Tailored chemotherapy for colorectal cancer peritoneal metastases based on a drug-screening platform in patient-derived organoids: a case report.

Background: Peritoneal metastasis from colorectal cancer (CRC) has limited therapeutic options and poor prognosis. Systemic chemotherapy combined with cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) or pressurized intraperitoneal aerosol chemotherapy (PIPAC) have yielded initial promising results. However, standard local therapies with oxaliplatin and mitomycin are not optimal and a better individualized management of these patients remains as an unmet clinical need. Patient-derived organoid (PDO) technology allows to culture in three dimensions normal and cancer stem cells (CSC) that self-organize in multicellular structures that recapitulates some of the features of the particular organ or tumor of origin, emerging as a promising tool for drug-testing and precision medicine. This technology could improve the efficacy of systemic and intraperitoneal chemotherapy and avoid unnecessary treatments and side effects to the patient. Case Description: Here we report a case of a 45-year-old man with a rectal adenocarcinoma with liver, lymph node and peritoneal metastases. The patient was treated with systemic chemotherapy (FOLFOXIRI plus Bevacizumab) and was subjected to mitomycin-based PIPAC. We generated patient-derived peritoneal carcinomatosis organoids in order to screen the activity of drugs for a personalized treatment. Both 5-FU and SN-38, the active irinotecan derivative, displayed strong cytotoxicity, while the response to oxaliplatin was much lower. Although the development of a colo-cutaneous fistulae prevented from further PIPAC, the patient continued with fluoropirimidine maintenance treatment based on standard clinical practice and the drug-screening test performed on organoids. Conclusions: Our results suggest that the peritoneal implant shows chemoresistance to oxaliplatin, while it might still be sensitive to irinotecan and 5-FU, which supports a potential benefit of these two drugs in the local and/or systemic treatment of our patient. This study shows the strength of the utility of the establishment of organoids for drug response assays and thus, for the personalized treatment of colorectal carcinomatosis patients.

"When and how are peritoneal metastases of colo-rectal origin treatable".

Peritoneal metastasis (PM) of colorectal cancer (CRC) origin can be treated and cured. This article presents a practical guide for CRC surgeons facing a patient with PM and presents the different options of treatment at expert centers on peritoneal surface malignancies. The unexpected finding of PM could be overwhelming, especially during an emergency CRC surgery. Clear indications on managing these situations call for clarification to avoid any negative impact on the oncologic outcome of patients with CRC. All patients with PM of CRC origin must be evaluated by a tumor board or multidisciplinary team specialized in the management of peritoneal surface malignancies since currently there are available options of treatment for patients with resectable peritoneal disease, unresectable peritoneal disease, and even patients with synchronous liver metastases (LM) could benefit from a multimodal approach.

Consensus guidelines for pressurized intraperitoneal aerosol chemotherapy: Technical aspects and treatment protocols.

BACKGROUND: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is increasingly used to treat patients with peritoneal cancer. A recent survey demonstrated considerable diversification of current practice of PIPAC raising issues of concern also regarding safety and efficacy. The study aim was to reach consensus on best practice of PIPAC treatment. METHODS: Current practice was critically discussed during an expert meeting and the available evidence was scrutinized to elaborate a 33-item closed-ended questionnaire. All active PIPAC centers were then invited to participate in an online two-round Delphi process with 3 reminders at least. Consensus was defined a priori as >70% agreement for a minimal response rate of 70%. RESULTS: Forty-nine out of 57 invited PIPAC centers participated in Delphi 1 and 2 (86%). Overall, there was agreement for 21/33 items. Consensus was reached for important aspects like advanced OR ventilation system (91.8%), remote monitoring (95.9%), use of the PRGS (85.7%) and use of a safety checklist (98%). The drug regimens oxaliplatin (87.8%) and cisplatin/doxorubicin (81.6%) were both confirmed by the expert panel. Important controversies included number and location of Biopsies during repeated PIPAC and the combination of PIPAC with additional surgical procedures. CONCLUSION: This consensus statement aims to allow for safe and efficacious PIPAC treatment and to facilitate multi-center analyses of the results. Additional preclinical and clinical studies are needed to resolve the remaining controversies.

Primary and metastatic peritoneal surface malignancies.

