Pierre; Bossi, Alberto; Theodore, Christine; Albiges, Laurence; Stefan, Dinu; Crevoisier, Renaud D E; Hennequin, Christophe; Lagrange, Jean-Léon; Grellard, Jean-Michel; Clarisse, Bénédicte; Licaj, Idlir; Habrand, Jean-Louis; Carrie, Christian; Joly, Florence

2018-06-01

Renal cell carcinoma (RCC) is usually considered radioresistant, but stereotactic radiation therapy (SRT) may increase local disease control. This study aimed to assess the benefit of SRT in the management of metastatic RCC patients. Data of all RCC patients who received SRT between 2008 and 2015 with curative intent were retrospectively collected in six French referral centres. Local control (LC), progression-free survival (PFS), local recurrence-free survival (LRFS), time to systemic therapy (TTS) and overall survival (OS) were assessed. One hundred and eighty-eight patients treated with SRT for 252 RCC metastases (brain [n = 120]; spine [n = 75]; and others [n = 57]) were recensed. SRT was performed for oligoprogressive disease (101 patients), oligometastatic disease (80 patients) or residual tumour after a partial response to systemic treatment (7 patients). The median biologically effective dose was 78 Gy. For the whole population, local control rates at 6, 12 and 24 months were 87.5%, 82.9% and 77.6%, respectively; median PFS, LRFS, TTS and OS were 8.5, 23.2, 13.2 and 29.2 months, respectively. Among patients treated for oligoprogressive/oligometastatic disease, the median PFS, TTS, and OS were 8.6/7.6, 10.5/14.2 and 23.2/33.9 months, respectively. Among the 7 patients treated with SRT after partial response to systemic treatment, no relapse occurred for 3 of them after a median follow-up of 22 months. Acute and late severe toxicities were noted in 5 (2.6%) patients. SRT is effective and safe for oligometastatic and oligoprogressive RCC patients and may delay introduction or change of systemic therapy. Copyright © 2018 Elsevier Ltd. All rights reserved.

Percutaneous cryoablation of metastatic renal cell carcinoma for local tumor control: feasibility, outcomes, and estimated cost-effectiveness for palliation.

PubMed

Bang, Hyun J; Littrup, Peter J; Goodrich, Dylan J; Currier, Brandt P; Aoun, Hussein D; Heilbrun, Lance K; Vaishampayan, Ulka; Adam, Barbara; Goodman, Allen C

2012-06-01

To assess complications, local tumor recurrences, overall survival (OS), and estimates of cost-effectiveness for multisite cryoablation (MCA) of oligometastatic renal cell carcinoma (RCC). A total of 60 computed tomography- and/or ultrasound-guided percutaneous MCA procedures were performed on 72 tumors in 27 patients (three women and 24 men). Average patient age was 63 years. Tumor location was grouped according to common metastatic sites. Established surgical selection criteria graded patient status. Median OS was determined by Kaplan-Meier method and defined life-years gained (LYGs). Estimates of MCA costs per LYG were compared with established values for systemic therapies. Total number of tumors and cryoablation procedures for each anatomic site are as follows: nephrectomy bed, 11 and 11; adrenal gland, nine and eight; paraaortic, seven and six; lung, 14 and 13; bone, 13 and 13; superficial, 12 and nine; intraperitoneal, five and three; and liver, one and one. A mean of 2.2 procedures per patient were performed, with a median clinical follow-up of 16 months. Major complication and local recurrence rates were 2% (one of 60) and 3% (two of 72), respectively. No patients were graded as having good surgical risk, but median OS was 2.69 years, with an estimated 5-year survival rate of 27%. Cryoablation remained cost-effective with or without the presence of systemic therapies according to historical cost comparisons, with an adjunctive cost-effectiveness ratio of $28,312-$59,554 per LYG. MCA was associated with very low morbidity and local tumor recurrence rates for all anatomic sites, with apparent increased OS. Even as an adjunct to systemic therapies, MCA appeared cost-effective for palliation of oligometastatic RCC. Copyright © 2012 SIR. Published by Elsevier Inc. All rights reserved.

HLA class I expression predicts prognosis and therapeutic benefits from tyrosine kinase inhibitors in metastatic renal-cell carcinoma patients.

PubMed

Wang, Jiajun; Liu, Li; Qu, Yang; Xi, Wei; Xia, Yu; Bai, Qi; Xiong, Ying; Long, Qilai; Xu, Jiejie; Guo, Jianming

2018-01-01

Classical HLA class I antigen is highly involved in antigen presentation and adaptive immune response against tumor. In this study, we explored its predictive value for treatment response and survival in metastatic renal-cell carcinoma (mRCC) patients. A TKI cohort of 111 mRCC patients treated with sunitinib or sorafenib and a non-TKI cohort of 160 mRCC patients treated with interleukin-2 or interferon-α-based immunotherapy at a single institution were retrospectively enrolled. HLA class I expression and cytotoxic T lymphocyte (CTL) density was assessed by immunohistochemistry on tissue microarrays. Association between HLA class I and CTL was also assessed in the TCGA KIRC cohort. In the TKI cohort, down-regulated HLA class I was associated with lower objective response rate of TKI therapy (P = 0.004), shorter overall survival (OS) (P = 0.001), and shorter progression free survival (PFS) (P < 0.001). Multivariate Cox regression model defined HLA expression as an independent prognostic factor for both OS [hazard ratio 1.687 (95% CI 1.045-2.724), P = 0.032] and PFS [hazard ratio 2.139 (95% CI 1.376-3.326), P = 0.001]. In the non-TKI cohort, HLA class I was not significantly associated with survival. HLA class I expression was associated with CTL infiltration and function, and its prognostic value was more predominant in CTL high-density tumors (P < 0.001) rather than CTL low-density tumors (P = 0.294). Classical HLA class I expression can serve as a potential predictive biomarker for TKI therapy in mRCC patients. Its predictive value was restricted in CTL high-density tumors. However, further external validations and functional investigations are still required.

Health economic changes as a result of implementation of targeted therapy for metastatic renal cell carcinoma: national results from DARENCA study 2.

