Outcome of Patients With Metastatic Chromophobe Renal Cell Carcinoma Treated With Sunitinib.

BACKGROUND: Sunitinib is a standard treatment for metastatic clear cell renal cell carcinoma (mccRCC). Data on its activity in the rare variant of metastatic chromophobe renal cell carcinoma (mchRCC), are limited. We aimed to analyze the activity of sunitinib in a relatively large and homogenous international cohort of mchRCC patients in terms of outcome and comparison with mccRCC. METHODS: Records from mchRCC patients treated with first-line sunitinib in 10 centers across 4 countries were retrospectively reviewed. Univariate and multivariate analyses of association between clinicopathologic factors and outcome were performed. Subsequently, mchRCC patients were individually matched to mccRCC patients. We compared the clinical benefit rate, progression-free survival (PFS), and overall survival (OS) between the groups. RESULTS: Between 2004 and 2014, 36 patients (median age, 64 years; 47% male) with mchRCC were treated with first-line sunitinib. Seventy-eight percent achieved a clinical benefit (partial response + stable disease). Median PFS and OS were 10 and 26 months, respectively. Factors associated with PFS were the Heng risk (hazard ratio [HR], 3.3; p = .03) and pretreatment neutrophil-to-lymphocyte ratio (NLR) >3 (HR, 0.63; p = .02). Factors associated with OS were the Heng risk (HR, 4.1; p = .04), liver metastases (HR, 3.8; p = .03), and pretreatment NLR <3 (HR, 0.55; p = .03). Treatment outcome was not significantly different between mchRCC patients and individually matched mccRCC patients. In mccRCC patients (p value versus mchRCC), 72% achieved a clinical benefit (p = .4) and median PFS and OS were 9 (p = .6) and 25 (p = .7) months, respectively. CONCLUSION: In metastatic chromophobe renal cell carcinoma, sunitinib therapy may be associated with similar outcome and toxicities as in metastatic clear cell renal cell carcinoma. The Heng risk and pretreatment NLR may be associated with PFS and OS. IMPLICATIONS FOR PRACTICE: Data on the activity of sunitinib in metastatic chromophobe renal cell carcinoma (mchRCC) are limited. This study analyzed the activity of sunitinib in a cohort of mchRCC patients. Of 36 patients with mchRCC who were treated with first-line sunitinib, 78% achieved a clinical benefit. Median PFS and OS were 10 and 26 months, respectively. Treatment outcome was not significantly different between mchRCC patients and individually matched metastatic clear cell RCC patients.

Active smoking may negatively affect response rate, progression-free survival, and overall survival of patients with metastatic renal cell carcinoma treated with sunitinib.

BACKGROUND: 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). METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Experience with sunitinib treatment for metastatic renal cell carcinoma in a large cohort of Israeli patients: outcome and associated factors.

BACKGROUND: The VEGFR/PDGFR inhibitor sunitinib was approved in Israel in 2008 for the treatment of metastatic renal cell carcinoma (mRCC), based on an international trial. However, the efficacy of sunitinib treatment in Israeli mRCC patients has not been previously reported. OBJECTIVES: To report the outcome and associated factors of sunitinib treatment in a large cohort of Israeli mRCC patients. METHODS: We conducted a retrospective study of an unselected cohort of mRCC patients who were treated with sunitinib during the period 2006-2013 in six Israeli hospitals. Univariate and multivariate analyses were performed to determine the association between treatment outcome and clinicopathologic factors. RESULTS: We identified 145 patients; the median age was 65 years, 63% were male, 80% had a nephrectomy, and 28% had prior systemic treatment. Seventy-nine percent (n = 115) had clinical benefit (complete response 5%, n = 7; partial response 33%, n = 48; stable disease 41%, n = 60); 21% (n = 30) were refractory to treatment. Median progression-free survival (PFS) was 12 months and median overall survival 21 months. Factors associated with clinical benefit were sunitinib-induced hypertension: [odds ratio (OR) 3.6, P = 0.042] and sunitinib dose reduction or treatment interruption (OR 2.4, P = 0.049). Factors associated with PFS were female gender [hazard ratio (HR) 2, P = 0.0041, pre-sunitinib treatment neutrophil-to-lymphocyte ratio < or = 3 (HR 2.19, P = 0.002), and active smoking (HR 0.19, P < 0.0001). Factors associated with overall survival were active smoking (HR 0.25, P < 0.0001) and sunitinib-induced hypertension (HR 0.48, P = 0.005). To minimize toxicity, the dose was reduced or the treatment interrupted in 39% (n = 57). CONCLUSIONS: The efficacy of sunitinib treatment for mRCC among Israeli patients is similar to that in international data.