Peritoneal surface malignancies comprise a heterogeneous group of primary tumours, including peritoneal mesothelioma, and peritoneal metastases of other tumours, including ovarian, gastric, colorectal, appendicular or pancreatic cancers. The pathophysiology of peritoneal malignancy is complex and not fully understood. The two main hypotheses are the transformation of mesothelial cells (peritoneal primary tumour) and shedding of cells from a primary tumour with implantation of cells in the peritoneal cavity (peritoneal metastasis). Diagnosis is challenging and often requires modern imaging and interventional techniques, including surgical exploration. In the past decade, new treatments and multimodal strategies helped to improve patient survival and quality of life and the premise that peritoneal malignancies are fatal diseases has been dismissed as management strategies, including complete cytoreductive surgery embedded in perioperative systemic chemotherapy, can provide cure in selected patients. Furthermore, intraperitoneal chemotherapy has become an important part of combination treatments. Improving locoregional treatment delivery to enhance penetration to tumour nodules and reduce systemic uptake is one of the most active research areas. The current main challenges involve not only offering the best treatment option and developing intraperitoneal therapies that are equivalent to current systemic therapies but also defining the optimal treatment sequence according to primary tumour, disease extent and patient preferences. New imaging modalities, less invasive surgery, nanomedicines and targeted therapies are the basis for a new era of intraperitoneal therapy and are beginning to show encouraging outcomes.

Priorities, actions and risks in the COVID-19 pandemic: a flash SoMe survey among surgical oncologists.

OBJECTIVES: Corona virus-induced disease 19 (COVID-19) pandemic has globally affected the surgical treatment of cancer patients and has challenged the ethical principles of surgical oncologists around the world. Not only treatment but also diagnosis and follow-up have been disrupted. METHODS: An online survey was sent through Twitter and by the surgical societies worldwide. The survey consisted of 29 closed-ended questions and was conducted over a period of 24 days beginning in March 26, 2020. RESULTS: Overall, 394 surgical oncologists from 41 different countries answered the questionnaire. The predominant guiding principle was "saving lives" 240 (62%), and the different aspects of lock-down found hence large support (mean 7.1-9.3 out of 10). Shut-down of elective surgery and modification of cancer care found a mean support of 7.0 ± 3.0 and 5.8 ± 3.1, respectively. Modification of cancer care longer than two weeks was considered unacceptable to 114 (29%) responders. Hundred and fifty six (40%) and 138 (36%) expect "return to normal" beyond six months for surgical practice and cancer care, respectively. CONCLUSIONS: Surgical oncologists show strong and long-lasting support for lock-down measures aiming to save lives. The impact of the pandemic on surgical oncology is perceived controversially, but the majority was forced already now to accept what is inacceptable for many of their colleagues.

Patterns of peritoneal dissemination and response to systemic chemotherapy in common and rare peritoneal tumours treated by cytoreductive surgery: study protocol of a prospective, multicentre, observational study.

INTRODUCTION: Despite optimal patient selection and surgical effort, recurrence is seen in over 70% of patients undergoing cytoreductive surgery (CRS) for peritoneal metastases (PM). Apart from the Peritoneal Cancer Index (PCI), completeness of cytoreduction and tumour grade, there are other factors like disease distribution in the peritoneal cavity, pathological response to systemic chemotherapy (SC), lymph node metastases and morphology of PM which may have prognostic value. One reason for the underutilisation of these factors is that they are known only after surgery. Identifying clinical predictors, specifically radiological predictors, could lead to better utilisation of these factors in clinical decision making and the extent of peritoneal resection performed for different tumours. This study aims to study these factors, their impact on survival and identify clinical and radiological predictors. METHODS AND ANALYSIS: There is no therapeutic intervention in the study. All patients with biopsy-proven PM from colorectal, appendiceal, gastric and ovarian cancer and peritoneal mesothelioma undergoing CRS will be included. The demographic, clinical, radiological, surgical and pathological details will be collected according to a prespecified format that includes details regarding distribution of disease, morphology of PM, regional node involvement and pathological response to SC. In addition to the absolute value of PCI, the structures bearing the largest tumour nodules and a description of the morphology in each region will be recorded. A correlation between the surgical, radiological and pathological findings will be performed and the impact of these potential prognostic factors on progression-free and overall survival determined. The practices pertaining to radiological and pathological reporting at different centres will be studied. ETHICS AND DISSEMINATION: The study protocol has been approved by the Zydus Hospital ethics committee (27 July, 2020) and Lyon-Sud ethics committee (A15-128). TRIAL REGISTRATION NUMBER: CTRI/2020/09/027709; Pre-results.