PubMed

Soerensen, Anne V; Donskov, Frede; Kjellberg, Jakob; Ibsen, Rikke; Hermann, Gregers G; Jensen, Niels V; Fode, Kirsten; Geertsen, Poul F

2015-09-01

Limited data exist on the economic consequences of implementing targeted therapy (TT) for metastatic renal cell carcinoma (RCC) in a real-world setting. To analyze health care and productivity costs for TT implementation in a national cohort of patients. Costs were measured per patient per year during a 2-yr follow-up during 2002-2005 (immunotherapy only) and 2006-2009 (TT implementation). All Danish patients with a diagnosis code for RCC and a procedure code for TT or immunotherapy were linked to the Danish National Patient Registry (contains information on all contacts with primary and secondary health sector). Health care and productivity costs were retrieved from the Danish case-mix system and Coherent Social Statistics, respectively. Drug costs were calculated separately from procedure codes and retail prices. Generalized linear models were used to analyze costs adjusted for age, gender, and civil status. A total of 439 patients were included for 2006-2009 and 192 for 2002-2005. Comparison of the health care cost per patient per year between 2006-2009 and 2002-2005 revealed lower inpatient costs (€11 899 vs €19 944, adjusted relative risk [RR] 0.64), higher outpatient costs (€14 308 vs €6209, RR 2.39), lower radiotherapy costs (€194 vs €633, RR 0.31), higher radiology costs (€676 vs €191, RR 3.73), and higher separately calculated drug costs (€12 040 vs €3103, RR 3.82, all p<0.001) for the former. Total health care costs per patient per year did not significantly differ (€27 676 vs €27 856, RR 1.05, p=0.5) between the two periods. Income from employment did not significantly differ between 2006-2009 and 2002-2005 (RR 1.11, p=0.11) and costs associated with loss of productivity were €7852 and €8265, respectively. A different pattern of health care costs were observed but total health care costs per patient per year did not significantly differ after implementation of TT for patients with mRCC. In this nationwide study, we found

SIAH and EGFR, Two RAS Pathway Biomarkers, are Highly Prognostic in Locally Advanced and Metastatic Breast Cancer.

PubMed

van Reesema, Lauren L Siewertsz; Zheleva, Vasilena; Winston, Janet S; Jansen, Rick J; O'Connor, Carolyn F; Isbell, Andrew J; Bian, Minglei; Qin, Rui; Bassett, Patricia T; Hinson, Virginia J; Dorsch, Kimberly A; Kirby, Brad W; Van Sciver, Robert E; Tang-Tan, Angela M; Harden, Elizabeth A; Chang, David Z; Allen, Cynthia A; Perry, Roger R; Hoefer, Richard A; Tang, Amy H

2016-09-01

Metastatic breast cancer exhibits diverse and rapidly evolving intra- and inter-tumor heterogeneity. Patients with similar clinical presentations often display distinct tumor responses to standard of care (SOC) therapies. Genome landscape studies indicate that EGFR/HER2/RAS "pathway" activation is highly prevalent in malignant breast cancers. The identification of therapy-responsive and prognostic biomarkers is paramount important to stratify patients and guide therapies in clinical oncology and personalized medicine. In this study, we analyzed matched pairs of tumor specimens collected from 182 patients who received neoadjuvant systemic therapies (NST). Statistical analyses were conducted to determine whether EGFR/HER2/RAS pathway biomarkers and clinicopathological predictors, alone and in combination, are prognostic in breast cancer. SIAH and EGFR outperform ER, PR, HER2 and Ki67 as two logical, sensitive and prognostic biomarkers in metastatic breast cancer. We found that increased SIAH and EGFR expression correlated with advanced pathological stage and aggressive molecular subtypes. Both SIAH expression post-NST and NST-induced changes in EGFR expression in invasive mammary tumors are associated with tumor regression and increased survival, whereas ER, PR, and HER2 were not. These results suggest that SIAH and EGFR are two prognostic biomarkers in breast cancer with lymph node metastases. The discovery of incorporating tumor heterogeneity-independent and growth-sensitive RAS pathway biomarkers, SIAH and EGFR, whose altered expression can be used to estimate therapeutic efficacy, detect emergence of resistant clones, forecast tumor regression, differentiate among partial responders, and predict patient survival in the neoadjuvant setting, has a clear clinical implication in personalizing breast cancer therapy. This work was supported by the Dorothy G. Hoefer Foundation for Breast Cancer Research (A.H. Tang); Center for Innovative Technology (CIT

Renal Outcomes and Dietary Potassium: The Overshadowed Electrolyte?

PubMed Central

Jablonski, Kristen L.; Kendrick, Jessica

2014-01-01

Smyth et al. examined the association between urinary sodium and potassium excretion and adverse renal outcomes in adults at high cardiovascular risk. They found no association between urinary sodium excretion and adverse renal outcomes, but a reduced odds of adverse renal outcomes with higher urinary potassium excretion. This finding is quite interesting and a major advancement from this study. It will be important to ascertain whether this finding holds true in individuals free from vascular disease and diabetes, as well as in patients with chronic kidney disease. PMID:25427082

Whole-Exome Sequencing of Metastatic Cancer and Biomarkers of Treatment Response.

PubMed

Beltran, Himisha; Eng, Kenneth; Mosquera, Juan Miguel; Sigaras, Alexandros; Romanel, Alessandro; Rennert, Hanna; Kossai, Myriam; Pauli, Chantal; Faltas, Bishoy; Fontugne, Jacqueline; Park, Kyung; Banfelder, Jason; Prandi, Davide; Madhukar, Neel; Zhang, Tuo; Padilla, Jessica; Greco, Noah; McNary, Terra J; Herrscher, Erick; Wilkes, David; MacDonald, Theresa Y; Xue, Hui; Vacic, Vladimir; Emde, Anne-Katrin; Oschwald, Dayna; Tan, Adrian Y; Chen, Zhengming; Collins, Colin; Gleave, Martin E; Wang, Yuzhuo; Chakravarty, Dimple; Schiffman, Marc; Kim, Robert; Campagne, Fabien; Robinson, Brian D; Nanus, David M; Tagawa, Scott T; Xiang, Jenny Z; Smogorzewska, Agata; Demichelis, Francesca; Rickman, David S; Sboner, Andrea; Elemento, Olivier; Rubin, Mark A

2015-07-01

Understanding molecular mechanisms of response and resistance to anticancer therapies requires prospective patient follow-up and clinical and functional validation of both common and low-frequency mutations. We describe a whole-exome sequencing (WES) precision medicine trial focused on patients with advanced cancer. To understand how WES data affect therapeutic decision making in patients with advanced cancer and to identify novel biomarkers of response. Patients with metastatic and treatment-resistant cancer were prospectively enrolled at a single academic center for paired metastatic tumor and normal tissue WES during a 19-month period (February 2013 through September 2014). A comprehensive computational pipeline was used to detect point mutations, indels, and copy number alterations. Mutations were categorized as category 1, 2, or 3 on the basis of actionability; clinical reports were generated and discussed in precision tumor board. Patients were observed for 7 to 25 months for correlation of molecular information with clinical response. Feasibility, use of WES for decision making, and identification of novel biomarkers. A total of 154 tumor-normal pairs from 97 patients with a range of metastatic cancers were sequenced, with a mean coverage of 95X and 16 somatic alterations detected per patient. In total, 16 mutations were category 1 (targeted therapy available), 98 were category 2 (biologically relevant), and 1474 were category 3 (unknown significance). Overall, WES provided informative results in 91 cases (94%), including alterations for which there is an approved drug, there are therapies in clinical or preclinical development, or they are considered drivers and potentially actionable (category 1-2); however, treatment was guided in only 5 patients (5%) on the basis of these recommendations because of access to clinical trials and/or off-label use of drugs. Among unexpected findings, a patient with prostate cancer with exceptional response to treatment was

Radiotherapy as an immunological booster in patients with metastatic melanoma or renal cell carcinoma treated with high-dose Interleukin-2: evaluation of biomarkers of immunologic and therapeutic response.

