Introduction Marfan syndrome patients are prone to aortic dilatation, dissection, and rupture. Success of aortic root replacement has generated a cohort of patients surviving longer and presenting ...with distal aortic dissection and enlargement. Thoracic endovascular stent-graft repair (TEVR) is being increasingly utilized to exclude aneurysms resulting from chronic aortic dissection. This report explores the role of TEVR in Marfan patients with this pathology. Methods Review of a prospectively maintained database identified seven patients with Marfan syndrome offered endovascular repair of aneurysmal chronic aortic dissection. All patients had previous aortic root repair. Talent or Valiant (Medtronic Vascular, Santa Rosa, Calif) aortic stent-grafts were used to occlude the dissection entry tear and cover the thoracic aorta. Electronic data, case notes, and radiological surveillance were analyzed. Results Seven consecutive patients (six male; mean age, 45.9 ± 10 years, range, 29 to 63) underwent successful thoracic stent-graft deployment. Mean aortic aneurysmal diameter was 63.4mm (±11.2) with six of seven dissections extending to the aortic bifurcation. No perioperative neurological events occurred. Thirty-day mortality was 1/7 (14%) due to congestive cardiac failure. At median 16 month follow-up, two of six cases (33%) required intervention for endoleak. Aortic false lumen thrombosis (FLT) occurred in 5/6 (83%) cases and partial FLT occurred in 1/6 (17%). All thoracic aortas continued to dilate during follow-up. Crude median aortic growth rate was 7.2 mm/year (range, 3.5 to 19 mm). Conclusion TEVR in Marfan syndrome patients with chronic aortic dissection is technically feasible. However, post intervention surveillance confirms that the aorta continues to dilate despite graft deployment and false lumen thrombosis. Endovascular repair may offer a viable option in patients who have contraindications to open surgery, but longer follow up of more patients is required to define the place of this therapy.
Chronic inflammation is hypothesized to influence prostate cancer development, although a definitive link has not been established.
Prostate cancer cases (N = 191) detected on a for-cause (clinically ...indicated) or end-of-study (protocol directed) biopsy, and frequency-matched controls (N = 209), defined as negative for cancer on an end-of-study biopsy, were sampled from the placebo arm of the Prostate Cancer Prevention Trial. Inflammation prevalence and extent in benign areas of biopsy cores were visually assessed using digital images of hematoxylin and eosin-stained sections. Logistic regression was used to estimate associations.
Of note, 86.2% of cases and 78.2% of controls had at least one biopsy core (of three assessed) with inflammation in benign areas, most of which was chronic. Men who had at least one biopsy core with inflammation had 1.78 95% confidence interval (CI), 1.04-3.06 times the odds of prostate cancer compared with men who had zero cores with inflammation. The association was stronger for high-grade disease (Gleason sum 7-10, N = 94; OR, 2.24; 95% CI, 1.06-4.71). These patterns were present when restricting to cases and controls in whom intraprostatic inflammation was the least likely to have influenced biopsy recommendation because their prostate-specific antigen (PSA) was low (<2 ng/mL at biopsy).
Inflammation, most of which was chronic, was common in benign prostate tissue, and was positively associated with prostate cancer, especially high grade. The association did not seem to be due to detection bias.
This study supports an etiologic link between inflammation and prostate carcinogenesis, and suggests an avenue for prevention by mitigating intraprostatic inflammation.
Reports have suggested that metastatic site is an important predictor of overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC), but these were based on a limited ...number of patients. We investigate the impact of site of metastases on OS of a substantial sample of men with mCRPC who received docetaxel chemotherapy in nine phase III trials.
Individual patient data from 8,820 men with mCRPC enrolled onto nine phase III trials were combined. Site of metastases was categorized as lymph node (LN) only, bone with or without LN (with no visceral metastases), any lung metastases (but no liver), and any liver metastases.
