Precision oncology and systemic targeted therapy in Pseudomyxoma Peritonei.

PURPOSE: Pseudomyxoma peritonei (PMP) is a rare and poorly understood malignant condition characterized by the accumulation of intra-abdominal mucin produced from peritoneal metastases. Currently, cytoreductive surgery remains the mainstay of treatment but disease recurrence and death after relapse frequently occur in PMP patients. New therapeutic strategies are therefore urgently needed for these patients. EXPERIMENTAL DESIGN: A total of 120 PMP samples from 50 patients were processed to generate a collection of 50 patient-derived organoids (PDO) and xenograft (PDX) models. Whole exome sequencing (WES), immunohistochemistry analyses and in vitro and in vivo drug efficacy studies were performed. RESULTS: In this study, we have generated a collection of PMP preclinical models and identified druggable targets, including BRAFV600E, KRASG12C and KRASG12D,that could also be detected in intra-abdominal mucin biopsies of PMP patients using droplet digital PCR. Preclinical models preserved the histopathological markers from the original patient sample. The BRAFV600E inhibitor encorafenib reduced cell viability of BRAFV600E PMP-PDO models. Proof-of-concept in vivo experiments showed that a systemic treatment with encorafenib significantly reduced tumor growth and prolonged survival in subcutaneous and orthotopic BRAFV600E-PMP-PDX mouse models. CONCLUSIONS: Our study demonstrates for the first time that systemic targeted therapies can effectively control PMP tumors. BRAF signaling pathway inhibition represents a new therapeutic opportunity for BRAFV600E PMP patients who have a poor prognosis. Importantly, our present data and collection of preclinical models pave the way for evaluating the efficacy of other systemic targeted therapies toward extending the promise of precision oncology to PMP patients.

Wound infiltration or transversus abdominis plane block after laparoscopic radical prostatectomy: a randomized clinical trial.

BACKGROUND: Regional anesthesia techniques are commonly used for postoperative pain management during laparoscopic surgery. Our aim was to compare the analgesic efficacy of pre-incisional subcutaneous wound infiltration (WI) with that of the transversus abdominis plane (TAP) block as part of a multimodal analgesic approach in laparoscopic radical prostatectomy. METHODS: In this prospective, double-blinded, randomized controlled clinical trial, 60 patients were assigned to either TAP or WI group. The main outcome was acute postoperative pain control assessed using the mean numeric rating scale (NRS) at the 24 hours postoperatively. The secondary outcomes were opioid requirements, procedure-related complications, overall complications, and length of stay. RESULTS: In this study, 60 patients were randomized: 30 to TAP group and 28 to WI (two were excluded due to conversion to open surgery). We found no significant difference in the median (1Q, 3Q) NRS scores during the 24 h postoperatively neither at rest (TAP, 0 (0, 1) vs. WI, 0 (0, 1), P = 0.812), nor during movement (TAP, 1 (0, 2) vs. WI, 1 (0, 2), P = 0.708). There were no statistical differences in the postoperative intravenous morphine requirements in the TAP vs. WI groups during the same period (1.7 ± 3.1 vs. 1.8 ± 4.1 mg; P = 0.910). Only one patient in the TAP group presented with postoperative nausea and vomiting. CONCLUSIONS: Both pre-incisional subcutaneous WI and TAP blockade were associated with very low pain scores as part of a non-opioid multimodal analgesic regimen in laparoscopic radical prostatectomy. This study did not demonstrate the benefits of WI over TAP.

Intravenous lidocaine infusion compared to thoracic epidural analgesia in cytoreductive surgery with or without heated intraperitoneal chemotherapy. A retrospective case-cohort study.