Pretreatment neutrophil-to-lymphocyte ratio in metastatic castration-resistant prostate cancer patients treated with ketoconazole: association with outcome and predictive nomogram.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR), an inflammation marker, is prognostic in several cancers. We assessed the association between the pretreatment NLR and outcome of patients with metastatic castration-resistant prostate cancer (mCRPC) treated with the CYP17 inhibitor ketoconazole. METHODS: This was an international, retrospective study of 156 mCRPC patients treated with ketoconazole. The independent effect of the pretreatment NLR and factors associated with treatment outcome were determined by multivariate analysis. RESULTS: Seventy-eight patients (50%) had a ≥50% decline in prostate-specific antigen (PSA). The median progression-free survival (PFS) time was 8 months. Excluded from the analysis were 23 patients without available data on their NLR and those with a recent health event or treatment associated with a blood count change. Sixty-two patients (47%) had a pretreatment NLR >3. Risk factors associated with the PFS outcome were a pretreatment NLR >3 and PSA doubling time (PSADT) <3 months and a prior response to a gonadotropin-releasing hormone agonist of <24 months or to an antiandrogen of <6 months. The number of risk factors was used to form a predictive nomogram by patient categorization into favorable (zero or one factor), intermediate (two factors), and poor (three or four factors) risk groups. CONCLUSIONS: In mCRPC patients treated with ketoconazole, the pretreatment NLR and PSADT, and prior response to androgen-deprivation therapy, may be associated with the PFS time and used to form a risk stratification predictive nomogram.

Ribosomal proteins as distinct "passengers" of microvesicles: new semantics in myeloma and mesenchymal stem cells' communication.

Aberrant mesenchymal stem cells (MSCs) in multiple myeloma (MM) bone marrows (BM) promote disease progression and drug resistance. Here, we assayed the protein cargo transported from MM-MSCs to MM cells via microvesicles (MVs) with focus on ribosomal proteins (RPs) and assessment of their influence on translation initiation and design of MM phenotype. Proteomics analysis (mass spectrometry) demonstrated increased levels and repertoire of RPs in MM-MSCs MVs compared to normal donors (ND) counterparts (n = 3-8; P = 9.96E - 08). We limited the RPs load in MM-MSCs MVs (starvation, RSK and XPO1 inhibitions), reapplied the modified MVs to MM cell lines (U266, MM1S), and demonstrated that the RPs are essential to the proliferative effect of MM-MSCs MVs on MM cells (n = 3; P < 0.05). We also observed that inhibition with KPT-185 (XPO1 inhibitor) displayed the most extensive effect on RPs delivery into the MVs (↓80%; P = 3.12E - 05). Using flow cytometry we assessed the expression of select RPs (n = 10) in BM-MSCs cell populations (ND and MM; n ≥ 6 each). This demonstrated a heterogeneous expression of RPs in MM-MSCs with distinct subgroups, a phenomenon absent from ND-MSCs samples. These findings bring to light a new mechanism in which the tumor microenvironment participates in cancer promotion. MVs-mediated horizontal transfer of RPs between niche MSCs and myeloma cells is a systemic way to bestow pro-cancer advantages. This capacity also differentiates normal MSCs from the MM-modified MSCs and may mark their reprogramming. Future studies will be aimed at assessing the clinical and therapeutic potential of the increased RPs levels in MM-MSCs MVs.

The endless differential diagnosis of acute obstructive renal failure: unusual challenges for the sharp-sighted clinician.

Obstruction of urine outflow can result from mechanical blockade as well as from functional defects. In adults, urinary tract obstruction is due mainly to acquired defects, such as pelvic tumors, calculi, and urethral stricture. In childhood it is mostly due to congenital malformations. In this article we present two rare cases of acute obstructive renal failure that presented with hydronephrosis. These cases underline the wide range of causes that may lead to this clinical feature.

The role of irradiation of the internal mammary lymph nodes in high-risk stage II to IIIA breast cancer patients after high-dose chemotherapy: a prospective sequential nonrandomized study.

