Outcome of Patients with Renal Cell Carcinoma and Multiple Glandular Metastases Treated with Targeted Agents.

PURPOSE: Pancreatic metastases (PM) from renal cell carcinoma (RCC) have been associated with long-term survival. The aim of this study was to evaluate the outcome of RCC patients with multiple glandular metastases (MGM) treated with targeted therapies (TTs). METHODS: Sixty-four MGM patients treated between 1993 and 2014 were retrospectively identified from a database of 274 RCC patients with PM from 11 European centers. The survival of MGM patients was compared with that of both patients with PM only and a cohort of 325 RCC patients with non-GM (control group) treated with TTs. Survival was estimated using the Kaplan-Meier method and was statistically compared using the log-rank test. RESULTS: Fifty-six patients (88%) had at least 2 MGM, 7 patients (11%) had 3 MGM and 1 patient had 4 MGM, while non-GM were present in the remaining patients. The median overall survival (OS) was 54.2 months for MGM and 73.4 months for patients with PM only. The median OS in the control group was 22.7 months and statistically inferior to both MGM (p < 0.001) and PM patients (p < 0.001). CONCLUSION: MGM from RCC are associated with a remarkable survival. Despite some limitations, these findings suggest that GM might be considered a predictor of a favorable prognosis.

Time from nephrectomy as a prognostic factor in metastatic renal cell carcinoma patients receiving targeted therapies: overall results from a large cohort of patients.

OBJECTIVE: To investigate whether time from nephrectomy (Nx) to the diagnosis of metastatic disease may be an independent prognostic factor in metastatic renal cell carcinoma (mRCC) patients treated with targeted therapies (TTs). SUBJECTS AND METHODS: All patients who underwent Nx and at least 1 TT were considered. The patients were divided into two groups based on time from Nx [>1 year (Nx >1) and <1 year (Nx <1)] and a third group for cytoreductive Nx (cNx). Median overall survival (OS) represented the primary outcome. RESULTS: A total of 297 patients met the inclusion criteria. The time from Nx was >1 year in 47%, <1 year in 26% and concomitant with the diagnosis of metastatic disease in 27% of the cases (i.e. cNx). The median OS was 40.6 months (95% CI 30.5-50.7) for the Nx >1 group, 24.3 months (95% CI 17.7-31) for the Nx <1 group and 16.2 months (95% CI 11.2-21.3) for the cNx group (p < 0.05 for all comparisons). On multivariate analysis, time from Nx resulted to be an independent prognostic factor (Nx <1 vs. cNx: HR = 0.62, 95% CI 0.42-0.90, p = 0.13; Nx >1 vs. cNx: HR = 0.43, 95% CI 0.31-0.61, p < 0.001). CONCLUSION: We report that time from Nx is an independent prognostic factor for OS in patients affected by mRCC treated with TTs.

Targeted therapies in advanced renal cell carcinoma: the role of metastatic sites as a prognostic factor.

AIM: This retrospective study evaluates whether metastatic sites were associated with progression-free survival (PFS) and overall survival (OS) in patients with renal cell carcinoma treated with targeted therapies. PATIENTS & METHODS: In total, 358 patients were analyzed. RESULTS & CONCLUSION: After a median follow-up of 56.1 months, median PFS was 11 months and median OS was 24.2 months. Metastatic sites were associated with PFS: lymph nodes (HR: 1.43; 95% CI: 1.12-1.83; p = 0.004), liver (HR: 1.41; 95% CI: 1.05-1.90; p = 0.021), bone (HR: 1.26; 95% CI: 0.96-1.65; p = 0.091), brain (HR: 0.81; 95% CI: 0.46-1.43; p = 0.474) and other sites (HR: 1.07; 95% CI: 0.83-1.38; p = 0.589). Metastatic sites were associated with OS: lymph nodes (HR: 1.73; 95% CI: 1.31-2.29; p < 0.001), liver (HR: 1.71; 95% CI: 1.23-2.37; p = 0.002), bone (HR: 1.48; 95% CI: 1.10-1.98; p = 0.009), brain (HR: 1.21; 95% CI: 0.64-2.28; p = 0.568) and other sites (HR: 1.09; 95% CI: 0.81-1.47; p = 0.568). Patients with >2 metastatic sites had shorter PFS and OS. Every association was lost when introducing the Motzer score in regression models.