BACKGROUND: Intravenous (IV) lidocaine is a proven analgesic therapy but has not been evaluated in extensive procedures such as cytoreductive surgery (CRS). Our aim was to assess the effectiveness and safety of IV lidocaine in this setting. METHODS: This is a retrospective hybrid case-cohort study investigating analgesic effectiveness and complications of perioperative IV lidocaine at 1.5 mg/kg/h for 48 h compared to thoracic epidural anaesthesia (TEA) among patients undergoing CRS in a high-volume centre. RESULTS: Sixty patients were included, 20 received IV lidocaine and 40 underwent TEA. Pain scores were low (median ≤2) and similar in both groups (p = 0.88). At 72 h, the lidocaine group had a lower median pain score (p = 0.03). Overall opioid consumption in the first 48 h was lower in the lidocaine compared to the TEA group (median 0 (IQR 0-9.5) mg vs. 45.4 (0-62.4) MME respectively, p = 0.001). Opioid consumption was also lower in the lidocaine compared to the TEA group during the whole 5-day period (median 1 (IQR 1-13.5) mg vs. 112 (36.6-137.85) MME respectively, p = 0.000). The incidence of PONV was significantly lower in the lidocaine group (27.5% vs 5%, p = 0.047) with no difference in other complications or length of in-hospital stay. CONCLUSION: Intravenous lidocaine infusion may be a safe and effective analgesic approach in CRS and is associated with a significant reduction of opioid use and PONV compared to opioid-containing TEA.

Retrospective Review of Outcomes in Non-Invasive Mucinous Appendiceal Neoplasms with and without Peritoneal Spread: A Cohort Study.

Patients treated surgically for local non-invasive mucinous appendiceal neoplasm (NI-MAN) may recur with the development of peritoneal dissemination (PD). The risk of recurrence and predictive factors are not well studied. Patients with NI-MAN, with or without peritoneal dissemination at presentation, were included. Patients with limited disease underwent surgical resection only. Patients with peritoneal dissemination underwent cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC). Patients without PD (nPD) were compared to those who presented with PD. Thirty-nine patients were included, 25 in nPD and 14 in PD. LAMN was diagnosed in 96% and 93% of patients in nPD and PD, respectively. Acellular mucin on the peritoneal surface was seen in 16% of nPD patients vs. 50% of PD patients (p = 0.019). Two (8%) patients in the nPD group who had LAMN without wall rupture recurred, at 57 and 68 months, with a PCI of 9 and 22. The recurrence rate in the PD group was 36%. All recurred patients underwent CRS+HIPEC. A peritoneal recurrence is possible in NI-MANs confined to the appendix even with an intact wall at initial diagnosis. The peritoneal disease may occur with significant delay, which is longer than a conventional follow-up.

Feasibility and effectiveness of opioid-free anesthesia in cytoreductive surgery with or without heated intraperitoneal chemotherapy.

BACKGROUND: Opioid-free anesthesia (OFA) provides analgesia minimizing opioids. OFA has not been evaluated in cytoreductive surgery (CRS) with or without heated intraperitoneal chemotherapy. We aim to evaluate OFA feasibility and effectiveness in CRS. METHODS: Retrospective cohort study of adult patients (84) undergoing CRS in a tertiary center from May 2020 until June 2021. Predefined protocols for either opioid-based anesthesia (OBA) or OFA were followed. RESULTS: OFA protocol patients (41) had better mean pain scores (1 ± 0.8 vs. 2 ± 1; p = 0.00) despite the avoidance of intravenous and epidural fentanyl intraoperatively (220 ± 104 and 194 ± 73 µg, respectively, in OBA vs. 0; p = 0.00). Postoperative epidural levobupivacaine was also lower in the OFA group (575 ± 192 vs. 706 ± 346 mg; p = 0.034) despite the lack of epidural fentanyl without difference in duration (4.3 ± 1.2 vs. 4 ± 1.2 days; p = 0.22). Morphine consumption was very low (4.1 ± 10 vs. 1.7 ± 5 mg; p = 0.16). Intraoperative hypertensive events and postoperative nausea and vomiting (PONV) were higher for OBA (43) (30.2% vs. 7.3%; p = 0.01% and 69.8% vs. 34.1%; p = 0.001, respectively). Postoperative epidural fentanyl was independently associated with PONV (p = 0.004). There was no difference in total complications or length of stay. CONCLUSION: OFA is feasible, safe, and offers optimal pain control while minimizing the use of opioids in CRS.

The Landmark Series: Surgical Treatment of Colorectal Cancer Peritoneal Metastases.