Most patients had bone with or without LN metastases (72.8%), followed by visceral disease (20.8%) and LN-only disease (6.4%). Men with liver metastases had the worst median OS (13.5 months). Although men with lung metastases had better median OS (19.4 months) compared with men with liver metastases, they had significantly worse median survival duration than men with nonvisceral bone metastases (21.3 months). Men with LN-only disease had a median OS of 31.6 months. The pooled hazard ratios for death in men with lung metastases compared with men with bone with or without LN metastases and in men with any liver metastases compared with men with lung metastases were 1.14 (95% CI, 1.04 to 1.25; P = .007) and 1.52 (95% CI, 1.35 to 1.73; P < .0001), respectively.
Specific sites of metastases in men with mCRPC are associated with differential OS, with successive increased lethality for lung and liver metastases compared with bone and nonvisceral involvement. These data may help in treatment decisions, the design of future clinical trials, and understanding the variation in biology of different sites of metastases in men with mCRPC.
The COXEN gene expression model was evaluated for prediction of response to neoadjuvant chemotherapy for muscle-invasive bladder cancer (MIBC).
To conduct a secondary analysis of the association of ...each COXEN score with event-free survival (EFS) and overall survival (OS) and by treatment arm.
This was a randomized phase 2 trial of neoadjuvant gemcitabine-cisplatin (GC) or dose-dense methotrexate-vinblastine-adriamycin-cisplatin (ddMVAC) in MIBC.
Patients were randomized to ddMVAC (every 14 d) or GC (every 21 d), both for four cycles.
EFS events were defined as progression or death before scheduled surgery, a decision to not undergo surgery, recurrence, or death due to any cause after surgery. Cox regression was used to evaluate the COXEN score or treatment arm association with EFS and OS.
A total of 167 evaluable patients were included in the COXEN analysis. The COXEN scores were not significantly prognostic for OS or EFS in the respective arms, but the GC COXEN score had a hazard ratio (HR) of 0.45 (95% confidence interval CI 0.20-0.99; p = 0.047) when the arms were pooled. In the intent-to-treat analysis (n = 227), there was no significant difference between ddMVAC and GC for OS (HR 0.87, 95% CI 0.54-1.40; p = 0.57) or EFS (HR 0.86, 95% CI 0.59-1.26; p = 0.45). Among the 192 patients who underwent surgery, pathologic response (pT0 vs downstaging vs no response) was strongly correlated with superior postsurgical survival (5-yr OS 90%, 89% and 52%, respectively).
The COXEN GC score has prognostic value for patients receiving cisplatin-based neoadjuvant treatment. The randomized, prospective design provides estimates of OS and EFS for GC and ddMVAC in this population. Pathologic response (<pT2) performed well as an intermediate endpoint in this modern cohort. For expediency in evaluating new regimens, pathologic response should continue to be used in phase 2 trials.
In this study, we evaluated a biomarker to predict the response to chemotherapy. The results did not meet the preset study parameters, but our study provides information on clinical outcomes with the use of chemotherapy before surgery for bladder cancer.
The risk factors for cardiovascular disease and erectile dysfunction are similar.
To examine the association of erectile dysfunction and subsequent cardiovascular disease.
Men aged 55 years or older ...who were randomized to the placebo group (n = 9457) in the Prostate Cancer Prevention Trial at 221 US centers were evaluated every 3 months for cardiovascular disease and erectile dysfunction between 1994 and 2003. Proportional hazards regression models were used to evaluate the association of erectile dysfunction and cardiovascular disease. In an adjusted model, covariates included age, body mass index, blood pressure, serum lipids, diabetes, family history of myocardial infarction, race, smoking history, physical activity, and quality of life.
Erectile dysfunction and cardiovascular disease.
