Peritoneal Gene Transfection of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand for Tumor Surveillance and Prophylaxis.

Peritoneal metastasis is very common in gastrointestinal, reproductive, and genitourinary tract cancers in late stages or postsurgery, causing poor prognosis, so effective and nontoxic prophylactic strategies against peritoneal metastasis are highly imperative. Herein, we demonstrate the first gene transfection as a nontoxic prophylaxis preventing peritoneal metastasis or operative metastatic dissemination. Lipopolyplexes of TNF-related-apoptosis-inducing-ligand (TRAIL) transfected peritonea and macrophages to express TRAIL for over 15 days. The expressed TRAIL selectively induced tumor cell apoptosis while exempting normal tissue, providing long-term tumor surveillance. Therefore, tumor cells inoculated in the pretransfected peritoneal cavity quickly underwent apoptosis and, thus, barely formed tumor nodules, significantly prolonging the mouse survival time compared with chemotherapy prophylaxis. Furthermore, lipopolyplex transfection showed no sign of toxicity. Therefore, this peritoneal TRAIL-transfection is an effective and safe prophylaxis, preventing peritoneal metastasis.

Addition of sintilimab to nanoparticle albumin-bound paclitaxel and S-1 as adjuvant therapy in stage IIIC gastric cancer.

The prognosis of stage III gastric cancer (GC) is not satisfying and the specific chemotherapy regimens for GC of stage IIIC based on the 8th edition of the UICC/AJCC TNM staging system are still inconclusive. Peritoneal recurrence is the common and severe relapse pattern. Nanoparticle albumin-bound paclitaxel (Nab-PTX) is safer and more effective than PTX in the peritoneal metastasis. Clinical trial has demonstrated the safety and efficacy of sintilimab in GC. A combination of Nab-PTX, S-1 and sintilimab could be a promising triplet regimen as adjuvant therapy for GC. The aim of this article is to describe the design of this prospective Dragon-VII trial, conducted to evaluate the safety and efficacy of the combination of Nab-PTX, S-1 and sintilimab. Clinical trial registration: NCT04781413.

Lay abstract The prognosis of stage IIIC gastric cancer is poor and the treatment for it is not satisfying. This is a clinical trial that aims to explore a more effective therapy in gastric cancer patients of stage IIIC. Patients with stage IIIC gastric cancer must meet all of the inclusion criteria and none of the exclusion criteria to be eligible for this trial. The eligible patients will be given eight cycles of combinatory therapy of albumin-bound paclitaxel, a chemotherapy (day 1 and day 8), and S-1, another chemotherapy (days 1 to 14), plus sintilimab, a type of immunotherapy called an immune checkpoint inhibitor (day 1) every 3 weeks and then sintilimab maintenance for up to 12 months.

Specialist oncological surgery for removal of the ovaries and fallopian tubes in BRCA1 and BRCA2 pathogenic variant carriers may reduce primary peritoneal cancer risk to very low levels.

Risk-reducing bilateral salpingo-oophorectomy (RRBSO) is highly effective for the prevention of high-grade serous ovarian cancer (HGSOC) in BRCA1/2 pathogenic variant carriers (PVCs), but does not completely eliminate future risk of primary peritoneal cancer (PPC). The requirement to completely remove fallopian tubes at RRBSO and carefully exclude occult cancer/serous tubal intraepithelial carcinoma (STIC) lesions may not have been appreciated historically. We calculated rates of HGSOC and PPC in confirmed BRCA1/2 PVCs registered on the regional database in those who did (cases) and did not (controls) undergo RRBSO after genetic testing. Expected annual rates of ovarian/peritoneal cancer were 1% for BRCA1 ≥ 35 years and 0.5% for BRCA2 ≥ 45 years. Follow-up before 35/45 years was "risk free" and lead time excluded RRBSO <35 years and <45 years for BRCA1 and BRCA2, respectively. Women were followed from personal mutation report (controls) or RRBSO (cases) to death, ovarian/peritoneal cancer or last follow-up, whichever was sooner. In total, 891 cases (BRCA1 = 468, BRCA2 = 423) and 1302 controls had follow-up ≥35 years (BRCA1 = 736) and ≥45 years (BRCA2 = 566), respectively, over a total of 7261.1 risk eligible years (mean = 8.15 years). Twenty-one occult ovarian cancers were found at RRBSO (2.4%), 16 at stage 1. Post RRBSO, 56.97 ovarian/peritoneal cancers were expected but only 3 were observed (HR = 0.053; 95% CI = 0.013-0.14), with combined Kaplan-Meier analysis HR = 0.029 (95% CI = 0.009-0.100, P < .001). Risk reduction was greater in specialist (HR = 0.03; 95% CI = 0.001-0.13) compared to non-specialist centres (HR = 0.11; 95% CI = 0.02-0.37) (P = .07). In controls, 23.35 ovarian/peritoneal cancers were expected with 32 observed (HR = 1.37; 95% CI = 0.95-1.91). RRBSO <35/<45 years reduces the risk of ovarian/peritoneal cancer by 95% in BRCA1/2 PVCs and may be greater in specialist centres.