BACKGROUND: Peritoneal metastases (PM) are a form of metastatic spread affecting approximately 5-15% of colon cancer patients. The attitude towards management of peritoneal metastases has evolved from therapeutic nihilism towards a more comprehensive and multidisciplinary approach, in large part due to the development of cytoreductive surgery (CRS), usually coupled with heated intraperitoneal chemotherapy (HIPEC), along with the constant improvement of systemic chemotherapy of colorectal cancer. Several landmark studies, including 5 randomized controlled trials have marked the development and refinement of surgical approaches to treating colorectal cancer peritoneal metastases. METHODS: This review article focuses on these landmark studies and their influence in 4 key areas: the evidence supporting surgical resection of peritoneal metastases, the identification and standardization of important prognostic variables influencing patient selection, the role of surgery and intraperitoneal chemotherapy in prevention of colorectal PM and the role of intraperitoneal chemotherapy as an adjuvant to surgical resection. RESULTS: These landmark studies indicate that surgical resection of colorectal PM should be considered as a therapeutic option in appropriately selected patients and when adequate surgical expertise is available. Standardized prognostic variables including the Peritoneal Cancer Index and the Completeness of Cytoreduction Score should be used for evaluating both indications and outcomes. CONCLUSIONS: Current evidence does not support the use of second look surgery with oxaliplatin HIPEC or prophylactic oxaliplatin HIPEC in patients with high risk colon cancer nor the use of oxaliplatin HIPEC with CRS of colorectal PM.

Safe Anastomoses without Ostomies in Cytoreductive Surgery with Heated Intraperitoneal Chemotherapy: Technical Considerations and Modifications.

BACKGROUND: Gastrointestinal complications, predominantly anastomotic leak (AL), are the most frequent source of severe morbidity after cytoreductive surgery (CRS). OBJECTIVE: The aim of this study was to present the technical standards for colorectal anastomoses developed and systematically applied to all patients undergoing CRS in a high-volume tertiary center, and the associated AL rates. METHODS: This was a descriptive study reporting the technical characteristics of a standardized protocol for three types of colorectal anastomoses (colorectal, ileorectal, and ileocolic) in CRS with heated intraperitoneal chemotherapy (HIPEC), and a retrospective analysis of prospectively collected data on anastomotic outcomes. All patients (1172) undergoing CRS with HIPEC from September 2006 to September 2020 were included. The anastomotic complications were classified according to the International Study Group of Rectal Cancer Surgery (ISGRCS) classification. RESULTS: Overall, 1172 patients underwent 1300 procedures and 1359 gastrointestinal anastomoses. An ileocolic anastomosis was performed in 408 patients, colorectal anastomosis in 469 patients, and ileorectal anastomosis in 16 patients, none with diverting ileostomy; 345 other gastrointestinal reconstructions and 82 urinary reconstructions were performed in these patients. The AL rate was 1% (4/408) for the ileocolic anastomosis, 0.85% (4/469) for the colorectal anastomosis, and 0% (0/16) for the ileorectal anastomosis. One patient died postoperatively due to AL. CONCLUSIONS: Systematic application of standardized techniques adapted to ensure optimal tissue healing (stapled anastomoses avoiding overlap, accurate staple deployment, and hand-sewn reinforcement) are associated with a very high level of anastomotic safety in a large cohort of patients undergoing CRS and HIPEC.

A Near-Zero Anastomotic Leak Rate in Cytoreductive Surgery with Heated Intraperitoneal Chemotherapy is Achievable.

Gastrointestinal complications are the main source of severe morbidity after cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC), mainly in the form of anastomotic leak. Reducing the rate of anastomotic leaks is of paramount importance and should be approached both through risk factor understanding and reduction, as well as optimization of surgical team performance. We performed a study that describes the details of a technical protocol for the creation of anastomoses after colorectal resections in CRS and HIPEC and the anastomotic outcomes associated with its systematic application in a high-volume peritoneal surface malignancy center. An extremely low, near-zero anastomotic leak rate (0.85% in colorectal anastomoses, 1% in ileo-colic anastomoses, and 0% in ileo-rectal anastomoses) was observed among 1172 patients. Extremely low, near-zero rates of anastomotic leak after colorectal resections in CRS and HIPEC could be achievable in high-volume peritoneal malignancy centers. The described techniques could be adopted and validated in other high-volume peritoneal malignancy centers.