PubMed

Ridolfi, Laura; de Rosa, Francesco; Ridolfi, Ruggero; Gentili, Giorgia; Valmorri, Linda; Scarpi, Emanuela; Parisi, Elisabetta; Romeo, Antonino; Guidoboni, Massimo

2014-09-23

Tumor cells killed by radiation therapy (RT) are a potentially good source of antigens for dendritic cell (DC) uptake and presentation to T-cells. RT upregulates cell death receptors such as Fas/CD95 and MHC-I, induces the expression of co-stimulatory molecules on tumor cells, and promotes production of pro-inflammatory cytokines. High-dose interleukin-2 (HD-IL-2) bolus has been shown to obtain objective response rates ranging from 15% to 17% in patients with metastatic melanoma or renal cell carcinoma (RCC), with 6% to 8% of cases experiencing a durable complete response. However, HD-IL-2 is also associated with severe side-effects; if it is to remain a component of the curative treatment strategy in patients with metastatic melanoma or RCC, its therapeutic efficacy must be improved and patients who are most likely to benefit from treatment must be identified a priori. We designed a clinical study combining immunomodulating RT and HD-IL-2 to evaluate their clinical and immunological efficacy and to explore the predictive and prognostic value of 1) tumor-specific immune response and 2) serum levels of proangiogenic cytokines. The primary endpoint of this proof-of-principle phase II study is immune response. Secondary endpoints are the identification of biomarkers potentially predictive of response, toxicity, response rate and overall survival. Three daily doses of booster radiotherapy (XRT) at 6-12 Gy will be administered to at least one metastatic field on days -3 to -1 before the first and third cycle. Treatment with IL-2 (dose 18 MIU/m2/day by continuous IV infusion for 72 hours) will start on day +1 and will be repeated every 3 weeks for up to 4 cycles and then every 4 weeks for a further 2 cycles. Immune response against tumor antigens expressed by melanoma and/or RCC will be evaluated during treatment. Circulating immune effectors and regulators, e.g. cytotoxic T lymphocytes and regulatory T cells, as well as serum levels of proangiogenic

[Fundus fluorescein angiography in metastatic choroidal carcinomas and differentiating metastatic choroidal carcinomas from primary choroidal melanomas].

PubMed

Li, Lei; Wang, Wen-Ji; Chen, Rong-Jia; Qian, Jiang; Luo, Chuan-Qi; Zhang, Yong-Jin; Shen, Ying; Ye, Xiao-Feng; Gao, Qiao-Yun

2011-01-01

To investigate the characteristics of fundus fluorescein angiography (FFA) in metastatic choroidal carcinomas and determine the value of FFA in differentiating metastatic choroidal carcinomas from primary choroidal melanomas. It was a retrospective case series. The retrospective analysis of clinical data and FFA findings was performed in 23 eyes of 22 patients with metastatic choroidal carcinomas and 31 eyes of 31 patients with primary choroidal melanomas as the control. Ocular fundus findings of metastatic choroidal carcinomas were divided into three types: solitary flat (tumor thickness less than 3 mm), solitary elevated (tumor thickness more than 3 mm) or diffuse type. FFA of the three types showed hypofluorescence during the arterial phase and progressive hyperfluorescence during the subsequent phases. The border of the lesions revealed retinal capillary dilation during the arteriovenous phase and persistent pinpoint leakage throughout the angiogram. Retinal capillary dilation and pinpoint leakage were more frequently presented in the solitary flat type. Simultaneous visualization of retinal and tumor circulation (the so called double circulation) was more frequently presented in the solitary elevated type. Pinpoint leakage could be detected in 17 (73.91%) eyes of metastatic choroidal carcinomas and in 5 (16.13%) eyes of primary choroidal melanomas. The difference between the visibility of pinpoint leakage in metastatic choroidal carcinomas and primary choroidal melanomas was statistically significant (P = 0.0000). When pinpoint leakage of FFA was used to differentiate metastatic choroidal carcinomas from primary choroidal melanomas, the sensitivity, specificity, accuracy, positive and negative predictive values were 73.91%, 83.87%, 79.63%, 77.27%, 81.25% respectively. FFA is helpful for the diagnosis of metastatic choroidal carcinomas. Pinpoint leakage on the border of lesions has some value in differentiating metastatic choroidal carcinomas from primary

Obesity as defined by waist circumference but not body mass index is associated with higher renal mass complexity.

PubMed

Bertrand, Laura A; Thomas, Lewis J; Li, Peng; Buchta, Claire M; Boi, Shannon K; Orlandella, Rachael M; Brown, James A; Nepple, Kenneth G; Norian, Lyse A

2017-11-01

Obesity, typically defined as a body mass index (BMI)≥30kg/m 2 , is an established risk factor for renal cell carcinoma (RCC) but is paradoxically linked to less advanced disease at diagnosis and improved outcomes. However, BMI has inherent flaws, and alternate obesity-defining metrics that emphasize abdominal fat are available. We investigated 3 obesity-defining metrics, to better examine the associations of abdominal fat vs. generalized obesity with renal tumor stage, grade, or R.E.N.A.L. nephrometry score. In a prospective cohort of 99 subjects with renal masses undergoing resection and no evidence of metastatic disease, obesity was assessed using 3 metrics: body mass index (BMI), radiographic waist circumference (WC), and retrorenal fat (RRF) pad distance. R.E.N.A.L. nephrometry scores were calculated based on preoperative CT or MRI. Univariate and multivariate analyses were performed to identify associations between obesity metrics and nephrometry score, tumor grade, and tumor stage. In the 99 subjects, surgery was partial nephrectomy in 51 and radical nephrectomy in 48. Pathology showed benign masses in 11 and RCC in 88 (of which 20 had stage T3 disease). WC was positively correlated with nephrometry score, even after controlling for age, sex, race, and diabetes status (P = 0.02), whereas BMI and RRF were not (P = 0.13, and P = 0.57, respectively). WC in stage T2/T3 subjects was higher than in subjects with benign masses (P = 0.03). In contrast, subjects with Fuhrman grade 1 and 2 tumors had higher BMI (P<0.01) and WC (P = 0.04) than subjects with grade 3 and 4 tumors. Our data suggest that obesity measured by WC, but not BMI or RRF, is associated with increased renal mass complexity. Tumor Fuhrman grade exhibited a different trend, with both high WC and BMI associated with lower-grade tumors. Our findings indicate that WC and BMI are not interchangeable obesity metrics. Further evaluation of RCC-specific outcomes using WC vs. BMI is warranted to better

First-in-Human Phase 1 Trial of Agarose Beads Containing Murine RENCA Cells in Advanced Solid Tumors.