Preventive HIPEC in combination with perioperative FLOT versus FLOT alone for resectable diffuse type gastric and gastroesophageal junction type II/III adenocarcinoma - the phase III "PREVENT"- (FLOT9) trial of the AIO /CAOGI /ACO.

BACKGROUND: The main reason for treatment failure after curative surgical resection of gastric cancer is intra-abdominal spread, with 40-50% peritoneal seeding as primary localization of recurrence. Peritoneal relapse is seen in 60-70% of tumors of diffuse type, compared to only 20-30% of intestinal type. Hyperthermic IntraPEritoneal Chemoperfusion (HIPEC) is an increasingly used therapy method for patients with peritoneal metastases. The preventive use of HIPEC could represent an elegant approach for patients (pts) before macroscopic peritoneal seeding, since pts. with operable disease are fit and may have potential risk of microscopic involvement, thus having a theoretical chance of cure with HIPEC even without the need for cytoreduction. No results from a PCRT from the Western hemisphere have yet been published. METHODS: This is a multicenter, randomized, controlled, open-label study including a total of 200 pts. with localized and locally advanced diffuse or mixed type (Laurens's classification) adenocarcinoma of the stomach and Type II/III GEJ. All enrolled pts. will have received 3-6 pre-operative cycles of biweekly FLOT (Docetaxel 50 mg/m2; Oxaliplatin 85 mg/m2; Leucovorin 200 mg/m2; 5-FU 2600 mg/m2, q2wk). Pts will be randomized 1:1 to receive surgery only and postoperative FLOT (control arm) or surgery + intraoperative HIPEC (cisplatin 75 mg/m2 solution administered at a temperature of 42 °C for 90 min) and postoperative FLOT (experimental arm). Surgery is carried out as gastrectomy or transhiatal extended gastrectomy. Primary endpoint is PFS/DFS, major secondary endpoints are OS, rate of pts. with peritoneal relapse at 2 and 3 years, perioperative morbidity/mortality and quality of life. The trial starts with a safety run-in phase. After 20 pts. had curatively intended resection in Arm B, an interim safety analysis is performed. Recruitment has already started and first patient in was on January 18th, 2021. DISCUSSION: If the PREVENT concept proves to be effective, this could potentially lead to a new standard of therapy. On the contrary, if the outcome is negative, pts. with gastric cancer and no peritoneal involvement will not be treated with HIPEC during surgery. TRIAL REGISTRATION: The study is registered on June 25th, 2020 under ClinicalTrials.gov Identifier: NCT04447352 ; EudraCT: 2017-003832-35 .

Mesothelin blockage by Amatuximab suppresses cell invasiveness, enhances gemcitabine sensitivity and regulates cancer cell stemness in mesothelin-positive pancreatic cancer cells.

