Silencing of genes by promoter hypermethylation shapes tumor microenvironment and resistance to immunotherapy in clear-cell renal cell carcinomas.

The efficacy of immune checkpoint inhibitors varies in clear-cell renal cell carcinoma (ccRCC), with notable primary resistance among patients. Here, we integrate epigenetic (DNA methylation) and transcriptome data to identify a ccRCC subtype characterized by cancer-specific promoter hypermethylation and epigenetic silencing of Polycomb targets. We develop and validate an index of methylation-based epigenetic silencing (iMES) that predicts primary resistance to immune checkpoint inhibition (ICI) in the BIONIKK trial. High iMES is associated with VEGF pathway silencing, endothelial cell depletion, immune activation/suppression, EZH2 activation, BAP1/SETD2 deficiency, and resistance to ICI. Combination therapy with hypomethylating agents or tyrosine kinase inhibitors may benefit patients with high iMES. Intriguingly, tumors with low iMES exhibit increased endothelial cells and improved ICI response, suggesting the importance of angiogenesis in ICI treatment. We also develop a transcriptome-based analogous system for extended applicability of iMES. Our study underscores the interplay between epigenetic alterations and tumor microenvironment in determining immunotherapy response.

Biweekly vs Triweekly Cabazitaxel in Older Patients With Metastatic Castration-Resistant Prostate Cancer: The CABASTY Phase 3 Randomized Clinical Trial.

Importance: Many patients 65 years or older with metastatic castration-resistant prostate cancer (mCRPC) are denied taxane chemotherapy because this treatment is considered unsuitable. Objective: To determine whether biweekly cabazitaxel (CBZ), 16 mg/m2 (biweekly CBZ16), plus prophylactic granulocyte colony-stimulating factor (G-CSF) at each cycle reduces the risk of grade 3 or higher neutropenia and/or neutropenic complications (eg, febrile neutropenia, neutropenic infection, or sepsis) compared with triweekly CBZ, 25 mg/m2 (triweekly CBZ25), plus G-CSF (standard regimen). Design, Setting, and Participants: A total of 196 patients 65 years or older with progressive mCRPC were enrolled in this prospective phase 3 randomized clinical trial conducted in France (18 centers) and Germany (7 centers) between May 5, 2017, and January 7, 2021. All patients had received docetaxel and at least 1 novel androgen receptor-targeted agent. Interventions: Patients were randomly assigned 1:1 to receive biweekly CBZ16 plus G-CSF and daily prednisolone (experimental group) or triweekly CBZ25 plus G-CSF and daily prednisolone (control group). Main Outcome and Measures: The primary end point was the occurrence of grade 3 or higher neutropenia measured at nadir and/or neutropenic complications. Results: Among 196 patients (97 in the triweekly CBZ25 group and 99 in the biweekly CBZ16 group), the median (IQR) age was 74.6 (70.4-79.3) years, and 181 (92.3%) had an Eastern Cooperative Oncology Group performance status of 0 or 1. The median (IQR) follow-up duration was 31.3 (22.5-37.5) months. Relative dose intensities were comparable between groups (median [IQR], 92.7% [83.7%-98.9%] in the triweekly CBZ25 group vs 92.8% [87.0%-98.9%] in the biweekly CBZ16 group). The rate of grade 3 or higher neutropenia and/or neutropenic complications was significantly higher with triweekly CBZ25 vs biweekly CBZ16 (60 of 96 [62.5%] vs 5 of 98 [5.1%]; odds ratio, 0.03; 95% CI, 0.01-0.08; P < .001). Grade 3 or higher adverse events were more common with triweekly CBZ25 (70 of 96 [72.9%]) vs biweekly CBZ16 (55 of 98 [56.1%]). One patient (triweekly CBZ25 group) died of a neutropenic complication. Conclusions and Relevance: In this randomized clinical trial, compared with the standard regimen, biweekly CBZ16 plus G-CSF significantly reduced by 12-fold the occurrence of grade 3 or higher neutropenia and/or neutropenic complications, with comparable clinical outcomes. The findings suggest that biweekly CBZ16 regimen should be offered to patients 65 years or older with mCRPC for whom the standard regimen is unsuitable. Trial Registration: ClinicalTrials.gov Identifier: NCT02961257.

Mesenchymal-like Tumor Cells and Myofibroblastic Cancer-Associated Fibroblasts Are Associated with Progression and Immunotherapy Response of Clear Cell Renal Cell Carcinoma.