PubMed

Smith, Barry H; Parikh, Tapan; Andrada, Zoe P; Fahey, Thomas J; Berman, Nathaniel; Wiles, Madeline; Nazarian, Angelica; Thomas, Joanne; Arreglado, Anna; Akahoho, Eugene; Wolf, David J; Levine, Daniel M; Parker, Thomas S; Gazda, Lawrence S; Ocean, Allyson J

2016-01-01

Agarose macrobeads containing mouse renal adenocarcinoma cells (RMBs) release factors, suppressing the growth of cancer cells and prolonging survival in spontaneous or induced tumor animals, mediated, in part, by increased levels of myocyte-enhancing factor (MEF2D) via EGFR-and AKT-signaling pathways. The primary objective of this study was to determine the safety of RMBs in advanced, treatment-resistant metastatic cancers, and then its efficacy (survival), which is the secondary objective. Thirty-one patients underwent up to four intraperitoneal implantations of RMBs (8 or 16 macrobeads/kg) via laparoscopy in this single-arm trial (FDA BB-IND 10091; NCT 00283075). Serial physical examinations, laboratory testing, and PET-CT imaging were performed before and three months after each implant. RMBs were well tolerated at both dose levels (mean 660.9 per implant). AEs were (Grade 1/2) with no treatment-related SAEs. The data support the safety of RMB therapy in advanced-malignancy patients, and the preliminary evidence for their potential efficacy is encouraging. A Phase 2 efficacy trial is ongoing.

Early tumor shrinkage is independently associated with improved overall survival among patients with metastatic renal cell carcinoma: a validation study using the COMPARZ cohort.

PubMed

Grünwald, Viktor; Dietrich, Marion; Pond, Gregory R

2018-04-13

Early tumor shrinkage (eTS) has prognostic value in metastatic renal cell carcinoma (mRCC). We aimed to validate the role of eTS in first line treatment from the COMPARZ study (NCT00720941). 1100 patients treated with sunitinib or pazopanib were analyzed for tumor response according to RECIST 1.0. eTS was defined as tumor shrinkage by ≥ 10%. A landmark analysis was performed on day (d) 42 and 90 and Cox proportional hazards regression was computed for the prognostic effect of eTS. In patients with eTS median OS was 34.1 [CI 95% 28.4; not reached (NR)] and 33.6 (CI 95% 30.1; NR) months (mo) at d 42 and 90, respectively, compared to 19.6 (CI 95% 14.0; 28.9) and 15.1 (CI 95% 12.4; 18.7) mo for patients without eTS. There was no interaction between type of treatment and eTS (d 42 p = 0.79; d 90 p = 0.37). eTS ≥ 10% remained an independent prognostic marker in multivariable analyses at both d 42 and 90. Similar results were found for eTS at the 42 and 90 days landmarks. eTS ≥ 10% has prognostic relevance in mRCC and reflects a putative tool to guide future clinical treatment.

Bone-targeted cabazitaxel nanoparticles for metastatic prostate cancer skeletal lesions and pain.

PubMed

Gdowski, Andrew S; Ranjan, Amalendu; Sarker, Marjana R; Vishwanatha, Jamboor K

2017-09-01

The aim of this study was to develop a novel cabazitaxel bone targeted nanoparticle (NP) system for improved drug delivery to the bone microenvironment. Nanoparticles were developed using poly(D,L-lactic-co-glycolic acid) and cabazitaxel as the core with amino-bisphosphonate surface conjugation. Optimization of nanoparticle physiochemical properties, in vitro evaluation in prostate cancer cell lines and in vivo testing in an intraosseous model of metastatic prostate cancer was performed. This bone targeted cabazitaxel nanocarrier system showed significant reduction in tumor burden, while at the same time maintaining bone structure integrity and reducing pain in the mouse tumor limb. This bone microenvironment targeted nanoparticle system and clinically relevant approach of evaluation represents a promising advancement for treating bone metastatic cancer.

Conditional deletion of p53 and Rb in the renin-expressing compartment of the pancreas leads to a highly penetrant metastatic pancreatic neuroendocrine carcinoma

PubMed Central

Glenn, Sean T.; Jones, Craig A.; Sexton, Sandra; LeVea, Charles M.; Caraker, Susan M.; Hajduczok, George; Gross, Kenneth W.

2014-01-01

Efforts to model human pancreatic neuroendocrine tumors (PanNET) in animals have been moderately successful, with minimal evidence for glucagonomas or metastatic spread. The renin gene while classically associated with expression in the kidney is also expressed in many other extra-renal tissues including the pancreas. To induce tumorigenesis within renin specific tissues, floxed alleles of p53 and Rb were selectively abrogated using Cre-recombinase driven by the renin promoter. The primary neoplasm generated is a highly metastatic islet cell carcinoma of the pancreas. Lineage tracing identifies descendants of renin-expressing cells as pancreatic alpha cells despite a lack of active renin expression in the mature pancreas. Both primary and metastatic tumors express high levels of glucagon, furthermore an increased level of glucagon is found in the serum identifying the pancreatic cancer as a functional glucagonoma. This new model is highly penetrant and exhibits robust frequency of metastases to lymph nodes and liver, mimicking human disease and provides a useful platform for better understanding pancreatic endocrine differentiation and development, as well as islet cell carcinogenesis. The use of fluorescent reporters for lineage tracing of the cells contributing to disease initiation and progression provides a unique opportunity to dissect the timeline of disease, examining mechanisms of the metastatic process, as well as recovering primary and metastatic cells for identifying co-operating mutations that are necessary for progression of disease. PMID:24292676

Percutaneous Cryoablation of Solitary, Sporadic Renal Cell Carcinoma: Outcome Analysis Based on Clear-Cell versus Papillary Subtypes.

PubMed

Haddad, Mustafa M; Schmit, Grant D; Kurup, A Nicholas; Schmitz, John J; Boorjian, Stephen A; Geske, Jennifer; Thompson, R Houston; Callstrom, Matthew R; Atwell, Thomas D

2018-06-07

To evaluate treatment outcomes with percutaneous cryoablation (PCA) based on renal cell carcinoma (RCC) histology. Patients treated with PCA for a solitary, sporadic stage T1a RCC from 2003 to 2016 were identified from a single institution's renal ablation registry. Patients with multiple tumors, history of RCC, or genetic syndromes associated with RCC (n = 60); no specific RCC subtype determined from core biopsy (n = 66); RCC subtype other than clear-cell or papillary (n = 7); or less than 3 mo of follow-up imaging (n = 5) were excluded. In total, 173 patients met study inclusion criteria. Oncologic outcomes, clinical outcomes, and complications were evaluated based on tumor subtype. Of the 173 patients who underwent PCA for a stage T1a RCC, 130 (75%) had clear-cell RCC (ccRCC) and 43 (25%) had papillary RCC (pRCC). Median tumor size was 2.9 cm (range, 1.3-4.0 cm). Technically successful cryoablation was achieved in all 173 patients. Local tumor recurrence developed in 6 patients with ccRCC (4.6%), new renal tumors developed in 1 patient (0.8%), and metastatic RCC developed in 1 patient (0.8%) who also had local tumor recurrence. No patients with pRCC showed local tumor recurrence, new renal tumors, or metastatic disease. The 5-year disease-free survival rate in patients with ccRCC was 88%, compared with 100% in patients with pRCC (P = .48). Nine patients (5.2%), all with ccRCC, experienced major complications (P = .11). Percutaneous ablation is a viable treatment option for patients with clinical stage T1a pRCC and ccRCC. Percutaneous ablation may be a very favorable treatment strategy particularly for pRCC. Copyright © 2018 SIR. Published by Elsevier Inc. All rights reserved.