Safety profile and treatment response of everolimus in different solid tumors: an observational study.

AIM: Only few efforts have been taken to investigate the potential existence of disease-specific differences in the safety profile of everolimus. We analyze here the correlation between different patient and tumor characteristics on the safety profile of this molecule. Information on treatment response is also provided. METHODS: Consecutive patients with metastatic renal cell carcinoma (mRCC), pancreatic neuroendocrine tumors (pNET) or biliary tract cancer were included in this retrospective study. All patients received everolimus 10 mg/day or 5 mg/day. Clinical assessments were performed every 3 weeks. RESULTS: In total, 98 patients were enrolled: 51 with mRCC, 25 with pNET and 22 with biliary tract cancer. The incidence of toxicities (any grade) was 76% with mRCC, 64% with pNET and 95% with biliary tract cancer. Patients with biliary tract cancer also presented a higher frequency of severe toxicities: 64 versus 18% with mRCC and 32% with pNET. Multivariate analysis disclosed that biliary tract cancer (odds ratio [OR]: 23.8; 95% CI: 6.0-117.8; p < 0.0001) is a predictive factor for the development of toxicities during everolimus treatment. No correlations between liver metastasis and toxicities were identified. Disease control rate (DCR) was 45% in mRCC patients, 96% in pNET and 50% for biliary tract cancer patients. pNET tumors were associated with a higher DCR than the mRCC and biliary tract cancer (OR vs mRCC: 66.7; 95% CI: 6.2-276.5; p = 0.004; OR vs biliary tract cancer: 2.6; 95% CI: 0.5-14.2; p = 0.025). CONCLUSION: This study suggests that the safety profile of everolimus is acceptable in patients with either mRCC or pNET. In addition, the onset of toxicities is associated with an improved DCR. In patients with biliary tract cancer, everolimus is safe but associated with a higher incidence of adverse events.

Patient approach in advanced/metastatic renal cell carcinoma: focus on the elderly population and treatment-related toxicity.

Recent therapeutic advances have changed the treatment landscape of metastatic renal cell carcinoma. Unfortunately, the seven agents now available are not based on biomarkers that would indicate which one could provide the best benefit for every patient. We have reviewed the avaliable information concerning the impact of each treatment on comorbidities or status that are frequently seen before commencing treatment for the advanced disease: elderly and patients with cardiovascular complications, metabolic and endocrinology disorders, and infections, as well as impaired organ function (kidney, liver and heart). Additional new drugs will be launched, but no predictive biomarkers are available. Head-to-head studies to evaluate the safety of the different drugs are rare. In this quite complex scenario, we believe that a decision-making approach focused on the patient may represent a suitable strategy.

Prospective Translational Study Investigating Molecular PrEdictors of Resistance to First-Line PazopanIb in Metastatic reNal CEll Carcinoma (PIPELINE Study).

OBJECTIVES: Despite the initial clinical benefit, resistance to antiangiogenic therapies develops through the activation of alternative pathways. We measured plasma levels of circulating angiogenic factors to explore their predictive role in metastatic renal cell carcinoma (mRCC) patients treated with pazopanib. MATERIALS AND METHODS: mRCC patients receiving first-line pazopanib were prospectively enrolled. The levels of circulating interleuchine (IL)-6, IL-8, stromal derived factor-1, vascular endothelial growth factor-A, hepatocyte growth factor (HGF), osteopontin, and E-selectin were quantified at baseline and every 4 weeks until disease progression (PD). Patients were dichotomized into "low" and "high" subgroups by a cutoff point defined by the respective median circulating angiogenic factor (CAF) value at baseline. Then, association with the objective response was determined. Changes in CAF levels between baseline and PD were also compared. RESULTS: Among 25 patients included in the final data set, 6 patients were still on treatment. As best response, 12 patients presented a partial response (48%), 9 showed stable disease, and 4 showed PD. The median follow-up was 31.9 months. The median progression-free survival was 14.8 months. Low baseline levels of IL-6, IL-8, HGF, and osteopontin were found to be significantly associated with objective response. In addition, patients with low baseline levels of HGF showed longer progression-free survival and overall survival, whereas patients with low baseline levels of IL-8 showed longer overall survival. Among patients experiencing PD, the median plasma levels of stromal derived factor-1 and vascular endothelial growth factor-A were significantly higher compared with the baseline (P=0.01; P=0.011). Conversely, the median levels of E-selectin were significantly lower compared with the baseline (P=0.017). CONCLUSION: Changes in levels of selected CAFs were associated with response/resistance to pazopanib in mRCC patients.

