To define dominant molecular and cellular features associated with PD-1/PD-L1 blockade resistance in metastatic urothelial cancer.
We pursued an unbiased approach using bulk RNA sequencing data from ...two clinical trials to discover (IMvigor 210) and validate (CheckMate 275) pretreatment molecular features associated with resistance to PD-1/PD-L1 blockade in metastatic urothelial cancer. We then generated single-cell RNA sequencing (scRNA-seq) data from muscle-invasive bladder cancer specimens to dissect the cellular composition underlying the identified gene signatures.
We identified an adaptive immune response gene signature associated with response and a protumorigenic inflammation gene signature associated with resistance to PD-1/PD-L1 blockade. The adaptive immune response:protumorigenic inflammation signature expression ratio, coined the 2IR score, best correlated with clinical outcomes, and was externally validated. Mapping these bulk gene signatures onto scRNA-seq data uncovered their underlying cellular diversity, with prominent expression of the protumorigenic inflammation signature by myeloid phagocytic cells. However, heterogeneity in expression of adaptive immune and protumorigenic inflammation genes was observed among single myeloid phagocytic cells, quantified as the myeloid single cell immune:protumorigenic inflammation ratio (M
2IR) score. Single myeloid phagocytic cells with low M
2IR scores demonstrated upregulation of proinflammatory cytokines/chemokines and downregulation of antigen presentation genes, were unrelated to M1 versus M2 polarization, and were enriched in pretreatment blood samples from patients with PD-L1 blockade-resistant metastatic urothelial cancer.
The balance of adaptive immunity and protumorigenic inflammation in individual tumor microenvironments is associated with PD-1/PD-L1 resistance in urothelial cancer with the latter linked to a proinflammatory cellular state of myeloid phagocytic cells detectable in tumor and blood.
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In 2018, robot‐assisted radical cystectomy will enter its 15th year. In an era where an effort is being made to standardize complication reporting and videos of the procedure are readily available, ...it is inevitable and justified that like everything novel, robot‐assisted radical cystectomy should be scrutinized against the gold standard, open radical cystectomy. The present comparison is focused on several parameters: oncological, functional and complication outcomes, and direct and indirect costs. Meta‐analysis and prospective randomized trials comparing robot‐assisted radical cystectomy versus open radical cystectomy have been published, showing an oncological equivalence and in some cases an advantage of robot‐assisted radical cystectomy in terms of postoperative morbidity. In the present review, we attempt to update the available knowledge on this debate and discuss the limitations of the current evidence that prevent us from drawing safe conclusions.
Objective
To report a single‐institution experience with totally intracorporeal neobladder urinary diversion (UD) after robot‐assisted laparoscopic radical cystectomy (RARC).
Patients and methods
A ...total of 158 patients underwent totally intracorporeal neobladder UD after RARC between 2003 and 2016. Patient demographics, intraoperative and pathological data, 30‐ and 90‐day perioperative mortality and complications were recorded. Complications were classified according to the modified Clavien–Dindo classification. The 5‐year overall (OS) and cancer‐specific survival (CSS) rates were estimated by Kaplan–Meier plots.
Results
Most of the patients were male (84%) and had clinical T Stage ≤2 (87%). The mean operation time was 359 (SD ±98) min, with a median (range) estimated blood loss of 300 (50–2200) mL. Most of the men (86%) received a nerve‐sparing procedure and 38% of the females an organ‐sparing approach. A lymph node dissection was performed in 156 (99%) patients, with a median (range) yield of 23 (7–48) nodes. Conversion to open surgery occurred in five patients (3%). We recorded negative margins in 156 patients (99%). The median (range) follow‐up was 34 (1–170) months, with 30‐ and 90‐day mortality rates of 0%. Clavien–Dindo Grade III–IV complications occurred in 29 of 158 (18%) patients at 30‐days and in eight of 158 (5%) between 30–90 days, resulting into a 90‐day overall high‐grade complication rate of 23%. The unadjusted estimated 5‐years recurrence‐free survival, CSS and OS rates were 70%, 72%, and 71%, respectively.
Conclusion
In our present series the complication and oncological results were similar to open RC series, suggesting that RARC followed by totally intracorporeal neobladder UD is a safe and feasible alternative.