Management of Bladder Cancer After Renal Transplantation.

PubMed

Demirdag, C; Citgez, S; Talat, Z; Onal, B

2017-03-01

In renal transplant recipients, the risk of developing bladder cancer and rate of diagnosis of advanced staged bladder cancer are generally higher than the general population. Also, it is more challenging to treat renal transplant recipients than the regular patient population. We aimed to evaluate the efficacy and safety of radical cystectomy (RC) and urinary diversion with ileal conduit in renal transplant recipients. We identified 2 patients with prior history of renal transplantation who underwent RC and ileal conduit urinary diversion for bladder cancer. Preoperative clinical and demographic data were presented and outcomes were assessed. The RC and ileal conduit urinary diversion were performed in the first patient 56 months after renal transplantation and in the second patient 64 months after renal transplantation. Clinical staging was high-grade T2 transitional cell cancer of the bladder for patient 1 and T2 with pure squamous cell cancer of the bladder for patient 2. No perioperative or postoperative complication and no graft dysfunction occurred in either patient. Our experience demonstrated that RC with ileal conduit reconstruction in renal transplant recipients is safe and feasible. Copyright © 2016 Elsevier Inc. All rights reserved.

Systemic chemotherapy in patients with advanced transitional cell carcinoma of the urothelium and impaired renal function.

PubMed

Demery, Mounira El; Thézenas, Simon; Pouessel, Damien; Culine, Stéphane

2012-02-01

Cisplatin is the backbone of chemotherapeutic regimens used in the treatment of advanced transitional cell carcinoma of the urothelium. However, about 50% of patients cannot be administered cisplatin because of impaired renal functions. A review of the different approaches that have been developed in this patient population was performed through a Medline search from 1 January 1998 to 31 December 2010. Twenty-six studies including 25 phase II and one randomized phase II/III studies were analyzed. All regimens, except one, were based on gemcitabine and/or carboplatin and/or paclitaxel. Only five (20%) out of 25 phase II studies actually include homogeneous patients with an impaired renal function defined by a creatinine clearance below 60 ml/min. One hundred and eight patients with a median creatinine clearance ranging from 28 to 48 ml/min received four different chemotherapy regimens including one to four drugs. The results showed the response rates to vary from 24 to 56% and survival to range from 7 to 15 months. No standard chemotherapy can be recommended from literature data. Future randomized studies will have to solve the following questions: what is the optimal definition of cisplatin eligibility? Which platinum salt should be used? Is a platinum salt necessary? How many drugs should be delivered?

[The drug of the month: everolimus (Afinitor) for the treatment of metastatic breast cancer].

PubMed

Jerusalem, G; Rorive, A; Collignon, J

2014-09-01

Sequential endocrine treatments are recommended for estrogen receptor (ER) positive human epidermal growth factor receptor 2 (HER 2) negative metastatic breast cancers except in the case of symptomatic visceral disease. However, patients who suffer from disease progression while receiving a non-steroidal aromatase inhibitor (NSAI) have a very poor prognosis with standard endocrine therapy alone. Recently, based onthe results of the BOLERO 2 trial, the mammalian target of rapamycin (mTOR) inhibitor everolimus, combined with exemestane, a steroidal aromatase inhibitor, has been approved in Europe and the US for patients suffering from ER positive HER2 negative advanced breast cancer previously treated by a NSAI. The median progression-free survival (PFS) increased from 3.2 to 7.8 months in patients receiving everolimus and exemestane compared to placebo and exemestane. The magnitude of benefit was consistent in all pre-specified subgroups. Side effects were manageable and the quality of life was at least maintained. Everolimus has also beenrecently studied in HER2 positive locally advanced or metastatic disease in heavily pretreated patients (BOLERO 3 trial). This trial met its primary endpoint. The median PFS was increased in patients receiving trastuzumab, vinorelbine and everolimus compared to patients receiving trastuzumab, vinorelbine and placebo. We review pharmacological data and side effects of the drug. We also review the most important clinical trials leading to reimbursement of everolimus in metastatic breast cancer.

Third-Line Chemotherapy for Metastatic Urothelial Cancer: A Retrospective Observational Study

PubMed Central

Di Lorenzo, Giuseppe; Buonerba, Carlo; Bellelli, Teresa; Romano, Concetta; Montanaro, Vittorino; Ferro, Matteo; Benincasa, Alfonso; Ribera, Dario; Lucarelli, Giuseppe; De Cobelli, Ottavio; Sonpavde, Guru; De Placido, Sabino

2015-01-01

Abstract The prognosis of locally advanced (T3/T4 or N1) and metastatic disease urothelial carcinoma is poor. In this retrospective study, we reviewed data about patients receiving third-line chemotherapy for metastatic disease, in view of the lack of data in this setting. We retrospectively analyzed medical records of patients with a pathologic diagnosis of urothelial carcinoma treated with systemic chemotherapy for metastatic disease at 4 participating Institutions between January, 2010, and January, 2015. Cox proportional hazards regression was used to evaluate the association of the chemotherapy agent used versus others with overall survival, adjusted for 5 externally validated prognostic factors in advanced urothelial carcinoma. Of 182 patients that received first-line chemotherapy/adjuvant chemotherapy as defined above, 116 patients (63.73%) received second-line salvage treatment. Fifty-two patients were finally included in this analysis, whereas 9 were excluded due to missing data. Third-line chemotherapy was based on cyclophosphamide, platinum, vinflunine, taxanes, and gemcitabine in 16, 12, 11, 10, and 3 patients, respectively. Median PFS (progression-free survival) and OS (overall survival) of the population were 13 (10–17) and 31 (28–36) weeks. Single-agent cyclophosphamide was associated with a PFS of 18 (13–22) and an OS of 38 (33–41) weeks, whereas platinum-based combinations were associated with a PFS of 5 weeks and an OS of 8 weeks. Multivariate analysis showed improved survival in patients treated with cyclophosphamide (hazard ratio (HR) = 0.42; 95% CI: 0.20–0.89; P = 0.025) and a worse survival in those treated with platinum-based regimens (HR: 4.37; 95% CI = 1.95–9.77; P < 0.01). We observed a significantly longer overall survival in patients receiving single-agent cyclophosphamide, with few grade 3 to 4 toxicities. Further studies should assess the efficacy of metronomic single-agent cyclophosphamide in advanced lines

Sunitinib-induced hypertension, neutropaenia and thrombocytopaenia as predictors of good prognosis in patients with metastatic renal cell carcinoma.