Pressurized Intraperitoneal Aerosol Chemotherapy: The Road from Promise to Proof.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is an innovative drug delivery technique invented to be used for the treatment of peritoneal metastasis. Its application gained popularity over the past years. Several prospective clinical trials are being conducted to determine efficacy and safety. At this moment, there remain many challenges to overcome before PIPAC can be widely adopted in clinical practice.See related article by Kim et al., p. 1875.

Minimally invasive surgery for T4 colon cancer is associated with better outcomes compared to open surgery in the National Cancer Database.

Minimally invasive surgery (MIS) is favored for T1-T3 colon cancer resection due to improved short and long-term outcomes. Recommendations regarding T4 cancers remain controversial due to a paucity of clinical trials or large datasets assessing outcomes. We aim to compare outcomes for pT4 colon cancer patients treated with MIS or open surgery (OS) in the National Cancer Database (NCDB). We analyzed adults having MIS or OS for stage II or III pT4 colon cancers between 2010 and 2014 using propensity-score matching, Cox and logistic regression modeling. Of 21 998 T4 patients, 7532 (34.2%) underwent MIS, 14 466 (65.8%) OS and 22.3% were MIS converted to OS. After propensity score matching, 5624 patients in each cohort were included. MIS was associated with improved postoperative mortality (3.4 vs. 7.2%, p > .001), surgical margins, optimal lymph node harvest, adjuvant chemotherapy use and 5-year survival (46% vs. 41%, P < .001). MIS was associated with improved short and long term outcomes for T4 colon cancers compared to OS on multivariate analysis. Based on these findings, well selected pT4 colon cancers can be considered appropriate for MIS however, prospective clinical trials are needed to better define the role of MIS in T4b colon cancer.

Decision-Making Analysis for Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer: A Survey by the Executive Committee of the Peritoneal Surface Oncology Group International (PSOGI).

OBJECTIVES: To assess the individual treatment strategies among international experts in peritoneal carcinosis, specifically their decision-making in the process of patient selection for hyperthermic intraperitoneal chemotherapy (HIPEC) in women suffering from ovarian cancer, to identify relevant decision-making criteria, and to quantify the level of consensus for or against HIPEC. METHODS: The members of the executive committee of the Peritoneal Surface Oncology Group International (PSOGI) were asked to describe the clinical conditions under which they would recommend HIPEC in patients with ovarian cancer and to describe any disease or patient characteristics relevant to their decision. All answers were then merged and converted into decision trees. The decision trees were then analyzed by applying the objective consensus methodology. RESULTS: Nine experts in surgical oncology provided information on their multidisciplinary treatment strategy including HIPEC for patients with advanced ovarian cancer. Three of the total of 12 experts did not perform HIPEC. Five criteria relevant to the decision on whether HIPEC is performed were applied. In patients with resectable disease, a peritoneal cancer index (PCI) <21, and epithelial ovarian cancer without distant metastasis, consent was received by 75% to perform HIPEC for women suffering from recurrent disease. Furthermore, in the primary disease setting, consent was received by 67% to perform HIPEC according to the same criteria. DISCUSSION AND CONCLUSION: Among surgical oncology experts in peritoneal surface malignancy and HIPEC, HIPEC plays an important role in primary and recurrent ovarian cancer, and the PCI is the most important criterion in this decision.

Five-year survival in patients with nodular and superficial spreading melanomas in the US population.

BACKGROUND: Although superficial spreading melanomas (SSM) are diagnosed as thinner lesions, nodular melanomas (NM) have a more rapid growth rate and are biologically more aggressive compared with other histologic subtypes. OBJECTIVE: To determine the difference in 5-year relative survival in patients with NM and SSM at the same Breslow depth and TNM stage. METHODS: A population-based cross-sectional analysis compared the 5-year relative survival of patients with NM and SSM using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER)∗Stat software (version 8.2.1-8.3.5). Chi-square tests compared the proportions, and Kaplan-Meier method with Z-score compared 5-year relative survival. RESULTS: For patients receiving a diagnosis between 2004 and 2009, 5-year relative survival was lower in NM compared with SSM (53.7% vs 87.3%; Z score, -41.35; P < .001). Similarly, for patients receiving a diagnosis between 2010 and 2015, 5-year relative survival was lower in NM compared with SSM (61.5% vs 89.7%; Z score, -2.7078; P < .01). Subgroup analyses showed inferior survival in NM in T1b, and survival differences remained significant after excluding patients with nodal or distant metastases. CONCLUSIONS: Five-year relative survival is worse in NM compared with SSM especially in T1b, T2a, and T2b melanomas. Melanoma subtype should be taken into consideration when making treatment recommendations.

