We previously reported a 35-gene expression classifier identifying four clear-cell renal cell carcinoma groups (ccrcc1 to ccrcc4) with different tumour microenvironments and sensitivities to ...sunitinib in metastatic clear-cell renal cell carcinoma. Efficacy profiles might differ with nivolumab and nivolumab–ipilimumab. We therefore aimed to evaluate treatment efficacy and tolerability of nivolumab, nivolumab–ipilimumab, and VEGFR-tyrosine kinase inhibitors (VEGFR-TKIs) in patients according to tumour molecular groups.
This biomarker-driven, open-label, non-comparative, randomised, phase 2 trial included patients from 15 university hospitals or expert cancer centres in France. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0–2, and had previously untreated metastatic clear-cell renal cell carcinoma. Patients were randomly assigned (1:1) using permuted blocks of varying sizes to receive either nivolumab or nivolumab–ipilimumab (ccrcc1 and ccrcc4 groups), or either a VEGFR-TKI or nivolumab–ipilimumab (ccrcc2 and ccrcc3 groups). Patients assigned to nivolumab–ipilimumab received intravenous nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by intravenous nivolumab 240 mg every 2 weeks. Patients assigned to nivolumab received intravenous nivolumab 240 mg every 2 weeks. Patients assigned to VEGFR-TKIs received oral sunitinib (50 mg/day for 4 weeks every 6 weeks) or oral pazopanib (800 mg daily continuously). The primary endpoint was the objective response rate by investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1. The primary endpoint and safety were assessed in the population who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02960906, and with the EU Clinical Trials Register, EudraCT 2016-003099-28, and is closed to enrolment.
Between June 28, 2017, and July 18, 2019, 303 patients were screened for eligibility, 202 of whom were randomly assigned to treatment (61 to nivolumab, 101 to nivolumab–ipilimumab, 40 to a VEGFR-TKI). In the nivolumab group, two patients were excluded due to a serious adverse event before the first study dose and one patient was excluded from analyses due to incorrect diagnosis. Median follow-up was 18·0 months (IQR 17·6–18·4). In the ccrcc1 group, objective responses were seen in 12 (29%; 95% CI 16–45) of 42 patients with nivolumab and 16 (39%; 24–55) of 41 patients with nivolumab–ipilimumab (odds ratio OR 0·63 95% CI 0·25–1·56). In the ccrcc4 group, objective responses were seen in seven (44%; 95% CI 20–70) of 16 patients with nivolumab and nine (50% 26–74) of 18 patients with nivolumab–ipilimumab (OR 0·78 95% CI 0·20–3·01). In the ccrcc2 group, objective responses were seen in 18 (50%; 95% CI 33–67) of 36 patients with a VEGFR-TKI and 19 (51%; 34–68) of 37 patients with nivolumab–ipilimumab (OR 0·95 95% CI 0·38–2·37). In the ccrcc3 group, no objective responses were seen in the four patients who received a VEGFR-TKI, and in one (20%; 95% CI 1–72) of five patients who received nivolumab–ipilimumab. The most common treatment-related grade 3–4 adverse events were hepatic failure and lipase increase (two 3% of 58 for both) with nivolumab, lipase increase and hepatobiliary disorders (six 6% of 101 for both) with nivolumab–ipilimumab, and hypertension (six 15% of 40) with a VEGFR-TKI. Serious treatment-related adverse events occurred in two (3%) patients in the nivolumab group, 38 (38%) in the nivolumab–ipilimumab group, and ten (25%) patients in the VEGFR-TKI group. Three deaths were treatment-related: one due to fulminant hepatitis with nivolumab–ipilimumab, one death from heart failure with sunitinib, and one due to thrombotic microangiopathy with sunitinib.
We demonstrate the feasibility and positive effect of a prospective patient selection based on tumour molecular phenotype to choose the most efficacious treatment between nivolumab with or without ipilimumab and a VEGFR-TKI in the first-line treatment of metastatic clear-cell renal cell carcinoma.
Bristol Myers Squibb, ARTIC.
Abstract
BACKGROUND AND AIMS
Partial nephrectomy (PN) has progressively replaced radical nephrectomy (RN) whenever feasible for renal tumors. However, its effects on renal outcomes are less known in ...patients with pre-existing chronic kidney disease (CKD) or with solitary kidney (SK). We aimed to assess renal and major clinical outcomes after PN or RN in patients with moderate to severe CKD or SK.