Immune checkpoint inhibitors (ICI) represent the cornerstone for the treatment of patients with metastatic clear cell renal cell carcinoma (ccRCC). Despite a favorable response for a subset of patients, others experience primary progressive disease, highlighting the need to precisely understand the plasticity of cancer cells and their cross-talk with the microenvironment to better predict therapeutic response and personalize treatment. Single-cell RNA sequencing of ccRCC at different disease stages and normal adjacent tissue (NAT) from patients identified 46 cell populations, including 5 tumor subpopulations, characterized by distinct transcriptional signatures representing an epithelial-to-mesenchymal transition gradient and a novel inflamed state. Deconvolution of the tumor and microenvironment signatures in public data sets and data from the BIONIKK clinical trial (NCT02960906) revealed a strong correlation between mesenchymal-like ccRCC cells and myofibroblastic cancer-associated fibroblasts (myCAF), which are both enriched in metastases and correlate with poor patient survival. Spatial transcriptomics and multiplex immune staining uncovered the spatial proximity of mesenchymal-like ccRCC cells and myCAFs at the tumor-NAT interface. Moreover, enrichment in myCAFs was associated with primary resistance to ICI therapy in the BIONIKK clinical trial. These data highlight the epithelial-mesenchymal plasticity of ccRCC cancer cells and their relationship with myCAFs, a critical component of the microenvironment associated with poor outcome and ICI resistance. SIGNIFICANCE: Single-cell and spatial transcriptomics reveal the proximity of mesenchymal tumor cells to myofibroblastic cancer-associated fibroblasts and their association with disease outcome and immune checkpoint inhibitor response in clear cell renal cell carcinoma.

An Enhancer Demethylator Phenotype Converged to Immune Dysfunction and Resistance to Immune Checkpoint Inhibitors in Clear-Cell Renal Cell Carcinomas.

PURPOSE: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of patients with clear-cell renal cell carcinomas (ccRCC). Although analyses of transcriptome, genetic alterations, and the tumor microenvironment (TME) have shed light into mechanisms of response and resistance to these agents, the role of epigenetic alterations in this process remains fully unknown. EXPERIMENTAL DESIGN: We investigated the methylome of six ccRCC cohorts as well as one cell line dataset. Of note, we took advantage of the BIONIKK trial aiming to tailor treatments according to Paris Descartes 4-gene expression subgroups, and performed Illumina EPIC profiling for 46 samples related to patients treated with ipilimumab plus nivolumab, and 17 samples related to patients treated with sunitinib. RESULTS: A group of tumors associated with enhancer demethylation was discovered, namely TED. TED was associated with tumors with sarcomatoid differentiation and poor clinical outcome. TED harbored TET1 promoter demethylation, activated the gene expression signature of epithelial-mesenchymal transition and IL6/JAK/STAT3 pathways, and displayed a TME characterized by both immune activation and suppressive populations, fibroblast infiltration, and endothelial depletion. In addition, TED was a predictive factor of resistance to the combination of first-line ipilimumab-nivolumab in the BIONIKK clinical trial. Finally, TED was associated with activation of specific regulons, which we also found to be predictive of resistance to immunotherapy in an independent cohort. CONCLUSIONS: We report on the discovery of a novel epigenetic phenotype associated with resistance to ICIs that may pave the way to better personalizing patients' treatments. See related commentary by Zhou and Kim, p. 1170.

Real-world Treatment Sequencing in Patients with Metastatic Castration-resistant Prostate Cancer: Results from the Prospective, International, Observational Prostate Cancer Registry.