Of the 9457 men randomized to placebo, 8063 (85%) had no cardiovascular disease at study entry; of these men, 3816 (47%) had erectile dysfunction at study entry. Among the 4247 men without erectile dysfunction at study entry, 2420 men (57%) reported incident erectile dysfunction after 5 years. After adjustment, incident erectile dysfunction was associated with a hazard ratio of 1.25 (95% confidence interval CI, 1.02-1.53; P = .04) for subsequent cardiovascular events during study follow-up. For men with either incident or prevalent erectile dysfunction, the hazard ratio was 1.45 (95% CI, 1.25-1.69; P<.001). For subsequent cardiovascular events, the unadjusted risk of an incident cardiovascular event was 0.015 per person-year among men without erectile dysfunction at study entry and was 0.024 per person-year for men with erectile dysfunction at study entry. This association was in the range of risk associated with current smoking or a family history of myocardial infarction.
Erectile dysfunction is a harbinger of cardiovascular clinical events in some men. Erectile dysfunction should prompt investigation and intervention for cardiovascular risk factors.
Radical cystectomy is the surgical standard for invasive bladder cancer. Robot-assisted cystectomy has been proposed to provide similar oncological outcomes with lower morbidity. We aimed to compare ...progression-free survival in patients with bladder cancer treated with open cystectomy and robot-assisted cystectomy.
The RAZOR study is a randomised, open-label, non-inferiority, phase 3 trial done in 15 medical centres in the USA. Eligible participants (aged ≥18 years) had biopsy-proven clinical stage T1–T4, N0–N1, M0 bladder cancer or refractory carcinoma in situ. Individuals who had previously had open abdominal or pelvic surgery, or who had any pre-existing health conditions that would preclude safe initiation or maintenance of pneumoperitoneum were excluded. Patients were centrally assigned (1:1) via a web-based system, with block randomisation by institution, stratified by type of urinary diversion, clinical T stage, and Eastern Cooperative Oncology Group performance status, to receive robot-assisted radical cystectomy or open radical cystectomy with extracorporeal urinary diversion. Treatment allocation was only masked from pathologists. The primary endpoint was 2-year progression-free survival, with non-inferiority established if the lower bound of the one-sided 97·5% CI for the treatment difference (robotic cystectomy minus open cystectomy) was greater than −15 percentage points. The primary analysis was done in the per-protocol population. Safety was assessed in the same population. This trial is registered with ClinicalTrials.gov, number NCT01157676.
Between July 1, 2011, and Nov 18, 2014, 350 participants were randomly assigned to treatment. The intended treatment was robotic cystectomy in 176 patients and open cystectomy in 174 patients. 17 (10%) of 176 patients in the robotic cystectomy group did not have surgery and nine (5%) patients had a different surgery to that they were assigned. 21 (12%) of 174 patients in the open cystectomy group did not have surgery and one (1%) patient had robotic cystectomy instead of open cystectomy. Thus, 302 patients (150 in the robotic cystectomy group and 152 in the open cystectomy group) were included in the per-protocol analysis set. 2-year progression-free survival was 72·3% (95% CI 64·3 to 78·8) in the robotic cystectomy group and 71·6% (95% CI 63·6 to 78·2) in the open cystectomy group (difference 0·7%, 95% CI −9·6% to 10·9%; pnon-inferiority=0·001), indicating non-inferiority of robotic cystectomy. Adverse events occurred in 101 (67%) of 150 patients in the robotic cystectomy group and 105 (69%) of 152 patients in the open cystectomy group. The most common adverse events were urinary tract infection (53 35% in the robotic cystectomy group vs 39 26% in the open cystectomy group) and postoperative ileus (33 22% in the robotic cystectomy group vs 31 20% in the open cystectomy group).
In patients with bladder cancer, robotic cystectomy was non-inferior to open cystectomy for 2-year progression-free survival. Increased adoption of robotic surgery in clinical practice should lead to future randomised trials to assess the true value of this surgical approach in patients with other cancer types.
National Institutes of Health National Cancer Institute.