Robot-assisted laparoscopic radical prostatectomy has gained widespread use. However, circulatory effects in patients subjected to an extreme Trendelenburg position (45°) are not well characterized.
...We studied 16 patients (ASA physical status I-II) with a mean age of 59 years scheduled for robot-assisted laparoscopic radical prostatectomy (45° head-down tilt, with an intraabdominal pressure of 11-12 mm Hg). Hemodynamics, echocardiography, gas exchange, and ventilation-perfusion distribution were investigated before and during pneumoperitoneum, in the Trendelenburg position and, in 8 of the patients, also after the conclusion of surgery.
In the 45° Trendelenburg position, central venous pressure increased almost 3-fold compared with the initial value, with an associated 2-fold increase in mean pulmonary artery pressure and pulmonary capillary wedge pressure (P<0.01). Mean arterial blood pressure increased by 35%. Heart rate, stroke volume, cardiac output, and mixed venous oxygen saturation were unaffected during surgery, as were echocardiographic heart dimensions. After induction of anesthesia, isovolumic relaxation time was prolonged, with no further change during the study. Deceleration time was normal and stable. In the horizontal position after pneumoperitoneum exsufflation, filling pressures and mean arterial blood pressure returned to baseline levels. Pneumoperitoneum reduced lung compliance by 40% (P<0.01). Addition of the Trendelenburg position caused a further decrease (P<0.05). Arterial blood acid-base balance was normal. End-tidal carbon dioxide tension increased whereas arterial carbon dioxide was unaffected with unchanged ventilation settings. Pneumoperitoneum increased PaO2 (P<0.05). Ventilation-perfusion distribution, shunt, and dead space were unaltered during the study.
Pneumoperitoneum and 45° Trendelenburg position caused 2- to 3-fold increases in filling pressures, without effects on cardiac performance. Filling pressures were normalized immediately after surgery. Lung compliance was halved. Gas exchange was unaffected. No perioperative cardiovascular complications occurred.
Abstract Context Radical cystectomy (RC) is associated with frequent morbidity and prolonged length of stay (LOS) irrespective of surgical approach. Increasing evidence from colorectal surgery ...indicates that minimally invasive surgery and enhanced recovery programmes (ERPs) can reduce surgical morbidity and LOS. ERPs are now recognised as an important component of surgical management for RC. However, there is comparatively little evidence for ERPs after robot-assisted radical cystectomy (RARC). Due to the multimodal nature of ERPs, they are not easily validated through randomised controlled trials. Objective To provide a European Association of Urology (EAU) Robotic Urology Section (ERUS) policy on ERPs to guide standardised perioperative management of RARC patients. Evidence acquisition The guidance was formulated in four phases: (1) systematic literature review of evidence for ERPs in robotic, laparoscopic, and open RC; (2) an online questionnaire survey formulated and sent to ERUS Scientific Working Group members; (3) achievement of consensus from an expert panel using the Delphi process; and (4) a standardised reporting template to audit compliance and outcome designed and approved by the committee. Evidence synthesis Consensus was reached in multiple areas of an ERP for RARC. The key principles include patient education, optimisation of nutrition, RARC approach, standardised anaesthetic, analgesic, and antiemetic regimens, and early mobilisation. Conclusions This consensus represents the views of an expert panel established to advise ERUS on ERPs for RARC. The ERUS Scientific Working Group recognises the role of ERPs and endorses them as standardised perioperative care for patients undergoing RARC. ERPs in robotic surgery will continue to evolve with technological and pharmaceutical advances and increasing understanding of the role of surgery-specific ERPs. Patient summary There is currently a lack of high-level evidence exploring the benefits of enhanced recovery programmes (ERPs) in patients undergoing robot-assisted radical cystectomy (RARC). We reported a consensus view on a standardised ERP specific to patients undergoing RARC. It was formulated by experts from high-volume RARC hospitals in Europe, combining current evidence for ERPs with experts’ knowledge of perioperative care for robotic surgery.
Radical cystectomy is the gold standard for nonmetastatic muscle invasive bladder cancer and for refractory nonmuscle invasive disease. Compared to open radical cystectomy, robot-assisted radical ...cystectomy has been shown to provide comparable early oncologic outcomes and improved perioperative outcomes. However, there is a paucity of data on long-term oncologic outcomes and concerns about a higher incidence of local recurrence after robot-assisted radical cystectomy. We report 10-year oncologic outcomes following robot-assisted radical cystectomy using a multinational database.
