We assessed the distribution of site-specific metastases in patients with renal cell carcinoma (RCC) according to age. Moreover, we evaluated recommendations proposed by guidelines and focused ...specifically on bone and brain metastases.
Patients with metastatic RCC (mRCC) were abstracted from the Nationwide Inpatient Sample (1998–2007). Age was stratified into four groups: <55, 55–64, 65–74 and ≥75 years. Cochran–Armitage trend test and multivariable logistic regression analysis tested the relationship between age and the rate of multiple metastatic sites. Finally, we examined the rates of brain or bone metastases according to the presence of other metastatic sites.
In 11 157 mRCC patients, the rate of multiple metastatic sites decreased with increasing age (P < 0.001). This phenomenon was confirmed in patients with lung, bone, liver and brain metastases (all P ≤ 0.01). The rate of bone metastases was 10% in patients with exclusive abdominal metastases and 49% in patients with abdominal, thoracic and brain metastases. The rate of brain metastases was 2% in patients with exclusive abdominal metastases and 16% in patients with thoracic and bone metastases.
The proportion of patients with multiple metastatic sites is higher in young patients. The rates of bone (10%–49%) and brain (2%–16%) metastases are nonnegligible in mRCC patients.
To investigate the prevalence of erectile dysfunction (ED) in patients with CAD according to clinical presentation, acute coronary syndrome (ACS) vs. chronic coronary syndrome (CCS), and extent of ...vessel involvement (single vs. multi-vessel disease).
285 patients with CAD divided into three age-matched groups: group 1 (G1, n=95), ACS and one-vessel disease (1-VD); group 2 (G2, n=95), ACS and 2,3-VD; group 3 (G3, n=95), chronic CS. Control group (C, n=95) was composed of patients with suspected CAD who were found to have entirely normal coronary arteries by angiography. Gensini's score used to assess extent of CAD. ED as any value <26 according to the International Index of Erectile Function (IIEF). ED prevalence was lower in G1 vs. G3 (22 vs. 65%, P<.0001) as a result of less atherosclerotic burden as expressed by Gensini's score 2 (0-6) vs. 40 (19-68), P=0.0001. Controls had ED rate values similar to G1 (24%). Group 2 ED rate, IIEF, and Gensini's scores were significantly different from G1 55%, P<0.0001; 24 (17-29), P=0.0001; 21 (12.5-32), P<0.0001 and similar to G3 suggesting that despite similar clinical presentation, ED in ACS differs according to the extent of CAD. No significant difference between groups was found in the number and type of conventional risk factors. Treatment with beta-blockers was more frequent in G3 vs. G1 and G2. In G3 patients who had ED, onset of sexual dysfunction occurred before CAD onset in 93%, with a mean time interval of 24 12-36 months. In logistic regression analysis, age (OR=1.1; 95% confidence interval (CI), 1.05-1.16; P=<0.0001), multi-vessel vs. single-vessel (OR=2.53; 95% CI, 1.43-4.51; P=0.0002), and CCS vs. ACS (OR=2.32; 95% CI, 1.22-4.41; P=0.01) were independent predictors of ED.
ED prevalence differs across subsets of patients with CAD and is related to coronary clinical presentation and extent of CAD. In patients with established CAD, ED comes before CAD in the majority by an average of 2 up to 3 years.
Abstract Objectives To examine perioperative and oncologic outcomes of open (ORC) and robot-assisted radical cystectomy (RARC) in bladder cancer (BCa) patients. Methods and materials 368 consecutive ...patients with cT1-4 M0 BCa treated at two high-volume European centers between 2004 and 2013 were evaluated. Data on complications, operative time, blood loss, postoperative transfusion, reoperation, length of stay (LOS), positive margins, recurrence, cancer-specific mortality (CSM), and overall survival were evaluated. Uni- and multivariable regression analyses tested the impact of the surgical approach on perioperative and oncologic outcomes. Results Overall, 230 (62.5%) and 138 (37.5%) patients were treated with ORC and RARC. In multivariable analyses RARC patients had higher odds of prolonged operative time and low-grade complications (all P ≤ 0.001). Patients treated with ORC had higher odds of blood loss >500 ml and prolonged LOS (all P ≤ 0.03). No differences were observed in high-grade complications and positive margins (all P ≥ 0.06). No differences were observed in 5-year recurrence-free and CSM-free survival rates between patients treated with ORC vs. RARC (57.1 vs. 54.2% and 61.9 vs. 73.5%; all P ≥ 0.3). This was confirmed in multivariable analyses, where the surgical approach was not associated with the risk of recurrence and CSM (all P ≥ 0.1). Conclusions Although ORC might be associated with a shorter operative time, RARC led to lower blood loss and shorter LOS. No differences exist in high-grade complications and positive margins. RARC and ORC provide similar oncologic control.