BACKGROUND: Mesothelin is a 40-kDa glycoprotein that is highly overexpressed in various types of cancers, however molecular mechanism of mesothelin has not been well-known. Amatuximab is a chimeric monoclonal IgG1/k antibody targeting mesothelin. We recently demonstrated that the combine therapy of Amatuximab and gemcitabine was effective for peritonitis of pancreatic cancer in mouse model. METHODS: We discover the role and potential mechanism of mesothelin blockage by Amatuximab in human pancreatic cells both expressing high or low level of mesothelin in vitro experiment and peritonitis mouse model of pancreatic cancer. RESULTS: Mesothelin blockage by Amatuximab lead to suppression of invasiveness and migration capacity in AsPC-1 and Capan-2 (high mesothelin expression) and reduce levels of pMET expression. The combination of Amatuximab and gemcitabine suppressed proliferation of AsPC-1 and Capan-2 more strongly than gemcitabine alone. These phenomena were not observed in Panc-1 and MIA Paca-2 (Mesothelin low expression). We previously demonstrated that Amatuximab reduced the peritoneal mass in mouse AsPC-1 peritonitis model and induced sherbet-like cancer cell aggregates, which were vanished by gemcitabine. In this study, we showed that the cancer stem cell related molecule such as ALDH1, CD44, c-MET, as well as proliferation related molecules, were suppressed in sherbet-like aggregates, but once sherbet-like aggregates attached to peritoneum, they expressed these molecules strongly without the morphological changes. CONCLUSIONS: Our work suggested that Amatuximab inhibits the adhesion of cancer cells to peritoneum and suppresses the stemness and viability of those, that lead to enhance the sensitivity for gemcitabine.

Entinostat, a selective HDAC1/2 inhibitor, potentiates the effects of olaparib in homologous recombination proficient ovarian cancer.

OBJECTIVE: Poly ADP ribose polymerase inhibitors (PARPi) are most effective in BRCA1/2 mutated ovarian tumors. Better treatments are needed for homologous recombination HR-proficient cancer, including CCNE1 amplified subtypes. We have shown that histone deacetylase inhibitors (HDACi) sensitize HR-proficient ovarian cancer to PARPi. In this study, we provide complementary preclinical data for an investigator-initiated phase 1/2 clinical trial of the combination of olaparib and entinostat in recurrent, HR-proficient ovarian cancer. METHODS: We assessed the in vitro effects of the combination of olaparib and entinostat in SKOV-3, OVCAR-3 and primary cells derived from CCNE1 amplified high grade serous ovarian cancer (HGSOC) patients. We then tested the combination in a SKOV-3 xenograft model and in a patient-derived xenograft (PDX) model. RESULTS: Entinostat potentiates the effect of olaparib in reducing cell viability and clonogenicity of HR-proficient ovarian cancer cells. The combination reduces peritoneal metastases in a SKOV-3 xenograft model and prolongs survival in a CCNE1 amplified HR-proficient PDX model. Entinostat also enhances olaparib-induced DNA damage. Further, entinostat decreases BRCA1, a key HR repair protein, associated with decreased Ki-67, a proliferation marker, and increased cleaved PARP, a marker of apoptosis. Finally, entinostat perturbs replication fork progression, which increases genome instability. CONCLUSION: Entinostat inhibits HR repair by reducing BRCA1 expression and stalling replication fork progression, leading to irreparable DNA damage and ultimate cell death. This work provides preclinical support for the clinical trial of the combination of olaparib and entinostat in HR-proficient ovarian cancer and suggests potential benefit even for CCNE1 amplified subtypes.

Prophylactic chemotherapeutic hyperthermic intraperitoneal perfusion reduces peritoneal metastasis in gastric cancer: a retrospective clinical study.

BACKGROUND: Peritoneal metastasis is the most frequent failure in gastric cancer. This study evaluated the role of prophylactic chemotherapeutic hyperthermic intraperitoneal perfusion (CHIP) in patients after D2 dissection. METHODS: Gastric cancer patients after D2 dissection were enrolled in this study. Patients received either chemotherapy (IV group) or CHIP (CHIP group). Sites of recurrence or metastasis, disease-free survival (DFS), overall survival (OS) and adverse events were evaluated. RESULTS: Twenty-two patients received CHIP treatment, and 21 patients received chemotherapy alone. The median DFS time was 24.5 and 36.5 months in the IV group and CHIP group (P = 0.044), respectively. The median OS time was 33.1 months in the IV group and not reached in the CHIP group (P = 0.037). We also found that CHIP could reduce the total recurrence/metastasis rate, especially that of peritoneal metastasis. In the subgroup analysis, DFS and OS were both superior in deficient mismatch repair (dMMR) patients than in proficient MMR (pMMR) patients. CONCLUSION: This hypothesis-generating study indicates that CHIP might be feasible for gastric cancer patients after D2 resection.

Prophylactic HIPEC with radical D2 gastrectomy improves survival and peritoneal recurrence rates for locally advanced gastric cancer: personal experience from a randomized case control study.