Background: Prostate cancer has a multifaceted treatment pattern. Evidence is lacking for optimal treatment sequences for metastatic castration-resistant prostate cancer (mCRPC). Objective: To increase the understanding of real-world treatment pathways and outcomes in patients with mCRPC. Design setting and participants: A prospective, noninterventional, real-world analysis of 3003 patients with mCRPC in the Prostate Cancer Registry (PCR; NCT02236637) from June 14, 2013 to July 9, 2018 was conducted. Intervention: Patients received first- and second-line hormonal treatment and chemotherapy as follows: abiraterone acetate plus prednisone (abiraterone)-docetaxel (ABI-DOCE), abiraterone-enzalutamide (ABI-ENZA), abiraterone-radium-223 (ABI-RAD), docetaxel-abiraterone (DOCE-ABI), docetaxel-cabazitaxel (DOCE-CABA), docetaxel-enzalutamide (DOCE-ENZA), and enzalutamide-docetaxel (ENZA-DOCE). Outcome measurements and statistical analysis: Baseline patient characteristics, quality of life, mCRPC treatments, and efficacy outcomes (progression and survival) were presented descriptively. Results and limitations: Data from 727 patients were eligible for the analysis (ABI-DOCE n = 178, ABI-ENZA n = 99, ABI-RAD n = 27, DOCE-ABI n = 191, DOCE-CABA n = 74, DOCE-ENZA n = 116, and ENZA-DOCE n = 42). Demographics and disease characteristics among patients between different sequences varied greatly. Most patients who started on abiraterone or enzalutamide stopped therapy because of disease progression. No randomisation to allow treatment/sequence comparisons limited this observational study. Conclusions: The real-world PCR data complement clinical trial data, reflecting more highly selected patient populations than seen in routine clinical practice. Baseline characteristics play a role in mCRPC first-line treatment selection, but other factors, such as treatment availability, have an impact. Efficacy observations are limited and should be interpreted with caution. Patient summary: Baseline characteristics appear to have a role in the first-line treatment selection of metastatic castration-resistant prostate cancer in the real-world setting. First-line abiraterone acetate plus prednisone seems to be the preferred treatment option for older patients and those with lower Gleason scores, first-line docetaxel for younger patients and those with more advanced disease, and first-line enzalutamide for patients with fewer metastases and more favourable performance status. The benefit to patients from these observations remains unknown.

Cabozantinib-nivolumab sequence in metastatic renal cell carcinoma: The CABIR study.

Nivolumab and cabozantinib are approved agents in mRCC patients after sunitinib/pazopanib (TKI) failure. However, the optimal sequence, cabozantinib then nivolumab (CN) or nivolumab then cabozantinib (NC), is still unknown. The CABIR study aimed to identify the optimal sequence between CN and NC after frontline VEGFR-TKI. In this multicenter retrospective study, we collected data from mRCC pts receiving CN or NC, after frontline VEGFR-TKI. A propensity score (PrS) was calculated to manage bias selection, and sequence comparisons were carried out with a cox model on a matched sample 1:1. The primary endpoint was progression-free survival (PFS) from the start of second line to progression in third line (PFS2-3 ). Key secondary endpoints included overall survival from second line (OS2 ). Out of 139 included mRCC patients, 38 (27%) and 101 (73%) received CN and NC, respectively. Overlap in PrS allowed 1:1 matching for each CN pts, with characteristics well balanced. For both PFS2-3 and OS2 , NC sequence was superior to CN (PFS2-3 : HR = 0.58 [0.34-0.98], P = .043; OS2 : 0.66 [0.42-1.05], P = .080). Superior PFS2-3 was in patients treated between 6 and 18 months with prior VEGFR-TKI (P = .019) and was driven by a higher PFSL3 with cabozantinib when given after nivolumab (P < .001). The CABIR study shows a prolonged PFS of the NC sequence compared to CN in mRCC after first line VEGFR-TKI failure. The data suggest that cabozantinib may be more effective than nivolumab in the third-line setting, possibly related to an ability of cabozantinib to overcome resistance to PD-1 blockade.

Nivolumab, nivolumab-ipilimumab, and VEGFR-tyrosine kinase inhibitors as first-line treatment for metastatic clear-cell renal cell carcinoma (BIONIKK): a biomarker-driven, open-label, non-comparative, randomised, phase 2 trial.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Bristol Myers Squibb, ARTIC.

REchallenge of NIVOlumab (RENIVO) or Nivolumab-Ipilimumab in Metastatic Renal Cell Carcinoma: An Ambispective Multicenter Study.