PubMed

Rautiola, Juhana; Donskov, Frede; Peltola, Katriina; Joensuu, Heikki; Bono, Petri

2016-01-01

To evaluate the clinical significance of hypertension (HTN), neutropaenia and thrombocytopaenia as possible new biomarkers of sunitinib efficacy in non-trial patients with metastatic renal cell carcinoma (mRCC). In all, 181 consecutive patients with mRCC were treated with sunitinib; 39 (22%) received sunitinib 50 mg/day 4 weeks on/2 weeks off, 80 (44%) received 37.5 mg/day continuously and 62 (34%) received 25 mg/day continuously as their starting dose. Treatment-induced adverse events (AEs) and their impact on outcome were analysed on multiple sunitinib doses. During sunitinib treatment 60 patients (33%) developed ≥grade 2 HTN, 88 (49%) ≥grade 2 neutropaenia and 135 (75%) ≥grade 1 thrombocytopaenia. These AEs were associated significantly with longer progression-free survival (PFS; 15.7 vs 6.7; 14.6 vs 6.9; 10.4 vs 4.2 months, respectively; P < 0.001) and overall survival (OS; 37.5 vs 16.2; 33.7 vs 13.2; 22.3 vs 13.2 months, respectively, P ≤ 0.008). Although only neutropaenia was associated with a significantly improved PFS and OS in all sunitinib doses, a similar trend was also seen with HTN and thrombocytopaenia in all sunitinib doses. In multivariate analysis, HTN and neutropaenia were significantly associated with PFS and OS and thrombocytopaenia was significantly associated with PFS. In a 12-week landmark analysis, HTN and thrombocytopaenia were significantly associated with PFS and OS. Patients who developed all three AEs (a favourable biomarker profile) had significantly better outcome than patients without these AEs (a poor biomarker profile); response rate 47% vs 4%, median PFS 27.1 vs 3.5 months and OS not reached vs 5.3 months (all P < 0.001). HTN, neutropaenia and thrombocytopaenia were all biomarkers of sunitinib efficacy in patients with mRCC. Our results may help to individualise sunitinib dosing during therapy based on these common sunitinib-related AEs. © 2014 The Authors BJU International © 2014 BJU International Published by John

Utility values associated with advanced or metastatic non-small cell lung cancer: data needs for economic modeling.

PubMed

Brown, Jacqueline; Cook, Keziah; Adamski, Kelly; Lau, Jocelyn; Bargo, Danielle; Breen, Sarah; Chawla, Anita

2017-04-01

Cost-effectiveness analyses often inform healthcare reimbursement decisions. The preferred measure of effectiveness is the quality adjusted life year (QALY) gained, where the quality of life adjustment is measured in terms of utility. Areas covered: We assessed the availability and variation of utility values for health states associated with advanced or metastatic non-small cell lung cancer (NSCLC) to identify values appropriate for cost-effectiveness models assessing alternative treatments. Our systematic search of six electronic databases (January 2000 to August 2015) found the current literature to be sparse in terms of utility values associated with NSCLC, identifying 27 studies. Utility values were most frequently reported over time and by treatment type, and less frequently by disease response, stage of disease, adverse events or disease comorbidities. Expert commentary: In response to rising healthcare costs, payers increasingly consider the cost-effectiveness of novel treatments in reimbursement decisions, especially in oncology. As the number of therapies available to treat NSCLC increases, cost-effectiveness analyses will play a key role in reimbursement decisions in this area. Quantifying the relationship between health and quality of life for NSCLC patients via utility values is an important component of assessing the cost effectiveness of novel treatments.

Recent Advances of Curcumin in the Prevention and Treatment of Renal Fibrosis.

PubMed

Sun, Xuejiao; Liu, Yi; Li, Cheng; Wang, Xiting; Zhu, Ruyuan; Liu, Chenyue; Liu, Haixia; Wang, Lili; Ma, Rufeng; Fu, Min; Zhang, Dongwei; Li, Yu

2017-01-01

Curcumin, a polyphenol derived from the turmeric, has received attention as a potential treatment for renal fibrosis primarily because it is a relatively safe and inexpensive compound that contributes to kidney health. Here, we review the literatures on the applications of curcumin in resolving renal fibrosis in animal models and summarize the mechanisms of curcumin and its analogs (C66 and (1E,4E)-1,5-bis(2-bromophenyl) penta-1,4-dien-3-one(B06)) in preventing inflammatory molecules release and reducing the deposition of extracellular matrix at the priming and activation stage of renal fibrosis in animal models by consulting PubMed and Cnki databases over the past 15 years. Curcumin exerts antifibrotic effect through reducing inflammation related factors (MCP-1, NF- κ B, TNF- α , IL-1 β , COX-2, and cav-1) and inducing the expression of anti-inflammation factors (HO-1, M6PRBP1, and NEDD4) as well as targeting TGF- β /Smads, MAPK/ERK, and PPAR- γ pathways in animal models. As a food derived compound, curcumin is becoming a promising drug candidate for improving renal health.

Development and evaluation of a decision aid for patients considering first‐line chemotherapy for metastatic breast cancer

PubMed Central

Chiew, Kimberly S.; Shepherd, Heather; Vardy, Janette; Tattersall, Martin H.N.; Butow, Phyllis N.; Leighl, Natasha B.

2007-01-01

Abstract Objective  Treatment decisions in advanced breast cancer are complex, with enhanced quality of life and survival among important treatment goals. Patients with metastatic breast cancer face the decision of whether or not to have chemotherapy, and many wish to be involved in this decision. We report the development and evaluation of a decision aid (DA) designed to assist patients facing this treatment decision. Design and sample  Women with metastatic breast cancer (n = 17) and medical oncologists in Australia and Canada (n = 7) were invited to evaluate the DA. Intervention  A DA was developed for patients with hormone‐resistant metastatic breast cancer considering chemotherapy. The DA presented options of supportive care, with or without chemotherapy. Potential benefits and side effects of different chemotherapy regimens, and evidence‐based prognostic estimates were described, and a values clarification exercise included. Main outcome measures  Patient questionnaires evaluating information and decision involvement preferences, attitudes toward the DA and oncologist feedback regarding attitudes toward the DA. Results  Seventeen patients participated; fifteen desired as much information about their illness as possible; sixteen wished to be actively involved in the decision‐making process. The majority rated the DA as highly acceptable, clear and informative, and would recommend it to others facing this treatment decision. Conclusion  This is the first DA for patients with advanced metastatic breast cancer considering chemotherapy. A randomized trial is underway to evaluate its role in clinical decision‐making. PMID:18297781

Weekly Multi-agent Chemotherapy (CMF-b) for Advanced Non-melanoma Skin Cancer.