BACKGROUND: To investigate the implications of prophylactic intraoperative Hyperthermic Intraperitoneal Chemotherapy (HIPEC) with D2 radical gastrectomy for locally advanced Gastric Cancer (AGC) in a randomized case control study. METHOD: Eighty consecutive patients with locally AGC were randomly separated into 2 groups: HIPEC group (Curative Resection + intraoperative HIPEC with cisplatin 50 mg/m2 at 42.0 ± 1.0 °C for 60 min) and Control group (Curative Resection only). Intraoperative and post-operative events, clinical recovery, morbidity and the disease-free survival (DFS) rates were closely monitored. RESULTS: Among the 40 HIPEC group patients, the highest intracranial temperature recorded during the procedure was 38.2 °C but the patient made an eventless recovery. Mild renal dysfunction, hyperbilirubinemia and mild liver dysfunction were recorded in the HIPEC group but their incidences were found to be statistically insignificant when compared with the control group (P > 0.05). The initial post-operative analysis revealed shorter post-operative stay for in the HIPEC group but further analysis revealed that it was related to the incidence of postoperative complication. During a median follow-up time of 41 months, there were 9/39 and 15/38 cases of disease progression in HIPEC and Control groups respectively, with a more favorable 3-year DFS (76.9% vs 60.5%) and a lower peritoneal recurrence rate (5% vs 30%) in the HIPEC group. CONCLUSION: Prophylactic HIPEC with radical D2 Gastrectomy is safe and shows favorable survival and peritoneal recurrence rates for AGC with acceptable morbidity. Nevertheless, more structured multi-centered RCT should be carried out for more substantial evidence.

Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer in Women: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Pathogenic mutations in breast cancer susceptibility genes BRCA1 and BRCA2 increase risks for breast, ovarian, fallopian tube, and peritoneal cancer in women; interventions reduce risk in mutation carriers. Objective: To update the 2013 US Preventive Services Task Force review on benefits and harms of risk assessment, genetic counseling, and genetic testing for BRCA1/2-related cancer in women. Data Sources: Cochrane libraries; MEDLINE, PsycINFO, EMBASE (January 1, 2013, to March 6, 2019, for updates; January 1, 1994, to March 6, 2019, for new key questions and populations); reference lists. Study Selection: Discriminatory accuracy studies, randomized clinical trials (RCTs), and observational studies of women without recently diagnosed BRCA1/2-related cancer. Data Extraction and Synthesis: Data on study methods, setting, population characteristics, eligibility criteria, interventions, numbers enrolled and lost to follow-up, outcome ascertainment, and results were abstracted. Two reviewers independently assessed study quality. Main Outcomes and Measures: Cancer incidence and mortality; discriminatory accuracy of risk assessment tools for BRCA1/2 mutations; benefits and harms of risk assessment, genetic counseling, genetic testing, and risk-reducing interventions. Results: For this review, 103 studies (110 articles; N = 92 712) were included. No studies evaluated the effectiveness of risk assessment, genetic counseling, and genetic testing in reducing incidence and mortality of BRCA1/2-related cancer. Fourteen studies (n = 43 813) of 8 risk assessment tools to guide referrals to genetic counseling demonstrated moderate to high accuracy (area under the receiver operating characteristic curve, 0.68-0.96). Twenty-eight studies (n = 8060) indicated that genetic counseling was associated with reduced breast cancer worry, anxiety, and depression; increased understanding of risk; and decreased intention for testing. Twenty studies (n = 4322) showed that breast cancer worry and anxiety were higher after testing for women with positive results and lower for others; understanding of risk was higher after testing. In 8 RCTs (n = 54 651), tamoxifen (relative risk [RR], 0.69 [95% CI, 0.59-0.84]; 4 trials), raloxifene (RR, 0.44 [95% CI, 0.24-0.80]; 2 trials), and aromatase inhibitors (RR, 0.45 [95% CI, 0.26-0.70]; 2 trials) were associated with lower risks of invasive breast cancer compared with placebo; results were not specific to mutation carriers. Mastectomy was associated with 90% to 100% reduction in breast cancer incidence (6 studies; n = 2546) and 81% to 100% reduction in breast cancer mortality (1 study; n = 639); oophorectomy was associated with 69% to 100% reduction in ovarian cancer (2 studies; n = 2108); complications were common with mastectomy. Conclusions and Relevance: Among women without recently diagnosed BRCA1/2-related cancer, the benefits and harms of risk assessment, genetic counseling, and genetic testing to reduce cancer incidence and mortality have not been directly evaluated by current research.