B-type natriuretic peptide after open-water and hyperbaric chamber exposure to 10 msw.

INTRODUCTION: Hyperbaric environment exposure in humans has cardiovascular effects mainly characterized by an increase in afterload and a decrease in cardiac output. In a previous study we did not find B-type natriuretic peptide (BNP) changes in healthy volunteers exposed to hyperbaric oxygen while other authors documented a significant increase in N-terminal pro-BNP after scuba diving. On the basis of these data we hypothesized that dry hyperbaric exposure and scuba diving could have different effects on BNP secretion. METHODS: Nine healthy volunteers performed a 1-h open-sea air dive at 10 m depth (T); a few days later they were compressed in air in a hyperbaric chamber (CT) using the same dive profile. Three venous blood samples were drawn for each session: before starting the dives (T0 and CT0), immediately after exiting the water and the chamber (T1 and CT1), and 5 h later (T2 and CT2). RESULTS: A significant increase in plasma BNP was found with respect to baseline conditions after scuba diving both at T1 (median increment +32.69% [interquartile range +25.62 to +65.35%]) and at T2 (+28.03% [+23.08 to +38.92%]) while no differences were documented after the same dive in dry conditions either at CT1 (+1.34% [-17.57 to +33.55%]) or at CT2 (0.00% [17,67 to +21.62%]). DISCUSSION: These preliminary findings show that scuba diving and dry hyperbaric exposure, although at the same environmental pressure, cause different effects on ventricular loads in healthy subjects.

The Conundrum of Septic Shock Imitators in Patients with Hematologic Cancers: Case Presentation and Possible Differential Diagnoses.

The authors describe the case of a patient treated with several cycles of chemotherapy due to an advanced stage non-Hodgkin lymphoma. One daafter the last cycle, he was admitted to our Intensive Care Unit with a septic shock-like clinical picture which didn't respond to the aggressive treatment and the patient died a few hours later. The autoptical findings cast some doubts on the diagnosis, and demonstrated the presence of other factors imitating its symptoms. In this article, the mimickers of septic shock are reviewed and discussed, as some of them require an aggressive immunosuppression instead of the recommended treatment for septic shock.

Exposure to Multiple Lines of Treatment and Survival of Patients With Metastatic Renal Cell Carcinoma: A Real-world Analysis.

BACKGROUND: The purpose of the present retrospective analysis was to describe the trends in exposure to multiple lines of treatment and overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC) who started therapy in 2 different periods (period 1, 2004-2010; and period 2, 2011-2017). PATIENTS AND METHODS: The proportion of patients who received subsequent lines of treatment after disease progression was compared between the 2 groups. OS was measured from the start of first-line treatment for metastatic disease to death or the last follow-up examination. Both univariate and multivariate analyses were performed. RESULTS: A total of 500 patients were included in the study; 274 started treatment in period 1 and 226 in period 2. Of those patients who stopped first-line treatment because of disease progression, the patients in period 2 had a greater conditional probability to receive second- and third-line treatment compared with patients in period 1 (77.2% vs. 63.7%; odds ratio [OR], 1.93; 95% confidence interval [CI], 1.20-3.11; P = .0065; and 69.6% vs. 48.1%; OR, 2.48; 95% CI, 1.40-4.40; P = .002, respectively). The median OS improved from 22.8 months for patients in period 1 to 38.2 months for patients in period 2 (univariate analysis: hazard ratio, 0.65; 95% CI, 0.50-0.83; P = .001). CONCLUSION: Patients who started treatment during the past 5 years were exposed to a greater number of treatment lines compared with patients treated before 2011. Our data suggest that the increase of treatment options available and clinician expertise could be associated with better outcomes.