PubMed

Espeli, Vittoria; Ruegg, Eva; Hottinger, Andreas F; Modarressi, Ali; Dietrich, Pierre-Yves

2016-05-01

Advanced unresectable and metastatic non-melanoma skin cancers (NMSC) are rare, but often arise in elderly patients. When surgery or irradiation are no longer feasible, chemotherapy is often precluded by the patient's age and comorbidities. Whether low-dose multi-agent chemotherapy could be an alternative for this vulnerable population in an outpatient setting was the issue examined in this retrospective analysis. Twenty-six patients with advanced unresectable or metastatic NMSC received weekly multi-agent chemotherapy with carboplatin at an area under the curve of 2 or 40 mg total dose of cisplatin, with 15 IU total dose of bleomycin, 40 mg total dose of methotrexate, and 500 mg total dose of 5-fluorouracil (CMF-b) until best response, toxicity, or progression of their disease. Twenty-four patients were treated as outpatients; two were hospitalized. Twenty-three patients were previously treated with surgery or radiotherapy. The median age was 68 years (range=44-100 years). The median number of cycles was 6 (range=1 to 17). The overall response rate was 61.5% (seven complete remissions, nine partial remissions) for the entire cohort and 63.6% (two complete remissions and five partial remissions) for patients >80 years. The median duration of response was 6.1 months (range=1.6-63 months). Responses longer than 6 months were obtained in 11/26 (42.3%) of the entire cohort and in 4/11 (36.3%) patients >80 years. Symptom improvement was observed in 17 patients (65.3%). Toxicity was acceptable, with grade 3 renal failure (n=1) and grade 3 or 4 myelotoxicity (n=2). CMF-b is a safe, weekly low-dose multi-agent regimen that offers palliation for vulnerable patients with NMSC. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Clinical characteristics and prognostic indicators for metastatic melanoma: data from 446 patients in north China.

PubMed

Hao, Mengze; Zhao, Gang; Du, Xiaoling; Yang, Yun; Yang, Jilong

2016-08-01

Melanoma is an extremely rare tumor in Asia. This retrospective study aimed to identify the clinical characteristics and prognostic factors of metastatic melanoma patients at Tianjin Medical University Cancer Hospital over the last 30 years. Survival analysis was performed with Kaplan-Meier, log-rank test, and multivariate Cox regression method using SPSS 19.0 software. The 1-, 2-, and 5-year survival rates of metastatic melanoma patients were 52, 32, and 16 %, respectively. Median overall survival (OS) was 13.5 months, median progression-free survival (PFS) 9.0 months, and median disease-free survival 20.3 months. Furthermore, patients with a single metastatic site achieved better OS and PFS than those with two or more metastatic lesions (OS 21.6 vs. 8.9 months, P < 0.001; PFS 11.3 vs. 7.1 months, P < 0.001). Survival times of patients with visceral metastases were the shortest (OS 8.5 months; PFS 7.5 months). Specifically, patients with primary mucosal lesions had a worse OS (9.7 months) and PFS (6.8 months) than those with acral (19.2 and 15.6 months, respectively) or non-acral primary lesions (11.8 and 11.1 months, respectively). The treatment of advanced melanoma was unitary, and prognoses of patients with metastatic melanoma in China were poor. Visceral metastasis, multiple metastatic sites, and primary mucosal lesions were significant predictors of survival of patients with metastatic melanoma. Those with primary mucosal lesions had significantly worse survivals than those with primary cutaneous lesions. More active involvement in clinical studies and more feedback on various treatment options are required.

Advances in the Immunobiological Therapies for Advanced Melanoma.

PubMed

Pérez Gago, M C; Saavedra Santa Gadea, O; de la Cruz-Merino, L

2017-10-01

Metastatic or locally advanced unresectable melanoma carries a high morbidity and mortality. However, notable advances have been made in recent years in the systemic treatment of this disease, with the appearance of targeted therapy using tyrosine kinase inhibitors that block the mitogen activated protein kinase pathway, and of modern immunotherapy with immune-modulating monoclonal antibodies. In this paper, we provide an update of available data on new immune therapies and we review the clinical development that led to their approval for use in routine clinical practice. Copyright © 2017 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

Sapanisertib and Ziv-Aflibercept in Treating Patients With Recurrent Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery

ClinicalTrials.gov

2018-03-07

Advanced Malignant Solid Neoplasm; Fibrolamellar Carcinoma; Metastatic Malignant Solid Neoplasm; Ovarian Carcinoma; Pancreatic Neuroendocrine Tumor; Recurrent Malignant Solid Neoplasm; Refractory Malignant Solid Neoplasm; Unresectable Solid Neoplasm

Renal accumulation of pentosidine in non-diabetic proteinuria-induced renal damage in rats.

PubMed

Waanders, Femke; Greven, Wendela L; Baynes, John W; Thorpe, Suzanne R; Kramer, Andrea B; Nagai, Ryoji; Sakata, Noriyuki; van Goor, Harry; Navis, Gerjan

2005-10-01

Advanced glycation end-products (AGEs) contribute to the pathogenesis of diabetic glomerulopathy. The role of AGEs in non-diabetic renal damage is not well characterized. First, we studied whether renal AGE accumulation occurs in non-diabetic proteinuria-induced renal damage and whether this is ameliorated by renoprotective treatment. Secondly, we investigated whether renal AGE accumulation was due to intrarenal effects of local protein trafficking. Pentosidine was measured (by high-performance liquid chromatography) in rats with chronic bilateral adriamycin nephropathy (AN), untreated and treated with lisinopril. Age-matched healthy rats served as negative controls. Secondly, we compared renal pentosidine in mild proteinuric and non-proteinuric kidneys of unilateral AN and in age-matched controls at 12 and 30 weeks. Intrarenal localization of pentosidine was studied by immunohistochemistry. Renal pentosidine was elevated in untreated AN (0.14+/-0.04 micromol/mol valine) vs healthy controls (0.04+/-0.01 micromol/mol valine, P<0.01). In lisinopril-treated AN, pentosidine was lower (0.09+/-0.02 micromol/mol valine) than in untreated AN (P<0.05). In unilateral proteinuria, pentosidine was similar in non-proteinuric and proteinuric kidneys. After 30 weeks of unilateral proteinuria, pentosidine was increased in both kidneys (0.26+/-0.10 micromol/mol valine) compared with controls (0.18+/-0.06 micromol/mol valine, P<0.05). Pentosidine (AN, week 30) was also increased compared with AN at week 12 (0.16+/-0.06 micromol/mol valine, P<0.01). In control and diseased kidneys, pentosidine was present in the collecting ducts. In proteinuric kidneys, in addition, pentosidine was present in the brush border and cytoplasm of dilated tubular structures, i.e. at sites of proteinuria-induced tubular damage. Pentosidine accumulates in non-diabetic proteinuric kidneys in damaged tubules, and renoprotective treatment by angiotensin-converting enzyme (ACE) inhibitors inhibits AGE

Recent advances in systemic therapy: Advances in systemic therapy for HER2-positive metastatic breast cancer.