Patient Selection for Hyperthermic Intraperitoneal Chemotherapy in Patients With Colorectal Cancer: Consensus on Decision Making Among International Experts.

BACKGROUND: Colorectal cancer (CRC) treatment for patients with peritoneal metastases is complex. The use of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has continued to be debated. The aim of the present study was to assess the consensus among international experts for decision-making regarding the use of CRS and HIPEC for patients with CRC. MATERIALS AND METHODS: Of 15 experts invited, 12 had provided their decision algorithms for CRS and HIPEC for patients with, or at high risk of, peritoneal metastases from CRC. Using the objective consensus method, the results were transformed into decision trees to provide information on the consensus and discordance. RESULTS: Only 1 scenario was found for which the consensus on performing HIPEC had reached 100%. The scenario was the treatment of young patients with complete cytoreduction and a peritoneal carcinomatosis index (PCI) of < 16 in the presence of certain risk factors. Five major decision criteria were identified: age, PCI, completeness of cytoreduction, extent of extraperitoneal metastases (EoMs), and, in the case of unverified EoMs, additional risk factors. Consensus was found regarding refraining from using HIPEC for older patients with a high PCI. The consensus further increased when addressing incomplete cytoreduction and an extensive extent of EoMs. CONCLUSION: A definite consensus concerning the use of HIPEC was only determined for very selected scenarios. These findings can be used for general guidance; however, owing to the heterogeneity of each individual situation, the impracticality of presenting the information through decision trees, and the unclear future of the role of HIPEC in the adjuvant setting, a one-on-one transfer to daily clinical practice could not be achieved.

Predictors and Outcomes of Surgery in Peritoneal Mesothelioma: an Analysis of 2000 Patients from the National Cancer Database.

INTRODUCTION: Diffuse malignant peritoneal mesothelioma (DMPM) is a rare malignancy associated with poor outcomes. Recent reports have shown longer survival with radical surgery, usually combined with intraperitoneal chemotherapy. However, surgical interventions in these patients have not been extensively studied at a population level. The objective of this retrospective cohort study is to assess the prevalence of surgical and nonsurgical interventions for DMPM patients, the influence of surgery on survival outcomes, and the associations between demographic and clinical factors with treatments and outcomes. METHODS: This study included adult patients diagnosed with DMPM from 2003 to 2014 and registered in the National Cancer Database (NCDB). The primary outcome was overall survival. Histologically confirmed mesothelioma was defined using International Classification of Diseases (ICD)-3 codes 9050/3, 9051/3, 90523, and 9053/3 and peritoneum as primary affected organ using ICD codes C17-19, C22-24, C26, C42, C48, and C76. Relationships between demographic and clinical variables, surgical treatments, and survival outcomes were evaluated using logistic and Cox modeling and log-rank tests. RESULTS: A total of 2062 patients were identified, of whom 1055 (51%) did not receive any surgery while 701 (34%) received radical surgery. Patients receiving radical surgery had overall survival of 38.4 months compared with 7.1 months for patients without surgery (p < 0.001) and 41.8 months in patients who received both radical surgery and systemic chemotherapy. CONCLUSIONS: Patients selected for and treated with radical surgery had significantly better overall survival compared with those receiving nonsurgical treatment. Patients newly diagnosed with DMPM should be evaluated for the possibility of receiving radical surgery.

Sixteen year-old with leiomyosarcoma in a prior benign myomectomy site.

Uterine leiomyosarcoma in a prior myomectomy site is a rare phenomenon. We report an unusual case of a leiomyosarcoma arising six months post myomectomy in a 16-year old female.