Initial studies of preoperative checkpoint inhibition before radical cystectomy (RC) have shown promising pathologic complete responses. We aimed to analyze the survival outcomes of patients enrolled ...in the PURE-01 study (NCT02736266).
We report the results of the secondary end points of PURE-01 in the final population of 143 patients. In particular, we report the event-free survival (EFS) outcomes, defined as the time from the first cycle of pembrolizumab to radiographic disease progression precluding RC, initiation of neoadjuvant chemotherapy (NAC), recurrence after RC, or death from any cause. Other end points were recurrence-free survival (RFS) and overall survival (OS). Subgroup analyses were carried out, including pathological response category, clinical complete responses (CR) assessed via multiparametric magnetic resonance imaging (mpMRI), and molecular subtyping. Cox regression analyses for EFS were also carried out.
After a median interquartile range (IQR) follow-up of 23 (15-29) months, 12- and 24-month EFS were 84.5% 95% confidence interval (CI): 78.5-90.9 and 71.7% (62.7-82). The prognosis was favorable across all the different pathological response subgroups, with the exception of ypN+ (N = 21), showing a 24-month RFS (95% CI) of 39.3% (19.2% to 80.5%). A statistically significant EFS benefit was observed in patients with a clinical CR (P = 0.002). Programmed cell-death-ligand-1 combined positive score was significantly associated with longer EFS in multivariable analyses. Four patients refused RC after clinical evidence of CR, and none of them have recurred after a median follow-up of 10 months (IQR: 11-15). The claudin-low subtype displayed a numerically longer EFS after pembrolizumab and RC compared with the other subtypes.
The EFS results from PURE-01 revealed that the immunotherapy effect was maintained post-RC in most patients. Pembrolizumab compared favorably with neoadjuvant chemotherapy, irrespective of the biomarker status. Molecular subtyping may be a useful tool to select the patients who are predicted to benefit the most from neoadjuvant pembrolizumab.
•The PURE-01 study tested neoadjuvant pembrolizumab in patients with muscle invasive bladder cancer.•Pembrolizumab has shown promising activity in this setting, reaching 38.5% of complete response (ypT0ypN0).•Event-free survival is also encouraging with 84.5% and 71.7% rates at 12 and 24 months from immunotherapy initiation.•Survival benefit seems spread to all pathological response subgroups with the exception of ypN+ patients.•Molecular subtyping may be a useful tool to select the patients who are predicted to benefit the most from neoadjuvant pembrolizumab.
Overwhelming evidence indicates that cancer is a genetic disease caused by the accumulation of mutations in oncogenes and tumor suppressor genes. It is also increasingly apparent, however, that ...cancer depends not only on mutations in these coding genes but also on alterations in the large class of non-coding RNAs. Here, we report that one such long non-coding RNA, TRPM2-AS, an antisense transcript of TRPM2, which encodes an oxidative stress-activated ion channel, is overexpressed in prostate cancer (PCa). The high expression of TRPM2-AS and its related gene signature were found to be linked to poor clinical outcome, with the related gene signature working also independently of the patient's Gleason score. Mechanistically, TRPM2-AS knockdown led to PCa cell apoptosis, with a transcriptional profile that indicated an unbearable increase in cellular stress in the dying cells, which was coupled to cell cycle arrest, an increase in intracellular hydrogen peroxide and activation of the sense TRPM2 gene. Moreover, targets of existing drugs and treatments were found to be consistently associated with high TRPM2-AS levels in both targeted cells and patients, ultimately suggesting that the measurement of the expression levels of TRPM2-AS allows not only for the early identification of aggressive PCa tumors, but also identifies a subset of at-risk patients who would benefit from currently available, but mostly differently purposed, therapeutic agents.
Summary
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A significant proportion of men with erectile dysfunction (ED) exhibit early signs of coronary artery disease (CAD), and this group may develop more severe CAD than men without ED (Level ...1, Grade A).
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The time interval among the onset of ED symptoms and the occurrence of CAD symptoms and cardiovascular events is estimated at 2–3 years and 3–5 years respectively; this interval allows for risk factor reduction (Level 2, Grade B).
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ED is associated with increased all‐cause mortality primarily due to increased cardiovascular mortality (Level 1, Grade A).
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All men with ED should undergo a thorough medical assessment, including testosterone, fasting lipids, fasting glucose and blood pressure measurement. Following assessment, patients should be stratified according to the risk of future cardiovascular events. Those at high risk of cardiovascular disease should be evaluated by stress testing with selective use of computed tomography (CT) or coronary angiography (Level 1, Grade A).