Prehabilitation of patients undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal malignancy.

Treatment of peritoneal malignancy with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) is often undertaken in patients who have nutritional, physical and psychological challenges as a result of advanced disease. Prehabilitation is a multimodal approach that helps optimize postoperative recovery and reduce morbidity and may be of benefit in this group of patients. It begins once the decision to operate is made and continues until recovery to baseline health. Here we present recommendations on Prehabilitation for patients undergoing cytoreductive surgery and HIPEC following discussion at the 10th Peritoneal Malignancy Workshop in Paris September 2018.

The American College of Surgeons Response to the COVID-19 Pandemic (Part I): Cancer Care, COVID-19 Registry, Surgeon Wellness.

From the onset of the COVID-19 global pandemic of 2020, the American College of Surgeons has been a leader in disseminating reliable information on the nature of the crisis and assuring quality of surgical care during the enforced lockdown of inpatient and outpatient care.

The American College of Surgeons Response to the COVID-19 Pandemic (Part III): Leadership in a Time of Crisis.

The response of the American College of Surgeons (ACS) to the COVID-19 pandemic was vigorous and effective because it had mature programs in surgical quality and health policy and advocacy, the legacy of decades of work by its officers and leaders and its current executive director, David Hoyt. Hoyt had the foresight to institute a digital communications platform upon which the College collected data for its clinical programs and conducted many of its meetings. Through internet portals, online communities, and social media it broadcasted news and information to the membership. When the global COVID-19 pandemic struck, the College was able to quickly mobilize its leaders and scientific experts to disseminate credible information, recommend protocols to maintain patient and provider safety in operating room environments, provide a rational scheme of prioritization of urgent surgical operations, and a sensible means of resumption of normal surgical practice. As the financial impact of the outbreak on surgical practice became apparent, the ACS represented the interests of surgeons in the White House, Capitol, federal agencies, and governors' mansions and statehouses. In an interview by Steven Wexner, a member of the ACS Board of Regents, Hoyt described the response of the ACS to an unprecedented threat to the surgical care of patients in the country and the world. His story demonstrates the legacy of credibility and professionalism built by decades of principled leadership of generations of officers and Regents of the College, and his own example of effective leadership in crisis.

The American College of Surgeons Response to the COVID-19 Pandemic (Part II) : Advocacy and Public Policy.

From the onset of the COVID-19 global pandemic of 2020, the American College of Surgeons (ACS) has been a leader in disseminating credible information on the clinical and scientific aspects of the disease. As governmental regulations enforced the closure of hospitals and operating rooms to elective surgical cases as part of its "shelter-in-place" public lockdown policies, the ACS brought specialty societies together to create guidelines to protect patients and preserve surgical quality. Federal agencies made available financial aid programs to mitigate the economic impact of the outbreak. The division of advocacy and health policy of the ACS made certain that the interests of surgeons and their patients were served. Steven Wexner, member of the Board of Regents of the ACS interviewed the medical directors of the division, Frank Opelka in quality and health policy, and Patrick Bailey in advocacy, for their stories of how the College responded to the many health and public policy issues that came before Congress and governmental agencies during the pandemic.

Expanding Uses of HIPEC for Locally Advanced Colorectal Cancer: A European Perspective.

Locally advanced colorectal cancer is a challenge for surgeons and medical oncologist; 10 to 20% colorectal cancer debut as locally advanced disease, with tumors extending through the colon wall with perforation and/or invasion of adjacent organs or structures. Those locally advanced tumors have a worse prognostic at any stage due not only to systemic dissemination but also in a high percentage of patients, to locoregional recurrence, in fact, peritoneal carcinomatosis of colorectal origin is so predictable that we can assess the risk for each patient according to some histopathological and clinical features: small peritoneal nodules resected in the first surgery (70% probability), ovarian metastases (60%), perforated tumor onset or intraoperative tumor rupture (50%), positive cytology (40%), and pT4/mucinous pT3 up to 40%. Prophylactic or adjuvant hyperthermic intraperitoneal chemotherapy seems to be a promising strategy for patients with advanced colorectal cancer to prevent the development of peritoneal recurrence and improve prognosis of this group of patients.