Endovenous ablation of varicose veins using radiofrequency ablation (RFA) and endovenous laser therapy (EVLT) has reported advantages over traditional open surgical treatment. There is little ...evidence comparing the efficacy and patient-reported outcomes between the 2 endovenous solutions. This study compares the RFA and EVLT strategies in a prospective double-blind clinical trial.
Consecutive patients with primary unilateral great saphenous vein (GSV) reflux undergoing endovenous treatment were randomized to RFA (VNUS ClosureFAST) or EVLT (810-nm diode laser). The primary outcome measure was GSV occlusion at 3 months after treatment. Secondary outcome measures were occlusion at 7 days, postoperative pain, analgesic requirement, and bruising, assessed at day 7 after surgery. Quality of life (QoL) was assessed preoperatively and 3 months after surgery using the Aberdeen Varicose Vein Questionnaire (AVVQ) and EQ-5D.
A total of 159 patients were randomized to RFA (79 patients) or EVLT (80 patients). Groups were well matched for demographics, disease extent, severity, and preoperative QoL. Duplex scanning confirmed 100% vein occlusion at 1 week in both groups. At 3 months, occlusion was 97% for RFA and 96% for EVLT; P = 0.67. Median (interquartile range) percentage above-knee bruise area was greater after EVLT 3.85% (6.1) than after RFA 0.6% (2); P = 0.0001. Postoperative pain assessed at each of the first 7 postoperative days was less after RFA (P = 0.001). Changes in the AVVQ (P = 0.12) and EQ-5D (P = 0.66) at 3 months were similar in both groups.
RFA and EVLT offer comparable venous occlusion rates at 3 months after treatment of primary GSV varices; with neither modality proving superior. RFA is associated with less periprocedural pain, analgesic requirement, and bruising.
ISRCTN63135694 (http://www.controlled-trials.com).
Although radical cystectomy (RC) is the standard of care for patients with bacillus Calmette-Guérin (BCG)-unresponsive high-risk non-muscle-invasive bladder cancer (NMIBC), many patients are ...ineligible for surgery or elect bladder preservation.
To evaluate the efficacy and safety of atezolizumab in BCG-unresponsive high-risk NMIBC.
This was a single-arm phase 2 trial in patients with BCG-unresponsive high-risk NMIBC who were ineligible for or declined RC.
Intravenous atezolizumab every 3 wk for 1 yr.
The primary endpoint was the pathological complete response (CR) rate for patients with carcinoma in situ (CIS) determined via mandatory biopsy at 6 mo. Event-free survival (EFS) at 18 mo for patients with non-CIS tumors and treatment-related adverse events (TRAEs) were key secondary endpoints.
Of 172 patients enrolled in the trial, 166 received at least one dose of atezolizumab (safety analysis) and 129 were eligible (efficacy analysis). Of the 74 patients with CIS, 20 (27%) experienced a CR at 6 mo. The median duration of response was 17 mo, and 56% (95% confidence interval CI 34-77%) of the responses were durable to at least 12 mo. The 18-mo actuarial EFS rate among 55 patients with Ta/T1 disease was 49% (90% CI 38-60%). Twelve of 129 eligible patients experienced progression to muscle-invasive or metastatic disease. Grade 3-5 TRAEs occurred in 26 patients (16%), including three treatment-related deaths. The study was limited by the small sample size and a high rate of patient ineligibility.
The efficacy of atezolizumab observed among patients with BCG-unresponsive NMIBC is similar to results from similar trials with other agents, but did not meet the prespecified efficacy threshold. Modest efficacy needs to be balanced with a significant rate of TRAEs and the risk of disease progression when considering systemic immunotherapy in early-stage bladder cancer.
We tested intravenous immunotherapy (atezolizumab) in patients with high-risk non-muscle-invasive bladder cancer that recurred after BCG (bacillus Calmette-Guérin) treatment. Although we found similar outcomes to previous trials, the benefit of this therapy is modest and needs to be carefully balanced with the significant risk of side effects. This trial is registered on ClinicalTrials.gov as NCT02844816.
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