TARIBO trial: targeted therapy with or without nephrectomy in metastatic renal cell carcinoma: liquid biopsy for biomarkers discovery.

PURPOSE:: Two randomized trials in the cytokine era showed that cytoreductive nephrectomy (CN) had a role in metastatic renal cell carcinoma (mRCC), increasing life expectancy. The survival benefit of tyrosine kinase inhibitors (TKIs), including first-line sunitinib and pazopanib, in mRCC has been demonstrated, but the majority of patients enrolled in the pivotal phase III studies had undergone nephrectomy. Therefore it is unknown if similar survival benefit with targeted agents could be achieved without CN. We hypothesize that in these patients CN could increase overall survival (OS) in comparison to targeted therapy without CN. We also will investigate mechanisms of primary and secondary resistance to TKIs in patients with mRCC and identify prognostic or predictive biomarkers. METHODS:: This is a randomized, open-label, controlled, multicenter phase 3 study comparing sunitinib or pazopanib vs CN followed by sunitinib or pazopanib as first-line therapy for patients with mRCC who have not received surgery and prior systemic treatment for metastatic disease. We will identify 270 patients eligible for randomization. The planned treatment duration per patient will be until progressive disease is observed. Secondary endpoints are the evaluation of progression-free survival (PFS) and response rate and the assessment of the safety profile. Exploratory objectives include the evaluation of circulating tumor cells and circulating tumor DNA and correlation with response/resistance to treatment. RESULTS:: The study is enrolling patients. CONCLUSIONS:: The use of CN in addition to targeted therapy in patients with renal cell carcinoma with synchronous metastases could lead to a significant improvement in OS and PFS.

Surgery of locally advanced and metastatic kidney cancer after tyrosine kinase inhibitors therapy: single institute experience.

PURPOSE:: Renal cell carcinoma (RCC) is the most common tumor of the kidney. Considering the TNM classification of 2009, locally advanced and metastatic diseases are included in the groups stage III and IV. The surgical treatment of these tumors could be divided into 3 categories: (1) curative (nephrectomy and/or metastasectomy), (2) cytoreductive, and (3) palliative. Targeted agents showed impressive antitumor efficacy and prolongation of progression-free survival. The integration between target therapy and surgery in patients with locally advanced or metastatic RCC has sometimes facilitated surgery. We aimed to evaluate patients' response to tyrosine kinase inhibitor (TKI) therapy and the feasibility of surgery after that and to observe complications related to surgery. METHODS:: From February 2007 to September 2014 in the Istituto Tumori of Milan, IRCCS, we selected patients with locally advanced or metastatic diseases, treated with target therapy before surgery (which comprised nephrectomy or partial nephrectomy, cytoreductive surgery, and metastasectomy) and cryoablation. RESULTS:: We selected 33 patients who underwent surgery after TKI therapy. As for response to TKIs, 20 patients (60%) had stable disease, 9 patients (28%) had a partial response, and 4 patients (12%) had progressive disease. A total of 17 patients (51%) presented complications directly or indirectly related to surgery and most of those were classified as grade II Clavien-Dindo score. CONCLUSIONS:: The association between TKI and surgery seems to have no contraindications. Our dataset provides an example of how surgery after TKI is possible in locally advanced metastatic tumor and does not have an excessive rate of postoperative complications.

B-type natriuretic peptide in healthy subjects after exposure to hyperbaric oxygen at 2.5 ATA.