INTRODUCTION: Immune checkpoint inhibitors (ICI) have been approved for front-line therapy in metastatic renal cell carcinoma (mRCC). However, progressive disease often occurs and subsequent therapies are needed. ICI rechallenge may be an option, but there is a lack of data regarding efficacy and prognostic factors. We assessed efficacy of ICI rechallenge and factors associated with better outcomes. Patients and Methods. This ambispective multicenter study included 45 mRCC patients rechallenged with nivolumab ± ipilimumab between 2014 and 2020. Primary endpoint was investigator-assessed best objective response rate (ORR) for ICI rechallenge (ICI-2). Factors associated with ICI-2 progression-free survival (PFS) were evaluated with multivariate Cox models. RESULTS: ORR was 51% (n = 23) at first ICI therapy (ICI-1) and 16% (n = 7) for ICI-2. Median PFS was 11.4 months (95% CI, 9.8-23.5) and 3.5 months (95% CI, 2.8-9.7), and median overall survival was not reached (NR) (95% CI, 37.8-NR) and 24 months (95% CI, 9.9-NR) for ICI-1 and ICI-2, respectively. Factors associated with poorer ICI-2 PFS were a high number of metastatic sites, presence of liver metastases, use of an intervening treatment between ICI regimens, Eastern Cooperative Oncology Group performance status ≥2, and poor International Metastatic RCC Database Consortium score at ICI-2 start. Conversely, ICI-1 PFS >6 months was associated with better ICI-2 PFS. In multivariate analysis, there were only statistical trends toward better ICI-2 PFS in patients with ICI-1 PFS >6 months (p=0.07) and toward poorer ICI-2 PFS in patients who received a treatment between ICI regimens (p=0.07). CONCLUSION: Rechallenge with nivolumab-based ICI has some efficacy in mRCC. We identified various prognostic factors in univariate analysis but only statistical trends in multivariate analysis. Our findings bring new evidence on ICI rechallenge and preliminary but unique data that may help clinicians to select patients who will benefit from this strategy.

The Cancer of the Bladder Risk Assessment (COBRA) score accurately predicts cancer-specific survival after radical cystectomy: external validation and lymphovascular invasion assessment value to improve its performance.

The Cancer of the Bladder Risk Assessment (COBRA) score is a predictive tool for estimating Cancer Specific Survival (CSS) after Radical Cystectomy (RC) for urothelial carcinoma. COBRA score variables are: age at RC, Tumor stage and Lymph Node Density (LND). We sought to externally validate the COBRA score and to improve its performance in estimating CSS adding Lymphovascular Invasion (LVI) as a further variable (Modified COBRA score). Clinicopathological and survival data from 789 patients who underwent RC and Pelvic Lymph Node Dissection (PLND) between January 2007 and December 2020 in two European referral centers (Paris, France and Badalona, Spain) were analyzed. COBRA score was applied to our cohort and CSS Kaplan-Meier curves were performed. Univariable and Multivariable analysis was performed in order to identify risk factors for Cancer Specific Mortality (CSM) and a score was assigned for any statistically significant risk factor; afterward, c-index calculation was performed and CCS curves have been plotted for the model after having integrated LVI variable to the COBRA score. Finally, we compared both COBRA score and Modified COBRA score models with the established AJCC model. A total of 789 patients underwent RC during the observation period. Complete data were available for 731 patients with a median follow-up of 32 months (8-47). CSM was 27.6% (no. 218 patients) at follow-up. When COBRA score was applied to our cohort, c-index was 0.76. Regression COX analysis has shown HR 0.36, CI 95% (0.16-0.83), P = .016 for patients with COBRA score 1; HR 0, CI 95% (0-1.77), P =.94 for score 2; HR 0.51, CI 95% (0.39 -0.67), P =.001 for score 3; HR 1.67, CI 95% (1.23-2.27), P =.001 for score 4; HR 2.45, CI 95% (1.51-3.99), P =.001 for score 5; HR 2.01, CI 95% (1.42-2.85), P =.001 for score 6 and HR 0.66, CI 95% (0.09-4.73), P =.682 for score 7. When the LVI variable was added to the CSS predictive model the discriminatory power increased to a c-index of 0.78. COBRA score adequately identifies those patients with a higher risk of CSM, with a c-index of 0.76. Moreover, LVI variable further improves its predictive accuracy from c-index of 0.76 to c-index of 0.78. LVI variable could be integrated in the COBRA score to optimizing prognosis stratification for patients who undergo RC.

The Immunoscore in Localized Urothelial Carcinoma Treated with Neoadjuvant Chemotherapy: Clinical Significance for Pathologic Responses and Overall Survival.