The role of mucin cell-free DNA detection as a new marker for the study of acellular pseudomyxoma peritonei of appendicular origin by liquid biopsy.

BACKGROUND: Acellular pseudomyxoma peritonei (aPMP) is a rare peritoneal malignancy characterized by the accumulation of large amounts of mucin (lacking tumor cells) in the peritoneum. Many cases account for several kilograms of mucin to be screened by the pathologist. This is a comprehensive study of three patients with aPMP, whose tumors showed KRAS mutation, allowing for the tracking of this marker by liquid biopsy. METHODS: Pre and post-surgery plasma, and mucin removed during cytoreductive surgery were collected from the patients. KRAS mutations were analyzed using droplet digital polymerase chain reaction (ddPCR). Mucin was injected in mice. KRAS and cytokine levels were measured in plasma of the mice using ddPCR and a magnetic bead-based assay. Mucin microbiome was analyzed by 16S rRNA sequencing. RESULTS: KRAS mutations were detected in mucin cell-free DNA (cfDNA) from the three patients but not in the pre or post-surgery plasma. Electron microscopy detected microparticles (diameter <0.4 µm) in mucin. Mucin from one patient grew up inside the peritoneal cavity of mice and human KRAS was identified in mucin cfDNA, but not in plasma. All mucins showed the same bacterial profile. Cytokine levels were slightly altered in mice. CONCLUSIONS: The three aPMP patients included in this study shared some common aspects: the absence of tumor cells in mucin, the presence of KRAS mutated cfDNA in mucin, and the absence of this tumor-derived mutation in the bloodstream, providing additional information to the routine pathological examinations and suggesting that mucin cfDNA could potentially play a role in aPMP recurrence and prognosis.

Lessons Learned and Experiences Shared From the Front Lines: United Kingdom.

This is the second installment of a series of interviews, conducted by the senior author (S.D.W.) and the American College of Surgeons (ACS), that feature international leaders in surgery telling of the challenges they faced during the global COVID-19 pandemic. The disease arrived in the United Kingdom with devastating effects within a few weeks of its spread to Western Europe from China. In Oxford, Professor Neil Mortensen used his position as the President-elect of the Royal College of Surgeons of England to help coordinate efforts among the 4 Royal Colleges in the United Kingdom (his own, London, Edinburgh, and Ireland) to mobilize and retrain surgeons for duty helping to support in the critical care of patients with respiratory illness from the virus. In London, Lord Ara Darzi, a colon and rectal surgeon and leading innovator in minimally invasive surgery, underwent re-education himself in respiratory care to help his medical colleagues. As a member of the House of Lords involved in matters regarding the National Health Service as former Parliamentary Undersecretary of Health, he facilitated legislative measures to increase the physician workforce necessary to meet the demand for skilled personnel. Professor Mortensen and Lord Darzi have been recognized as honorary fellows of the ACS for their contributions to surgery. "Lots of people do not think it can possibly happen to them", Professor Mortensen said, "Our experience is that it will happen to you, and you cannot be prepared enough. Preparation, preparation, preparation is what you need to do."

Lessons Learned and Experiences Shared From the Front Lines: Milan and Madrid.

Under the aegis of the American College of Surgeons (ACS), the senior author (SDW), a member of the Board of Regents of the ACS, interviewed 3 of his international colleagues in colon and rectal surgery who found themselves dealing with a flood of patients from the COVID-19 pandemic. Each was in a "hot spot" where the outbreak overwhelmed the capacities of the hospitals. Professor Antonino Spinelli of Milan dealt with the sudden increase in COVID-19 patients that threatened to push all other emergencies and urgent cancer cases aside. Providers lacked the personal protective equipment to be adequately safe in the environment. In Madrid, Dr Julio Mayol recounted how 10%-15% of the workers in his hospital were incapacitated by the virus, many of them doctors providing direct care to patients. The disease is so prevalent that all emergency patients are treated as though they have the infection. Having practices in Saudi Arabia and Spain, Dr Delia Cortés-Guiral saw how the former country controlled the epidemic through a strict lockdown of travel and closure of holy pilgrimage sites and social gatherings. In contrast, upon her return to her native country, she experienced the near-breakdown of the health care system by the suddenness of the outbreak. "There are now no specialists now, she says." All of the specialties are treating COVID-19 patients and all of us are learning at the same time how to deal with this disease."It is a nightmare now here in Spain".