We retrospectively reviewed the prospective International Robotic Cystectomy Consortium database. Consecutive patients who underwent robot-assisted radical cystectomy 10 years ago or earlier were included in analysis. Data were reviewed for demographics, and perioperative, pathological and oncologic outcomes. Kaplan-Meier curves were used to depict recurrence-free, disease specific and overall survival. Multivariate stepwise Cox regression models were applied to identify variables associated with recurrence-free, disease specific and overall survival.
We identified 446 patients with a median age of 67 years (IQR 59-76). Of the patients 10% received neoadjuvant chemotherapy, 51% experienced any complication, 23% had high grade complications and 4% died within 3 months of robot-assisted radical cystectomy. Disease was pT3 or greater in 43% of patients and pN+ in 24% while a positive soft tissue surgical margin was observed in 7%. At a median followup of 5 years (IQR 2-10, maximum 14) local and distant recurrence had developed in 15% and 29% of patients, respectively. Ten-year recurrence-free, disease specific and overall survival rates were 59%, 65% and 35%, respectively. Patients with pT3 or greater and pN+ disease showed worse recurrence-free, disease specific and overall survival.
Long-term oncologic outcomes, and recurrence rates and patterns after robot-assisted radical cystectomy seem comparable to those in open series. Advanced disease stage and positive surgical margins remain the main determinants of survival after radical cystectomy.
Purpose We present a 2-institution experience with completely intracorporeal robotic orthotopic ileal neobladder after radical cystectomy in 132 patients. Materials and Methods Established open ...surgical techniques were duplicated robotically with all neobladders suture constructed intracorporeally in a globular configuration. Nerve sparing was performed in 56% of males. Lymphadenectomy was extended (up to aortic bifurcation in 51, 44%) and superextended (up to the inferior mesenteric artery in 20, 17%). Ureteroileal anastomoses were Wallace-type (86, 65%) or Bricker-type (46, 35%). The learning curve at each institution was assessed using chronological subgroups and by trends across the entire cohort. Data were prospectively collected and retrospectively queried. Results Mean operating time was 7.6 hours (range 4.4 to 13), blood loss was 430 cc (range 50 to 2,200) and hospital stay was 11 days (median 8, range 3 to 78). Clavien grade I, II, III, IV and V complications within 30 days were 7%, 25%, 13%, 2% and 0%, respectively, and between 30 and 90 days were 5%, 9%, 11%, 1% and 2%, respectively. Mean nodal yield was 29 (range 7 to 164) and the node positivity rate was 17%. Operative time, blood loss, hospital stay and prevalence of late complications improved with experience. During a mean followup of 2.1 years (range 0.1 to 9.8) cancer recurred in 20 patients (15%). Five-year overall, cancer specific and recurrence-free survival was 72%, 72% and 71%, respectively. Conclusions We developed a refined technique of robotic intracorporeal orthotopic neobladder diversion, duplicating open principles. Operative efficiency and outcomes improved with experience. Going forward, we propose a prospective randomized comparison between open and robotic intracorporeal neobladder surgery.
Abstract Context Multimodal treatment for men with locally advanced prostate cancer (PCa) using neoadjuvant/adjuvant systemic therapy, surgery, and radiation therapy is being increasingly explored. ...There is also interest in the oncologic benefit of treating the primary tumor in the setting of metastatic PCa (mPCa). Objective To perform a review of the literature regarding the treatment of the primary tumor in the setting of mPCa. Evidence acquisition Medline, PubMed, and Scopus electronic databases were queried for English language articles from January 1990 to September 2014. Prospective and retrospective studies were included. Evidence synthesis There is no published randomized controlled trial (RCT) comparing local therapy and systemic therapy to systemic therapy alone in the treatment of mPCa. Prospective studies of men with locally advanced PCa and retrospective studies of occult node-positive PCa have consistently shown the addition of local therapy to a multimodal treatment regimen improves outcomes. Molecular and genomic evidence further suggests the primary tumor may have an active role in mPCa. Conclusions Treatment of the primary tumor in mPCa is being increasingly explored. While preclinical, translational, and retrospective evidence supports local therapy in advanced disease, further prospective studies are under way to evaluate this multimodal approach and identify the patients most likely to benefit from the inclusion of local therapy in the setting of metastatic disease. Patient summary In this review we explored preclinical and clinical evidence for treatment of the primary tumor in metastatic prostate cancer (mPCa). We found evidence to support clinical trials investigating mPCa therapy that includes local treatment of the primary tumor. Currently, treating the primary tumor in mPCa is controversial and lacks high-level evidence sufficient for routine recommendation.