(1) Background-The five-year overall survival (OS) of muscle-invasive bladder cancer (MIBC) with neoadjuvant chemotherapy and cystectomy is around 50%. There is no validated biomarker to guide the treatment decision. We investigated whether the Immunoscore (IS) could predict the pathologic response to neoadjuvant chemotherapy and survival outcomes. (2) Methods-This retrospective study evaluated the IS in 117 patients treated using neoadjuvant chemotherapy for localized MIBC from six centers (France and Greece). Pre-treatment tumor samples were immunostained for CD3+ and CD8+ T cells and quantified to determine the IS. The results were associated with the response to neoadjuvant chemotherapy, time to recurrence (TTR), and OS. (3) Results-Low (IS-0), intermediate (IS-1-2), and high (IS-3-4) ISs were observed in 36.5, 43.7, and 19.8% of the cohort, respectively. IS was positively associated with a pathologic complete response (pCR; p-value = 0.0096). A high IS was found in 35.7% of patients with a pCR, whereas it was found in 11.3% of patients without a pCR. A low IS was observed in 48.4% of patients with no pCR and in 21.4% of patients with a pCR. Low-, intermediate-, and high-IS patients had five-year recurrence-free rates of 37.2%, 36.5%, and 72.6%, respectively. In the multivariable analysis, a high IS was associated with a prolonged TTR (high vs. low: p = 0.0134) and OS (high vs. low: p = 0.011). (4) Conclusions-This study showed the significant prognostic and predictive roles of IS regarding localized MIBC.

Does Chemotherapy-Induced Liver Injury Impair Postoperative Outcomes After Laparoscopic Liver Resection for Colorectal Metastases?

BACKGROUND: Chemotherapy-associated liver injuries (CALI) have been associated with poor postoperative outcome after open liver resection. To date, no data concerning any correlation of CALI and laparoscopic liver resection (LLR) are available. In the present study, we evaluated the impact of CALI on short-term outcomes in patients undergoing LLR. MATERIALS AND METHODS: All patients who underwent in our department LLR for colorectal liver metastases (CRLM) from 2000 to 2016 were retrospectively reviewed. Patients were divided in 4 groups according to their pathological histology. In group 1 patients had normal liver parenchyma. Group 2 included patients with steatosis and steatohepatitis. Patients with sinusoidal obstruction syndrome (SOS) and nodular regenerative hyperplasia (NRH) were allocated to group 3, whereas the remaining with fibrosis and cirrhosis, were assigned to group 4. RESULTS: A total of 490 LLR for CRLM were included in the study. Perioperative details and morbidity did not differ significantly between the four groups. Subgroup analysis showed that NRH was associated with higher amount of blood loss (p = 0.043), overall (p = 0.021) and liver-specific morbidity (p = 0.039). CONCLUSION: NRH is a severe form of CALI that may worsen the short-term outcomes of patients undergoing LLR for CRLM. However, the remaining forms of CALI do not have a significant impact on perioperative outcomes after LLR.

Does the difficulty grade of laparoscopic liver resection for colorectal liver metastases correlate with long-term outcomes?

INTRODUCTION: Prognosis of patients with colorectal liver metastases (CRLM) is strongly correlated with the oncological outcome after liver resection. The aim of this study was to analyze the impact of laparoscopic liver resection (LLR) difficulty score (IMM difficulty score) on the oncological results in patients treated for CRLM. METHODS: All patients who underwent LLRs for CRLM from 2000 to 2016 in our department, were retrospectively reviewed. Data regarding difficulty classification, -according to the Institute Mutualiste Montsouris score (IMM)-, recurrence rate, recurrence-free survival (RFS), overall survival (OS) and data regarding margin status were analyzed. RESULTS: A total of 520 patients were included. Patients were allocated into 3 groups based on IMM difficulty score of the LLR they underwent: there were 227 (43,6%), 84 (16,2%) and 209 (40,2%) patients in groups I, II and III, respectively. The R1 resection rate in group I, II and III were 8,8% (20/227), 11,9% (10/84) and 12,4% (26/209) respectively (p = 0.841). Three- and 5-year RFS rates were 77% and 73% in group I, 58% and 51% in group II, 61% and 53% in group III, respectively (p = 0.038). Three and 5-year OS rates were 87% and 80% for group I, 77% and 66% for group II, 80% and 69% for group III respectively (p = 0.022). CONCLUSION: The higher LLR difficulty score correlates with significant morbidity and worse RFS and OS, although the more technically demanding and difficult cases are not associated with increased rates of positive resection margins and recurrence.

Comparing Perioperative Complications Between Laparoscopic and Robotic Radical Cystectomy for Bladder Cancer.