Liquid biopsy in peritoneal fluid and plasma as a prognostic factor in advanced colorectal and appendiceal tumors after complete cytoreduction and hyperthermic intraperitoneal chemotherapy.

BACKGROUND: Positive cytology has been identified as an independent negative prognostic factor in patients with peritoneal metastases (PM) of colorectal origin. Liquid biopsy in plasma may detect increasing levels of circulating tumor DNA (ctDNA) and could help predict systemic relapse in patients with colorectal cancer, but little is known about the role of liquid biopsy in peritoneal fluid. The aim of this study was to evaluate the prognostic value of peritoneal fluid and plasma liquid biopsy in patients undergoing complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CC-HIPEC). METHODS: A longitudinal prospective study was designed in patients with KRAS-mutated colorectal or appendiceal primary tumor, including PM of colorectal origin, pseudomyxoma peritonei and patients at high risk of developing PM (selected for second-look surgery). Eleven patients were recruited according to inclusion and exclusion criteria. ctDNA from plasma and peritoneal fluid before and after HIPEC was studied by droplet digital PCR looking for KRAS mutation. A close follow-up was scheduled (mean of 28.5 months) to monitor for systemic and peritoneal recurrences. RESULTS: All patients with positive plasma postHIPEC had systemic relapse and four patients died as a result, while those with negative plasma postHIPEC did not relapse. Patients with negative peritoneal ctDNA after CC-HIPEC did not present peritoneal relapse. Of six patients with positive peritoneal ctDNA postHIPEC, two presented peritoneal recurrence and four systemic relapses. CONCLUSIONS: Treatment with CC-HIPEC does not always neutralize ctDNA in peritoneal fluid, and its persistence after treatment may predict adverse outcome. Despite being a proof of concept, an adequate correlation between liquid biopsy in plasma and peritoneal fluid with both systemic and peritoneal relapse has been observed.

Omental torsion: an infrequent cause of abdominal pain.

Omental torsion is an infrecuent cause of acute abdomen. It is related to obesity, abdominal surgery and abdominal trauma. Urgent exploratory laparotomy allows diagnosis and prevents complications as intrabdominal abcess. We present CT imaging of a Omenat torsion clinical case.

Torsión omental: una causa infrecuente de abdomen agudo / Omental torsion: an infrequent cause of abdominal pain

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Second-look surgery plus hyperthermic intraperitoneal chemotherapy for patients with colorectal cancer at high risk of peritoneal carcinomatosis: Does it really save lives?

The treatment of peritoneal carcinomatosis (PC) of colorectal origin with cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) has a 5-year recurrence-free or cure rate of at least 16%, so it is no longer labeled as a fatal disease, and offers prolonged survival for patients with a low peritoneal carcinomatosis index. Metachronous PC of colorectal origin is so predictable that there is a model which has been used to successfully determine the individual risk of each patient. Patients at risk are clearly identified; those with the highest risk have small peritoneal nodules present in the first surgery (70% probability of developing PC), ovarian metastases (60%), perforated tumor onset or intraoperative tumor rupture (50%). Current clinical, biological and imaging techniques still lack sufficient sensitivity to diagnose PC in its initial stages, when CRS plus HIPEC has a greater impact and a higher cure rate. Second-look surgery with HIPEC or prophylactic HIPEC at the time of the first intervention have been proposed as means of preventing and/or anticipating clinical or radiological relapse in at-risk patients. Both techniques have shown a significant decrease in peritoneal relapses and should be considered essential weapons in the management of colorectal cancer.

Infarto hemorrágico suprarrenal bilateral como causa infrecuente de dolor abdominal agudo durante el postoperatorio inmediato de la cirugía de colon / Bilateral adrenal hemorrhagic infarction as a rare cause of acute abdominal pain in the immediate postoperative period of colonic surgery

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