PubMed

Morrow, Phuong Khanh H; Zambrana, Francisco; Esteva, Francisco J

2009-01-01

Human epidermal growth factor receptor (HER)2 over-expression is associated with a shortened disease-free interval and poor survival. Although the addition of trastuzumab to chemotherapy in the first-line setting has improved response rates, progression-free survival, and overall survival, response rates declined when trastuzumab was used beyond the first-line setting because of multiple mechanisms of resistance. Studies have demonstrated the clinical utility of continuing trastuzumab beyond progression, and further trials to explore this concept are ongoing. New tyrosine kinase inhibitors, monoclonal antibodies, PTEN (phosphatase and tensin homolog) pathway regulators, HER2 antibody-drug conjugates, and inhibitors of heat shock protein-90 are being evaluated to determine whether they may have a role to play in treating trastuzumab-resistant metastatic breast cancer.

Barriers to Advance Care Planning in End-Stage Renal Disease: Who is to Blame, and What Can be Done?

PubMed

Kelley, Alan Taylor; Turner, Jeffrey; Doolittle, Benjamin

2018-07-01

Patients with end-stage renal disease experience significant mortality and morbidity, including cognitive decline. Advance care planning has been emphasized as a responsibility and priority of physicians caring for patients with chronic kidney disease in order to align with patient values before decision-making capacity is lost and to avoid suffering. This emphasis has proven ineffective, as illustrated in the case of a patient treated in our hospital. Is this ineffectiveness a consequence of failure in the courtroom or the clinic? Through our own experience we affirm what has been written before: that legal precedent favors intensive treatment in virtually all cases without 'clear and convincing evidence' of a patient's previously declared wishes to the contrary. Equally clear is that more than 20 years of support in the clinical literature suggesting advance care planning early in the course of disease can address challenges in the legal system for those lacking capacity. However, many physicians fail to recognize the need for advance care planning in a timely manner and lack the necessary training to provide it. The need for more training and new tools to recognize opportunities for advance care planning in daily practice remains unmet.

Emerging therapeutic targets in metastatic progression: a focus on breast cancer

PubMed Central

Li, Zhuo; Kang, Yibin

2016-01-01

Metastasis is the underlying cause of death for the majority of breast cancer patients. Despite significant advances in recent years in basic research and clinical development, therapies that specifically target metastatic breast cancer remain inadequate, and represents the single greatest obstacle to reducing mortality of late-stage breast cancer. Recent efforts have leveraged genomic analysis of breast cancer and molecular dissection of tumor-stromal cross-talk to uncover a number of promising candidates for targeted treatment of metastatic breast cancer. Rational combinations of therapeutic agents targeting tumor-intrinsic properties and microenvironmental components provide a promising strategy to develop precision treatments with higher specificity and less toxicity. In this review, we discuss the emerging therapeutic targets in breast cancer metastasis, from tumor-intrinsic pathways to those that involve the host tissue components, including the immune system. PMID:27000769

Renal Denervation: Intractable Hypertension and Beyond

PubMed Central

Ariyanon, Wassawon; Mao, Huijuan; Adýbelli, Zelal; Romano, Silvia; Rodighiero, Mariapia; Reimers, Bernhard; La Vecchia, Luigi; Ronco, Claudio

2014-01-01

Background Hypertension continues to be a major burden of public health concern despite the recent advances and proven benefit of pharmacological therapy. A certain subset of patients has hypertension resistant to maximal medical therapy and appropriate lifestyle measures. A novel catheter-based technique for renal denervation (RDN) as a new therapeutic avenue has great promise for the treatment of refractory hypertension. Summary This review included the physiology of the renal sympathetic nervous system and the renal nerve anatomy. Furthermore, the RDN procedure, technology systems, and RDN clinical trials as well as findings besides antihypertensive effects were discussed. Findings on safety and efficacy seem to suggest that renal sympathetic denervation could be of therapeutic benefit in refractory hypertensive patients. Despite the fast pace of development in RDN therapies, only initial and very limited clinical data are available. Large gaps in knowledge concerning the long-term effects and consequences of RDN still exist, and solid, randomized data are warranted. PMID:24847331

Chemotherapy in metastatic retinoblastoma.

PubMed

Kingston, J E; Hungerford, J L; Plowman, P N

1987-03-01

Eleven children with metastatic retinoblastoma diagnosed during the period 1970-1984 were treated with chemotherapy. Short-term complete responses were observed in three children treated with a four-drug combination which included cisplatinum, and in one child treated with vincristine and cyclophosphamide. The median duration of survival of the 11 children receiving chemotherapy was nine months, whilst the median survival of 13 children with metastatic retinoblastoma who were not given chemotherapy was only 2.3 months (p = 0.06). This suggests that retinoblastoma is a chemosensitive tumour and therefore adjuvant chemotherapy may have a role in children with retinoblastoma who at diagnosis are thought to be at high risk of developing metastatic disease.

Economic evaluation of everolimus versus sorafenib for the treatment of metastatic renal cell carcinoma after failure of first-line sunitinib.

PubMed

Casciano, Roman; Chulikavit, Maruit; Di Lorenzo, Giuseppe; Liu, Zhimei; Baladi, Jean-Francois; Wang, Xufang; Robertson, Justin; Garrison, Lou

2011-01-01

A recent indirect comparison study showed that sunitinib-refractory metastatic renal cell carcinoma (mRCC) patients treated with everolimus are expected to have improved overall survival outcomes compared to patients treated with sorafenib. This analysis examines the likely cost-effectiveness of everolimus versus sorafenib in this setting from a US payer perspective. A Markov model was developed to simulate a cohort of sunitinib-refractory mRCC patients and to estimate the cost per incremental life-years gained (LYG) and quality-adjusted life-years (QALYs) gained. Markov states included are stable disease without adverse events, stable disease with adverse events, disease progression, and death. Transition probabilities were estimated using a subset of the RECORD-1 patient population receiving everolimus after sunitinib, and a comparable population receiving sorafenib in a single-arm phase II study. Costs of antitumor therapies were based on wholesale acquisition cost. Health state costs accounted for physician visits, tests, adverse events, postprogression therapy, and end-of-life care. The model extrapolated beyond the trial time horizon for up to 6 years based on published trial data. Deterministic and probabilistic sensitivity analyses were conducted. The estimated gain over sorafenib treatment was 1.273 LYs (0.916 QALYs) at an incremental cost of $81,643. The deterministic analysis resulted in an incremental cost-effectiveness ratio (ICER) of $64,155/LYG ($89,160/QALY). The probabilistic sensitivity analysis demonstrated that results were highly consistent across simulations. As the ICER fell within the cost per QALY range for many other widely used oncology medicines, everolimus is projected to be a cost-effective treatment relative to sorafenib for sunitinib-refractory mRCC. Copyright © 2011 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Evaluation of treatment response and resistance in metastatic renal cell cancer (mRCC) using integrated 18F-Fluorodeoxyglucose (18F-FDG) positron emission tomography/magnetic resonance imaging (PET/MRI); The REMAP study.

PubMed