METHOD
We included all surgical procedures conducted between 2013 and 2018 in the Hospices Civils de Lyon, in patients with last pre-operative estimated glomerular filtration rate (eGFR) <60mL/min/1.73m², or with SK. Exclusion criteria were eGFR < 15mL/min/1.73m² or dialysis, RN on SK, ablative therapy. Demographic, tumors and surgeries characteristics were collected, as well as eGFR 1 month and 1 year after surgery. Main outcome was a composite criterion including CKD progression or major cardio-vascular events or death, assessed 1 year after surgery. Predictors of the main outcome were determined using multivariate analyses.
RESULTS
We included 173 procedures (67 RN and 79 PN on CKD patients, 27 PN on SK patients). Patients undergoing RN were older, had bigger tumors and higher T stages on TNM classification. Preoperative estimated glomerular filtration rate (eGFR) and CKD stages were not different between the groups. One year after surgery, PN was associated with less occurrence of the main composite outcome compared to RN (42.9% versus 70.7%, P < 0.01). On multivariate analysis, independent risk factors for the main outcome were postoperative AKI (no AKI as reference; AKI stage 1 odds ratio (OR) = 8.68, 95% confidence interval (CI) 3.23–23.33; AKI stage 2 OR = 23.50, 95% CI 2.33–236.51; AKI stage 3 OR = 28.87, 95% CI 4.77–167.61) and bigger tumor size (OR = 1.21/cm, 95% CI 1.02–1.45), while preoperative eGFR was not (Table 1). Compared to pre-operative values, eGFR significantly decreased both after RN or PN 1 month after surgery (eGFR loss -12mL/min 1.73m² after RN P < 0.001, −3mL/min/1.73m² after PN, P < 0.05) and this decrease remained stable 1 year after surgery (eGFR loss -11mL/min/1.73m² after RN, P < 0.001, −3mL/min/1.73m² after PN, P < 0.05), but renal function was better preserved after PN than after RN at 1 month (P < 0.05) or 1 year (P < 0.01) (Figure 1).
CONCLUSION
In moderate to severe CKD patients, PN was associated with less risk of CKD progression or major cardio-vascular event or death 1 year after surgery, compared to RN. Postoperative AKI was the major determinant of clinical and renal outcomes.
Transperineal repair of rectourethral fistula (RUF) following prostate cancer treatment with gracilis muscle flap interposition (GMFI) leads to favourable outcomes, but published data are still ...lacking, notably concerning functional aspects.
To assess surgical and functional outcomes of this treatment of RUF.
A retrospective study was conducted in two referral hospitals including 21 patients who underwent RUF transperineal repair with GMFI between 2008 and 2020.
The standard vertical perineal approach is performed for fistula dissection. Bladder and rectal defects are closed separately. After dissection from its facia, the flap is harvested, preserving its pedicle; it is brought to the perineum and placed between the urethra and the rectum to fully cover the sutures.
Fistula closure (clinical data and postoperative cystography), digestive stoma closure, and complications graded according to the Clavien-Dindo classification were reviewed. Functional results were assessed using the Urinary Symptom Profile (USP) questionnaire, anal incontinence St Mark’s score, Patient Observer Scar Assessment Scale (POSAS) score, and a nonvalidated Likert scale questionnaire assessing issues with lower extremity functionality.
The median (interquartile range) follow-up was 27 (8–47) mo. Fistula closure was successful for 20 patients (95% success). Digestive stoma was closed in 10/12 shunted patients (83%). Two (9%) Clavien-Dindo grade ≥3b complications were reported (one urinoma in a kidney transplant patient and one thigh haematoma evacuation). Eighteen patients (86%) completed the postoperative questionnaire; 11/18 (61%) had significant urinary incontinence. The mean (standard deviation) USP dysuria score was 1/9 (1.2), mean St Mark’s score was 5/24 (5), mean POSAS score was 19/70 (11), mean lower extremity functionality score was 2/20 (4), and mean procedure patient satisfaction score was 9/10 (2). The retrospective design and limited number of patients are the main limitations.
The present study found an excellent success rate and low morbidity for RUF transperineal repair with GMFI. Functional outcomes were satisfactory despite a high urinary incontinence rate.
We performed an analysis of the outcomes of perineal approach surgery with muscle interposition for closing abnormal communication between the bladder and the rectum after prostate cancer treatment. This surgical technique was found to be safe to perform and provides a high success rate, with patients being satisfied despite poor urinary continence outcomes.