Background: Minimally invasive cystectomy is being increasingly performed, however, data comparing laparoscopic radical cystectomy (LRC) and robotic radical cystectomy (RRC) are scarce. We compared 30- and 90-day Clavien-Dindo Classification (CDC) complications between patients undergoing LRC and RRC at our center. Materials and Methods: We retrospectively evaluated 300 patients who underwent minimally invasive radical cystectomy from January 2007 to July 2019 and grouped them into LRC (112 patients) and RRC (188 patients). We compared the two groups for demographic variables, perioperative characteristics, and 30- and 90-day CDC overall, minor, and major complications. Multivariable logistic regression analysis was performed to identify variables that predict perioperative complications. Results: The two groups were comparable for the duration of surgery (270 minutes in LRC vs 265 minutes in RRC) and rate of conversion to open surgery. The RRC cohort had a higher estimated blood loss (EBL) (675 mL vs 500 mL, p = 0.006), but the two groups had a comparable need for intraoperative transfusion. Patients undergoing RRC also had a shorter duration of hospital stay (13 days vs 14 days, p < 0.001). There was no difference between the two groups for 30- and 90-day CDC overall, minor, and major complications. The incidence of rehospitalization within 30 days (p = 0.1) and surgical reintervention (p = 0.5) was also comparable between the two groups. On multivariable logistic regression analysis, approach to cystectomy (RRC vs LRC) was not a significant predictor of 30-day CDC overall and major complications. Conclusion: LRC was associated with lesser EBL, whereas the hospital stay was shorter in patients undergoing RRC. The two approaches were comparable with each other for 30- and 90-day CDC overall, minor, and major complications. The choice between the two approaches should depend on availability and surgeon experience and preference, rather than any specific perioperative parameter.

Higher nodal yield with robot-assisted pelvic lymph node dissection for bladder cancer compared to laparoscopic dissection: implications for more accurate staging.

OBJECTIVES: To compare the lymph node (LN) yield and adequacy of laparoscopic pelvic lymph node dissection (L-PLND) and robot-assisted PLND (R-PLND), as PLND is a fundamental component of radical cystectomy (RC) for bladder cancer (BCa), where a positive status is the most powerful predictor of disease recurrence and survival. PATENTS AND METHODS: We retrospectively reviewed patients undergoing RC with PLND for BCa from January 2007 to July 2019 and grouped them in to L- and R-PLND. Until 2011, patients underwent a standard PLND (S-PLND) with the cranial limit as bifurcation of common iliac artery. Since 2012, an extended PLND (E-PLND) up to aortic bifurcation has been performed. An adequate S- and E-PLND were defined as those that yielded at least 10 and 16 LNs, respectively. The groups were compared for LN yield and adequacy of PLND. RESULTS: During the study period, 305 patients underwent minimally invasive RC in our centre, of which 274 (89.8%) underwent a concomitant PLND (98 L-PLND, 176 R-PLND). R-PLND resulted in a significantly greater median LN yield compared to L-PLND, both in the S-PLND (16 vs 11, P < 0.001) and the E-PLND (19 vs 14, P < 0.001) eras. Also, a significantly higher proportion of patients in the R-PLND group had an adequate PLND compared to the L-PLND group. Surgical approach to PLND (R- vs L-PLND) was the only variable that was significantly associated with an adequate PLND on both univariable (odds ratio [OR] 1.860, 95% confidence interval [CI] 1.114-3.105; P = 0.01) and multivariable (OR 2.109, 95% CI 1.222-3.641; P = 0.007) analyses. CONCLUSION: R-PLND leads to a higher LN yield and a greater probability of an adequate PLND compared to L-PLND for both standard and extended templates. Therefore, the robot-assisted approach would lead to more accurate staging following RC with PLND.

Perioperative and long-term outcomes of laparoscopic liver resections for non-colorectal liver metastases.