INTRODUCTION: B-type natriuretic peptide (BNP) is a cardiac hormone used as a marker of cardiac dysfunction with diuretic and vasodilating properties secreted by the ventricles in response to wall stress. Hyperbaric oxygen (HBO) exposure is known to induce hemodynamic effects in humans which can be complicated by acute pulmonary edema. The aim of this study was to investigate if HBO has any effects on the secretion of BNP in healthy human subjects. METHODS: Eight healthy volunteers underwent the following HBO protocol in a hyperbaric chamber: compression to 2.5 atmospheres absolute (ATA); 45 min breathing 100% oxygen; 5 min breathing air; another 45 min in 100% oxygen; then decompression to atmospheric pressure. A venous blood sample was drawn before entering the chamber (To), immediately at the end of the treatment (T1), and at 5 h from To (T2). BNP concentration was determined using a rapid point-of-care immunoassay. Non-parametric statistics were used to analyze data. RESULTS: No difference in BNP levels was found between T0 and T1 or T2. DISCUSSION: The findings of this preliminary study show that in healthy subjects a single HBO exposure does not significantly modify BNP plasma levels. We hypothesize that this can be the net result between the stimulating effect of the HBO-induced vasoconstriction and the direct inhibitory effect on BNP secretion of myocyte hyperoxia. We conclude that HBO does not modify BNP secretion in healthy volunteers and that the direct effect of extreme hyperoxia on BNP secretion deserves further investigation.

Pure small cell recurrent prostate cancer developing syndrome of inappropriate antidiuretic hormone secretion.

PURPOSE: Pure small cell neuroendocrine carcinoma of the prostate is a rare entity characterized by a poor prognosis due to early metastatic spread as well as resistance to treatment. Considering its increasing occurrence, clinicians should be aware of its aggressive behavior, the relevance of an early diagnosis, and proper management. METHODS: A 71-year-old man treated with brachytherapy for localized low-risk prostate cancer developed widespread disease 7 years later with a prostate-specific antigen-negative neuroendocrine small cell phenotype. He was also diagnosed with syndrome of inappropriate antidiuretic hormone secretion (SIADH) soon after starting chemotherapy. RESULTS: A substantial radiologic and clinical response to chemotherapy was observed and the paraneoplastic SIADH was successfully treated with oral vaptan therapy. CONCLUSIONS: Secondary small cell prostate carcinoma is an underestimated entity with high sensitivity to chemotherapy, although a standard treatment has not yet been defined. Moreover, oral vaptans demonstrated prompt efficacy and simple management in correcting SIADH-related hyponatremia.

Multimodal treatment of advanced renal cancer in 2017.

INTRODUCTION: in the last decades, the treatment of renal cell carcinoma has become more complex due to the introduction of novel systemic agents and the improvement of the loco-regional therapies that prolong survival maintaining a good quality of life. Areas covered: in this review, we summarize the currently available local and systemic treatment options, their indications and their hypothetical role in the management of advanced renal cell carcinoma, highlighting the need of multimodality treatment paradigms within interdisciplinary decision-making. Expert commentary: in early disease, radical or partial nephrectomy remains the standard of care, but innovative ablation techniques, including radiofrequency ablation, microwave ablation, cryoablation and so on, may represent an alternative option of treatment for small renal lesions in unfit patients who cannot undergo surgery. In metastatic setting, it is imperative a multidisciplinary team approach to select patients for a cytoreductive nephrectomy, metastasectomy, and/or systemic treatment, aiming to the optimization of the treatment strategy.

Does Dose Modification Affect Efficacy of First-Line Pazopanib in Metastatic Renal Cell Carcinoma?