PURPOSE: This phase II single-institution prospective, nonrandomized trial investigates high-dose adjuvant chemotherapy and locoregional radiotherapy in patients with breast cancer. We compared the outcome of patients in this study treated with radiotherapy fields including the internal mammary nodes (IMN) to a group of patients who did not receive IMN irradiation. PATIENTS AND METHODS: 100 patients with high-risk stage II-III breast cancer received doxorubicin-based adjuvant chemotherapy followed by high-dose chemotherapy, stem-cell support, and locoregional radiotherapy. The radiotherapy included electron-beam irradiation to the IMN. For 20 months during the study, no electron-beam facility was available and we were unable to deliver the IMN irradiation as planned to 33 patients. The remaining 67 patients (32 treated before and 35 treated after this period) received IMN irradiation. Patients with receptor-positive tumors received tamoxifen for 5 years. RESULTS: At a median follow-up of 77 months for all of the patients, disease-free survival (DFS) was significantly prolonged in patients receiving IMN radiation compared to those without IMN radiation (73% v 52%; P =.02). A trend was seen for overall survival (OS; 78% v 64%; P =.08). Cox regression multivariate analysis found IMN radiotherapy to be significant both for DFS and OS. Estrogen receptor positivity was also significant for DFS. There was no treatment related mortality. CONCLUSION: In patients with high-risk stage II to III breast cancer, the inclusion of the IMN in the radiotherapy field was associated with a statistically significant increase in DFS and a borderline increase in OS.

Advanced but not localized prostate cancer is associated with increased oxidative stress.

PURPOSE: Oxidative damage has been linked to prostate carcinogenesis but its role in disease development and progression remains elusive. We investigated associations between indexes of oxidative stress with localized and advanced prostate cancer. Specifically we assessed the susceptibility of serum lipids to copper induced peroxidation (oxidizability). MATERIALS AND METHODS: Serum oxidizability, and levels of alpha-tocopherol, malonyldialdehyde and uric acid were assessed in samples from 79 patients with prostate cancer, including 42 with localized and 37 with metastatic disease receiving androgen deprivation therapy, and 25 control subjects. Oxidizability was assayed by continuous spectroscopic monitoring of the accumulation of peroxidation products. The lag preceding oxidation, that is the delay between the induction and propagation of the reaction, served as a measure of the resistance of serum lipids to oxidation. RESULTS: Compared to control subjects patients with localized prostate cancer had no difference in oxidative stress indexes, whereas those with metastatic disease had a shorter lag preceding oxidation and increased malonyldialdehyde (p <0.05), each reflecting a state of high oxidative stress. In patients with prostate cancer the probability of disease progression from localized to advanced state increased with a shorter lag preceding oxidation (p <0.001), increased malonyldialdehyde (p <0.03) and decreased uric acid (p <0.04). Localized and metastatic disease was associated with increased rather than decreased alpha-tocopherol (p <0.008 and <0.005, respectively). CONCLUSIONS: Patients with advanced prostate cancer are subject to high oxidative stress, as determined by increased susceptibility of serum lipids to peroxidation. This association was not detected in patients with localized cancer and it is not attributable to altered levels of alpha-tocopherol.

The effects of doxorubicin on apoptosis and adhesion molecules of normal peripheral blood leukocytes-an ex vivo study.

This ex vivo study was designed to evaluate the effect of doxorubicin (Dox) on normal peripheral blood leukocytes (PBL) in terms of apoptosis and membranal expression levels of adhesion molecules. Blood was drawn immediately prior to and after Dox administration from 21 breast cancer patients, and incubated at room temperature for 24 h. Flow cytometry was employed in analysis of apoptosis with Annexin-V and protein membranal expression levels with monoclonal antibodies to CD49d, CD18, CD11a-c and CD63. Dox induced statistically significant apoptosis in all three major PBL subpopulations (p<0.01). Between 70 and 90% of samples underwent apoptosis in all PBL subgroups. No significant change was observed in the membranal level of CD63, CD49d and CD11a-c after chemotherapy in any PBL subpopulation. However, a significant reduction in the membranal level of CD18 was demonstrated in polymorphonuclear cells after Dox (p<0.005) both in apoptotic and non-apoptotic cells (p<0.05), suggesting a direct effect of Dox rather than an apoptosis-associated phenomenon. We observed the expected leukopenia 10 days after Dox administration with no correlation to apoptosis, suggesting that leukopenia by Dox is largely attributed to toxicity of blood progenitors.