Objectives
To determine the risk of COVID‐19 transmission during minimally invasive surgical (MIS) procedures
Methods
Surgical society statements regarding the risk of COVID transmission during MIS ...procedures were reviewed. In addition, the available literature on COVID‐19 and other viral transmission in CO2 pneumoperitoneum, as well as the presence of virus in the plume created by electrocautery during MIS was reviewed. The society recommendations were compared to the available literature on the topic to create our review and recommendations to mitigate COVID‐19 transmission.
Results
The recommendations promulgated by various surgical societies evolved over time as more information became available on COVID‐19 transmission. Review of the available literature on the presence of COVID‐19 in CO2 pneumoperitoneum was inconclusive. There is no clear evidence of the presence of COVID‐19 in plume created by electrocautery. Technologies to reduce CO2 pneumoperitoneum release into the operating room as well as filter viral particles are available and should reduce the exposure risk to operating room personnel.
Conclusion
There is no clear evidence of COVID‐19 virus in the CO2 used during MIS procedures or in the plume created by electrocautery. Until the presence or absence of COVID‐19 viral particles has been clearly established, measures to mitigate CO2 and surgical cautery plume release into the operating room should be performed. Further study on the presence of COVID‐19 in MIS pneumoperitoneum and cautery plume is needed.
Abstract Background Many elderly or impotent men with prostate cancer may not receive a bundle-preserving radical prostatectomy as a result of uncertainty regarding the effect on urinary ...incontinence. Objective We searched for predictors of urinary incontinence 1 yr after surgery among surgical steps during radical prostatectomy. Design, setting, and participants More than 100 surgeons in 14 centers prospectively collected data on surgical steps during an open or robot-assisted laparoscopic radical prostatectomy. At 1 yr after surgery, a neutral third-party secretariat collected patient-reported information on urinary incontinence. After excluding men with preoperative urinary incontinence or postoperative irradiation, data were available for 3379 men. Intervention Surgical steps during radical prostatectomy, including dissection plane as a measure of the degree of preservation of the two neurovascular bundles. Outcome measurements and statistical analysis Urinary incontinence 1 yr after surgery was measured as patient-reported use of pads. In different categories of surgical steps, we calculated the percentage of men changing pads “about once per 24 h” or more often. Relative risks were calculated as percentage ratios between categories. Results and limitations A strong association was found between the degree of bundle preservation and urinary incontinence 1 yr after surgery. We set the highest degree of bundle preservation (bilateral intrafascial dissection) as the reference category (relative risk = 1.0). For the men in the remaining six groups, ordered according to the degree of preservation, we obtained the following relative risks (95% confidence interval CI): 1.07 (0.63–1.83), 1.19 (0.77–1.85), 1.56 (0.99–2.45), 1.78 (1.13–2.81), 2.27 (1.45–3.53), and 2.37 (1.52–3.69). In the latter group, no preservation of any of the bundles was performed. The pattern was similar for preoperatively impotent men and for elderly men. Limitations of this analysis include the fact that noise influences the relative risks, due to variations between surgeons in the use of undocumented surgical steps of the procedure, variations in surgical experience and in how the surgical steps are reported, as well as variations in the metrics of patient-reported use of pads. Conclusions We found that the degree of preservation of the two neurovascular bundles during radical prostatectomy predicts the rate of urinary incontinence 1 yr after the operation. According to our findings, preservation of both neurovascular bundles to avoid urinary incontinence is also meaningful for elderly and impotent men. Patient summary We studied the degree of preservation of the two neurovascular bundles during radical prostatectomy and found that the risk of incontinence decreases if the surgeon preserves two bundles instead of one, and if the surgeon preserves some part of a bundle rather than not doing so.
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