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Improvement in cardiovascular risk factors such as weight loss and increased physical activity has been reported to improve erectile function (Level 1, Grade A).
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In men with ED, hypertension, diabetes and hyperlipidaemia should be treated aggressively, bearing in mind the potential side effects (Level 1, Grade A).
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Management of ED is secondary to stabilising cardiovascular function, and controlling cardiovascular symptoms and exercise tolerance should be established prior to initiation of ED therapy (Level 1, Grade A).
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Clinical evidence supports the use of phosphodiesterase 5 (PDE5) inhibitors as first‐line therapy in men with CAD and comorbid ED and those with diabetes and ED (Level 1, Grade A).
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Total testosterone and selectively free testosterone levels should be measured in all men with ED in accordance with contemporary guidelines and particularly in those who fail to respond to PDE5 inhibitors or have a chronic illness associated with low testosterone (Level 1, Grade A).
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Testosterone replacement therapy may lead to symptomatic improvement (improved wellbeing) and enhance the effectiveness of PDE5 inhibitors (Level 1, Grade A).
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Review of cardiovascular status and response to ED therapy should be performed at regular intervals (Level 1, Grade A).
Four weeks after bilateral nerve-sparing radical retropubic prostatectomy, men with normal erectile function before surgery were randomized to double-blind sildenafil (50 or 100 mg) or placebo ...nightly for 36 weeks, followed by an 8-week drug-free period before assessment of erectile function. Enrollment was prematurely ceased and only 76 men completed because, assuming a placebo response rate similar to the published literature (for example, 34% in meta-analysis), the 25% response at blinded interim review suggested a lack of treatment effect. On the contrary, spontaneous erectile function (a combined score of >or=8 for questions 3 and 4 of the International Index of Erectile Function and a positive response to 'Were erections good enough for satisfactory sexual activity?') occurred in only 4% of the placebo group (n=1 of 25) versus 27% (n=14 of 51, P=0.0156, Fisher's exact test) of the sildenafil group. Nightly sildenafil administration for 36 weeks after surgery markedly increased the return of normal spontaneous erections.
Pembrolizumab is a new standard of care for patients with platinum-treated, metastatic urothelial carcinoma (UC). Nab-paclitaxel is active in advanced UC. In the PEANUT study (NCT03464734) we ...investigated their combination in advanced UC.
PEANUT was an open-label, single-arm, phase II trial that included patients who had failed one or two chemotherapy regimens, including platinum chemotherapy. Biomarker analyses focused on programmed cell-death ligand-1 combined positive score (CPS) and comprehensive genomic profiling on tumor samples and circulating tumor DNA. Patients received 200 mg pembrolizumab on day 1 (D1), and 125 mg/m2 nab-paclitaxel on D1 and D8, every 3 weeks, until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) according to RECIST (v1.1). The assumption was to detect an improvement in the median PFS from ≤3.0 months (H0) to ≥5.0 months (H1).
Between January 2019 and January 2020, the PEANUT study enrolled 70 patients: 24% had failed two prior systemic therapies; 31% had an Eastern Cooperative Oncology Group (ECOG) performance status of 1; and 28.6% had liver metastases. After a median follow-up of 9.8 months, 40 patients have relapsed (57.1%). The median PFS was 5.9 months 95% confidence interval (CI) 3.1–11.5. The confirmed objective response rate (ORR) was 38.6% (95% CI 27–51) with 17 partial responses and 10 complete responses (14.3%). The median duration of response was not reached. Five patients (7.1%) had ongoing responses lasting >12 months. The most common any-grade treatment-related adverse events included alopecia (71.4%), neutropenia (32.9%), and peripheral neuropathy (34.3%). Neither tumor mutational burden nor CPS was significantly associated with PFS at univariable analyses. The single-arm design of the trial was the major limitation.
Pembrolizumab combined with nab-paclitaxel, as second- and third-line chemoimmunotherapy for metastatic UC, showed a favorable safety profile, durable PFS, and a clinically meaningful ORR in these preliminary analyses. This combination warrants additional randomized studies in earlier disease stages.
ClinicalTrials.govNCT03464734; https://clinicaltrials.gov/ct2/show/NCT03464734.
•Pembrolizumab and nab-paclitaxel were evaluated in 70 patients with platinum-treated, metastatic urothelial carcinoma.•The median PFS was 5.9 months, the objective response rate was 38.6%, and the median duration of response was not reached.•Grade 3–4 treatment-related adverse events were observed in 17 patients (24.3%).•This study presented results from one of the first salvage chemoimmunotherapy regimens in advanced urothelial carcinoma.
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