Transperineal repair of rectourethral fistula with gracilis muscle flap interposition is a safe surgery with a high success rate. Urinary continence is a serious issue, but patients may be reassured as to the impact on digestive continence, lower extremity functionality, and scar aesthetics.
The creation of a neophallus is a complex surgery that must meet functional and esthetic requirements. It is a long and demanding surgical process whose final stage consists of the implantation of a ...rigid or inflatable material that can be used to reproduce an erection. Data in the literature are scarce, with only the pioneering series present, which includes the use of the first devices and techniques.
To report the outcome of patients with phalloplasty after implantation of erectile implants using standardized surgical techniques and the use of recent prosthesis types with or without a vascular graft.
This is a retrospective hospital-based analysis of all patients with phalloplasty who underwent implantation of an erectile prosthesis from March 2007 to May 2015. Factors associated with complications were investigated by multivariate logistic regression analysis.
Early-onset (during the first month after surgery) and late-onset complications, including erosion, infections, malpositioning, and dysfunction.
Sixty-nine patients were included in the study and 95 procedures were analyzed. After a median follow-up of 4 years (minimum = 169 days, maximum = 6.1 years), the original prosthesis was still in place in 43 patients (62.3%). Patients underwent phalloplasty after female-to-male transsexualism (n = 62, 89.9%), malformation (n = 4, 5.8%), or trauma (n = 3, 4.3%). The proportions for the different types of phalloplasty were 58% for forearm free flap phalloplasty (n = 40), 33.3% for suprapubic phalloplasty (n = 23), and 7% for other (n = 6). The erectile prostheses used were the two-piece AMS Ambicor (n = 71, 74.7%), the Ambicor with a vascular graft (n = 19, 20.0%), and the AMS 700CXR, AMS 700CX, or AMS600-650 (n = 5, 5.2%). There were no early-onset complications in 89 procedures (93.7%) and, when present, they were always related to infection (n = 4, 4.2%). Late-onset complications were erosion (n = 4, 4.2%), infection (n = 4, 4.2%), dysfunction (n = 10, 10.5%), and malpositioning (n = 12, 12.6%). No significant difference was observed for malpositioning (12.7% vs 10.5%, P = .87) and dysfunction (7.0% vs 10.5%, P = .78) between the AMS Ambicor prosthesis and the Ambicor prosthesis with a vascular graft.
This study provides updated data on complications after the implantation of erectile implants. Multicenter studies, including the evaluation of patient satisfaction, are needed to increase our understanding of factors associated with the outcomes.
To analyze surgical and functional outcomes of bilateral pedicled scrotal flaps for penile shaft reconstruction.
A retrospective analysis was performed on 22 patients who underwent penile shaft ...reconstruction with bilateral pedicled scrotal flaps between 2009 and 2017. Demographics, peri-operative data, and surgical complications were collected. Functional outcomes were analyzed using a questionnaire made of the erection hardness score, the patient and observer scar assessment scale, and a 10-point Likert scale measuring patients... satisfaction about their skin coloration, sensitivity, elasticity and thickness, penile size, scrotal volume, erection quality, penetration ability, pain, sexual satisfaction, body image, masculinity, self-esteem, and global satisfaction.
Patients exhibited a wide range of indications, including buried penis (27.2%), or subcutaneous injections of foreign material (27.2%). Early complications were suture dehiscence (31.8%), infection (13.6%) and hematoma (4.6%), associated with 9.1% of surgical revisions. Late complications were skin retraction (27.3%), testicular ascension (22.7%), pyramidal shape (4.6%) or shortening (13.6%) of the penis, associated with 27.3% of surgical revisions. For the 12 patients who answered the questionnaire, median erection hardness score and patient and observer scar assessment scale score IQR were 3.5 out of 4 2.5-4 and 11.5 out of 60 9.5-22, respectively. The patients reported a positive impact of the surgery on their psychological condition, with a median score of global satisfaction of 8 IQR 7.5-9.5.
Bilateral pedicled scrotal flaps seem.ßto be a safe alternative for shaft defects reconstruction despite a potential need of surgical revision, providing satisfactory functional outcomes.
Stereotactic body radiation therapy (SBRT) has become a new therapeutic option for primary renal cell carcinoma. However, treatment doses lack consistency in the literature. The primary objective of ...this study was to determine the maximum tolerated dose for renal cancer SBRT.