BACKGROUND: Liver is a common metastatic site not only of colorectal but of non-colorectal neoplasms, as well. However, resection of non-colorectal liver metastases (NCRLMs) remains controversial. The aim of this retrospective study was to analyze the short- and long-term outcomes of patients undergoing laparoscopic liver resection (LLR) for NCRLMs. METHODS: From a prospectively maintained database between 2000 and 2018, patients undergoing LLR for colorectal liver metastases (CRLMs) and NCRLMs were selected. Clinicopathologic, operative, short- and long-term outcome data were collected, analyzed, and compared among patients with CRLMs and NCRLMs. RESULTS: The primary tumor was colorectal in 354 (82.1%), neuroendocrine in 21 (4.9%), and non-colorectal, non-neuroendocrine in the remaining 56 (13%) patients. Major postoperative morbidities were 12.7%, 19%, and 3.6%, respectively (p = 0.001), whereas the mortality was 0.6% for patients with CRLMs and zero for patients with NCRLMs. The rate of R1 surgical margin was comparable (p = 0.432) among groups. According to the survival analysis, 3- and 5-year recurrence-free survival (RFS) rates were 76.1% and 64.3% in the CRLM group, 57.1% and 42.3% in the neuroendocrine liver metastase (NELM) group, 33% and 20.8% in the non-colorectal, non-neuroendocrine liver metastase (NCRNNELM) group (p = 0.001), respectively. Three- and 5-year overall survival (OS) rates were 88.3% and 82.7% in the CRLM group, 85.7% and 70.6% in the NELM group, 71.4% and 52.9% in the NCRNNELM group (p = 0.001), respectively. In total, 113 out of 354 (31.9%) patients with CRLMs, 2 out of 21(9.5%) with NELMs, and 8 out of 56 (14.3%) patients with NCRNNELMs underwent repeat LLR for recurrent metastatic tumors. CONCLUSION: LLR is safe and feasible in the context of a multimodal management where an aggressive surgical approach, necessitating even complex procedures for bilobar multifocal metastases and repeat hepatectomy for recurrences, is the mainstay and may be of benefit in the long-term survival, in selected patients with NCRNNELMs.

Limited Sensitivity of Circulating Tumor DNA Detection by Droplet Digital PCR in Non-Metastatic Operable Gastric Cancer Patients.

This study was designed to monitor circulating tumor DNA (ctDNA) levels during perioperative chemotherapy in patients with non-metastatic gastric adenocarcinoma. Plasma samples were prospectively collected in patients undergoing perioperative chemotherapy for non-metastatic gastric adenocarcinoma (excluding T1N0) prior to the initiation of perioperative chemotherapy, before and after surgery (NCT02220556). In each patient, mutations retrieved by targeted next-generation sequencing (NGS) on tumor samples were then tracked in circulating cell-free DNA from 4 mL of plasma by droplet digital PCR. Thirty-two patients with a diagnosis of non-metastatic gastric adenocarcinoma were included. A trackable mutation was identified in the tumor in 20 patients, seven of whom experienced relapse during follow-up. ctDNA was detectable in four patients (N = 4/19, sensitivity: 21%; 95% confidence interval CI = 8.5⁻43%, no baseline plasma sample was available for one patient), with a median allelic frequency (MAF) of 1.6% (range: 0.8⁻2.3%). No patient with available plasma samples (N = 0/18) had detectable ctDNA levels before surgery. After surgery, one of the 13 patients with available plasma samples had a detectable ctDNA level with a low allelic frequency (0.7%); this patient experienced a very short-term distant relapse only 3 months after surgery. No ctDNA was detected after surgery in the other four patients with available plasma samples who experienced a later relapse (median = 14.4, range: 9.3⁻26 months). ctDNA monitoring during preoperative chemotherapy and after surgery does not appear to be a useful tool in clinical practice for non-metastatic gastric cancer to predict the efficacy of chemotherapy and subsequent relapse, essentially due to the poor sensitivity of ctDNA detection.

Liver resection for extra-pancreatic biliary cancer: what is the role of laparoscopic approach?