BACKGROUND: Pazopanib is a standard treatment for metastatic renal cell carcinoma (mRCC), and 800 mg/daily is considered the optimal dose. However, some patients require dose modification because of toxicity. Whether a reduced dose of pazopanib is as effective as the standard dose in achieving clinical benefit remains unclear. OBJECTIVES: Our objective was to conduct a retrospective analysis to investigate the clinical effect of different therapeutic doses of first-line pazopanib in patients with mRCC. METHODS: Consecutive patients with mRCC treated with first-line pazopanib between 2011 and 2016 at the Istituto Nazionale Tumori of Milan were retrospectively analysed for demographics, response, outcomes, and toxicity. Three patient groups were compared: group 1 received the standard dose of 800 mg/day; group 2 started with 800 mg/day and then reduced the dose to 400 or 600 mg/day because of toxicity; and group 3 received a reduced starting dose of 400 or 600 mg/day because they had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 and/or comorbidities. RESULTS: In total, 69 patients were evaluated: 34 in group 1, 19 in group 2, and 16 in group 3. After a median follow-up of 13.9 months (range 0.3-43.8), 27 (39.1%) patients had progressive disease (PD) and three (4.3%) patients had died. The incidence rate of PD or death per 100 person-months was 2.5 [95% confidence interval (CI) 0.6-4.4; hazard ratio (HR) 1] in group 1 and 3.9 (95% CI 0-14.3; HR 1.43) in the combined group (2 + 3). The discontinuation rate due to PD was 28% in group 1, 42% in group 2, and 44% in group 3. The objective response rate was 44, 11, and 19% in groups 1, 2, and 3, respectively. CONCLUSIONS: Our results may suggest that patients with mRCC receiving a lower dose of first-line pazopanib might not have a meaningful progression-free survival advantage compared with those receiving a standard dose. These data highlight that proper management of treatment-related side effects may lead to optimal drug exposure.

Everolimus treatment for neuroendocrine tumors: latest results and clinical potential.

Neuroendocrine tumors (NETs) are a heterogeneous class of diseases characterized by challenging management. Preclinical evidence shows that the PI3K/AKT/mTOR signaling pathway plays a central role in the pathogenesis and progression of NETs. Everolimus is a direct inhibitor of this pathway, and therefore this molecule appears to be a well-grounded strategy for the treatment of NETs, capable of changing clinical practice. The efficacy and safety of everolimus was demonstrated in the RADIANT trials. In this work, we comment on the results of the RADIANT trials, and other recent key evidence from fully published clinical trials on everolimus, and we discuss the current role of everolimus in the treatment of NETs.

Anti-inflammatory activity of two diterpenes of Hyptis suaveolens from El Salvador.

Separation and isolation of the two main compounds suaveolol and methyl suaveolate from leaves of chichinguaste (Hyptis suaveolens Poit., Lamiaceae) could be achieved by means of repeated column chromatography and repeated preparative thin layer chromatography. Their chemical structures were approved by MS, 1H NMR, 13C NMR and 2D-NMR experiments. The anti-inflammatory activity of the two compounds was tested for the first time as inhibition of croton oil-induced dermatitis of the mouse ear. Suaveolol and methyl suaveolate showed nearly the same dose-dependent topical anti-inflammatory activity, only two to three times lower than that of the reference drug indomethacin. The anti-inflammatory properties of these compounds could contribute to the antiphlogistic activity of extracts of Hyptis species and confirm the rational use of Hyptis suaveolens extracts in dermatological diseases.

Nivolumab in the treatment of advanced renal cell carcinoma: clinical trial evidence and experience.

Renal cell carcinoma (RCC) is considered an immunogenic tumor with a prominent dysfunctional immune cell infiltrate, unable to control tumor growth. Cytokine-based immunotherapies, including interferon-α and interleukin-2, have been used for the treatment of metastatic RCC (mRCC). Long-term responses and complete remissions were observed, but durable clinical benefit efficacy in the overall population was limited and associated with significant toxicity. As a consequence, new generation agents targeting the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways replaced interferon alpha (IFN-α). Strategies of tumor immune evasion include T-cell suppression by negative signals deriving from the interaction between programmed death-1 (PD-1) on the T cell and its ligand (PDL-1) on the tumor cells. Nivolumab, a programmed death 1 checkpoint inhibitor, blocks this pathway, thus reversing T-cell suppression and activating antitumor responses. The aim of this review is to summarize the safety and efficacy data of nivolumab in mRCC. Objective responses and safety profile of single-agent nivolumab are favorable in both previously treated and treatment-naïve mRCC patients. Despite toxic effects, combination therapies with nivolumab have shown promising results, indicating a potential role in the treatment of mRCC. Tailoring immunotherapy on a patient-to-patient basis represents a major challenge for the future.