This phase 1 multicentric dose-escalation study assessed 4 dose levels: 8 Gy × 4, 8 Gy × 5, 10 Gy × 4, and 12 Gy × 4. The primary objective of this study was to determine the maximal tolerated dose, defined by the occurrence of dose-limiting toxicity was defined as any acute side effect of grade ≥4 based on the Common Terminology Criteria for Averse Events, version 4.0.
From October 2010 to September 2017, 13 patients were enrolled. The median follow-up was 23 months. There was no dose-limiting toxicity in our study, and the highest dose was reached successfully. No acute or late toxic effects above grade 2 were seen. There was no significant alteration of renal function after treatment. At 24 months, 2 patients had partial response and the others had stable disease.
After 24 months of follow-up, no dose-limiting toxicity was seen at any of the prescribed dose levels in our study. The findings suggest that our last dose level of 48 Gy in 4 12-Gy fractions can be considered safe and can be used in further studies.
Objective
Renal cell carcinomas represent the sixth- and tenth-most frequently diagnosed cancer in men and women. Recently, percutaneous-guided thermal ablations have proved to be as effective as ...partial nephrectomy and safer for treating small renal masses (i.e., < 3 cm). This study compared the perioperative and recurrence outcomes of percutaneous thermal ablation (TA) and robotic-assisted partial nephrectomy (RAPN) for the treatment of T1b renal cell carcinomas (4.1–7 cm).
Methods
Retrospective data from 11 centers on the national database, between 2010 and 2020, included 81 patients treated with thermal ablation (TA) and 308 patients treated with RAPN for T1b renal cell carcinoma, collected retrospectively and matched for tumor size, histology results, and the RENAL score. TA included cryoablation and microwave ablation. Endpoints compared the rate between the two groups: local recurrence, metastases, complications, renal function decrease, and length of hospitalization.
Results
After matching, 75 patients were included in each group; mean age was 76.6 (± 9) in the TA group and 61.1 (± 12) in the RAPN group, including 69.3% and 76% men respectively. The local recurrence (LR) rate was significantly higher in the TA group than in the PN group (14.6% vs 4%;
p
= 0.02). The LR rate was 20% (1/5) after microwave ablation, 11.1% (1/9) after radiofrequency ablation, and 14.7% (9/61) after cryoablation. The major complication rate (Clavien–Dindo ≥ 3) was higher following PN than after TA (5.3% vs 0%;
p
< 0.001). Metastases, eGFR decrease, and length of hospitalization did not differ significantly between the two groups.
Conclusions
The local recurrence rate was significantly higher after thermal ablation; however, thermal ablation resulted in significantly lower rates of complications.
Summary statement
Thermal ablation and robotic-assisted partial nephrectomy are effective treatments for T1b renal cancer; however, the local recurrence rate was higher after thermal ablation.
Key Points
• The local recurrence rate was significantly higher in the thermal ablation group than in the partial nephrectomy group.
• The major complication rate (Clavien–Dindo ≥ 3) was higher following PN than after TA (5.3% vs. 0%; p < 0.001).
Objective
To evaluate the surgical and functional outcomes of urethral reconstruction associated with phalloplasty, depending on the surgical techniques and patient history.
Materials and Methods
We ...conducted a single‐centre retrospective study including 89 patients who underwent phalloplasty with urethral reconstruction between 2007 and 2018. Patients included were trans‐male patients undergoing gender‐affirming surgery and cis‐male patients undergoing penile reconstruction after trauma, congenital malformation, or cancer. Urethral reconstructions were performed by free flap or skin graft (total or thin). Secondary urethroplasty may include direct vision urethrotomy, excision‐anastomosis, or augmentation urethroplasty (skin graft, buccal mucosa graft). Patient demographics, medical history, peri‐ and postoperative data were collected from patient files. Functional results were evaluated using individual questionnaires.
Results
The mean (±sd) follow‐up duration was 5.5 (±3.7) years. No significant difference was found for total urethral complication rate (fistula and/or stricture) according to type of urethral construction (70.9% for free flap urethra vs 73.5% for skin graft urethra; P = 0.911), nor according to the patient's grounds for surgery (72.7% for cis‐male vs 71.8% for trans‐male patients; P = 1). A total of 36 patients (40.5%) answered the functional questionnaire, of whom 80.5% reported usually voiding while standing and 47.5% were comfortable with urinating in public.
Conclusions
Urethral construction in phalloplasty is associated with a high complication and revision rate regardless of the type of urethral reconstruction. Voiding in a standing position is generally possible but should not conceal feeble functional results.