BACKGROUND: Laparoscopic liver resection (LLR) has evolved over time, yet its role in extra-pancreatic biliary cancer has been limited due to several factors. We aimed to evaluate the short-term outcome of LLR in extra-pancreatic biliary tract cancer. METHODS: From January 2002 to 2016, all patients who underwent LLR for extra-pancreatic biliary tract cancer including gallbladder cancer (GBC), intra-hepatic cholangiocarcinoma (ICC), and peri-hilar cholangiocarcinoma (PHC) with curative intent (R0 or R1) at Institute Mutualiste Montsouris were identified from prospectively collected databases. Patient characteristics, and perioperative outcomes, were analyzed in all three groups. RESULTS: A total of 35 patients were included: 10 with GBC, 14 with ICC, and 11 with PHC. There were 19 (54%) women and median age was 71 years. Median operative time was 240 min, and estimated blood loss was 200 ml. Conversion to an open procedure was more common in patients with PHC (45% vs. 7% for ICC and 0% for GBC, p = 0.010). R0 resection was achieved in 10 (100%), 12 (86%), and 8 (73%) patients in GBC, ICC, and PHC groups, respectively (p = 0.204). Postoperative morbidity was reported in 19 (54%) patients of whom 12 (34%) had minor complications. Postoperative mortality was reported in 4 (11%) patients; one (7%) in GBC group, one (7%) in ICC group, and two (18%) in PHC, p = 0.681. Median hospital stay was 11 days. CONCLUSIONS: The present series suggests that LLR is feasible in GBC, challenging but achievable in ICC but unsuitable for the moment in PHC.

After laparoscopic liver resection for colorectal liver metastases, age does not influence morbi-mortality.

BACKGROUND: Hepatectomy remains the only curative option in patients presenting with colorectal liver metastases (CLM). Although laparoscopic approach has improved postoperative morbidity and mortality rates, its suitability for patients of all age groups has yet to be confirmed. The aim of this study was to analyze postoperative outcomes following laparoscopic liver resection (LLR) in different age groups of patients presenting with CLM. METHODS: All patients who underwent LLR for CLM from 2008 to 2017 were reviewed. Patients were divided into four age groups: < 55, 55-65 years, 65-75 and > 75 years. Baseline and intraoperative characteristics as well as postoperative morbidity and mortality were compared between all four groups. RESULTS: Overall, 335 patients were included with 34 (10%), 113 (34%), 136 (41%) and 52 (15%) in < 55, 55-65, 65-75 and > 75 years subgroups. Baseline characteristics were similar between all four groups except for elevated pressure, dyslipidemia and ASA score which were higher in older patients. Regarding surgical procedures, major hepatectomy, uni- or bisegmentectomy and wedge resection were performed in 122 (36%), 87 (26%) and 126 (38%) patients, respectively, with no significant differences between age groups. Overall, 90-day postoperative mortality rate was nil and postoperative morbidity was similar between all four groups except for biliary fistula occurrence, which was higher in < 55 years patients (p = 0.006). CONCLUSION: Short-term postoperative outcome following LLR for CLM does not seem to be affected by age. Curative laparoscopic treatment should therefore be considered whenever possible, regardless of patient age.

Switch from abiraterone plus prednisone to abiraterone plus dexamethasone at asymptomatic PSA progression in patients with metastatic castration-resistant prostate cancer.

OBJECTIVE: To evaluate the effects of switching from prednisone (P) to dexamethasone (D) at asymptomatic prostate-specific antigen (PSA) progression in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate (AA). MATERIALS AND METHODS: Among 93 patients treated with AA between January 2013 and April 2016 in our institution, 48 consecutive asymptomatic patients with mCRPC, who experienced biochemical progression on treatment with AA+P 10 mg/day, were included. A corticosteroid switch to AA+D 0.5 mg/day at PSA increase was administered until radiological and/or clinical progression. The primary endpoint was progression-free-survival (PFS). A prognostic score based on independent prognostic factors was defined. RESULTS: The median time to PSA progression on AA+P was 8.94 months. The median PFS on AA+D and AA+corticosteroids (P then D) was 10.35 and 20.07 months, respectively. A total of 56.25% of patients showed a decrease or stabilization in PSA levels after the switch. In univariate analysis, three markers of switch efficiency were significantly associated with a longer PFS: long hormone-sensitivity duration (≥5 years; median PFS 16.62 vs 4.17 months, hazard ratio [HR] 0.30, 90% confidence interval [CI] 0.16-0.56); low PSA level at the time of switch (<50 ng/mL; median PFS 15.21 vs 3.86 months, HR 0.33, 90% CI 0.18-0.60); and short time to PSA progression on AA+P (<6 months; median PFS 28.02 vs 6.65 months, HR 0.41 (90% CI 0.21-0.81). In multivariate analysis, hormone sensitivity duration and PSA level were independent prognostic factors. CONCLUSION: A steroid switch from P to D appears to be a safe and non-expensive way of obtaining long-term responses to AA in selected patients with mCRPC. A longer PFS has been observed in patients with previous long hormone sensitivity duration, and/or low PSA level and/or short time to PSA progression on AA+P.