[Prevention of carcinomatosis in colon cancer]. / Profilaktika kartsinomatoza pri rake obodochnoi kishki.

Colorectal cancer (CRC) is one of the leading forms of cancer. In 2017, over 72,000 of Russian citizens have been diagnosed with CRC. Cancer stage IV was diagnosed in 18 149 of them. Peritoneal carcinomatosis (PC) is one of the forms of metastatic dissemination throughout the peritoneum. There no any unified and standardized approaches to the treatment or prevention of PC associated with CRC. Therefore, it is advisable to identify PC predictors in patients with colon cancer and prevention measures.

Palliative Management of Peritoneal Metastases.

Despite significant recent advances in the management of peritoneal carcinomatosis, this diagnosis still is accompanied frequently by a grim survival prognosis, often measured in weeks to months. The poor prognosis also is accompanied often by complications and symptoms that have a dramatic impact on quality of life and are challenging to the managing health care provider and devastating to loved ones caring for the person who is suffering. Consequently, management of carcinomatosis often revolves around palliation of symptoms such as bowel obstruction, nausea, pain, fatigue, and cachexia as well as emotional and existential concerns. This article reviews several palliative treatment options for some of the more common symptoms and complications associated with advanced, incurable peritoneal carcinomatosis. Although readers should recognize that carcinomatosis is no longer an imminent death sentence, providers caring for patients with peritoneal carcinomatosis also must be well-versed in the palliative management of this condition and recognize the utility of early palliative care referral in this setting.

Current Management and Future Opportunities for Peritoneal Metastases: Peritoneal Mesothelioma.

PURPOSE: Diffuse malignant peritoneal mesothelioma (MPM) is a rare and ultimately fatal cancer that was first described just over a century ago. It is a diffuse malignancy arising from the mesothelial lining of the peritoneum; morbidity and mortality from MPM is due to its propensity to progress locoregionally within the abdominal cavity. METHODS: The purpose of this article is to review the current state-of-the-science related to the diagnosis, staging, and treatment of MPM. RESULTS: The condition afflicts men and women equally and the peak incidence is between 55 and 60 years of age although it can arise in the young and elderly. Patients afflicted with MPM most commonly present with nonspecific abdominal symptoms that usually lead to diagnosis when the condition is relatively advanced. Historically, median overall survival for MPM patients without treatment is < 1 year. The couplet of systemic pemetrexed and cisplatin has an overall response rate of approximately 25% and a median overall survival of approximately 1 year. CONCLUSION: The available data, almost all retrospective in nature, have shown that in selected patients, operative cytoreduction (CRS) and regional chemotherapy administered as hyperthermic intraoperative peritoneal chemotherapy (HIPEC) or early postoperative intraperitoneal chemotherapy (EPIC) is associated with long-term survival. Studies on the molecular biology of MPM have yielded new insights relating to the potentially important role of the phosphoinsitide-3-kinase/mammalian target of rapamycin (PI3 K/mTOR) pathways and immune checkpoint inhibitors that may translate into new therapeutic options for patients with diffuse MPM.

Synaptotagmin XIII expression and peritoneal metastasis in gastric cancer.

BACKGROUND: Peritoneal metastasis is a frequent cause of death in patients with gastric cancer. The aim of this study was to identify molecules responsible for mediating peritoneal metastasis of gastric cancer. METHODS: Transcriptome and bioinformatics analyses were conducted to identify molecules associated with peritoneal metastasis. The therapeutic effects of intraperitoneally administered small interfering (si) RNA were evaluated using mouse xenograft models. Expression of mRNA and protein was determined in gastric tissues from patients with gastric cancer. RESULTS: Synaptotagmin XIII (SYT13) was expressed at significantly higher levels in patients with peritoneal recurrence, but not in those with hepatic or distant lymph node recurrence. Inhibition of SYT13 expression in a gastric cancer cell line transfected with SYT13-specific siRNA (siSYT13) was associated with decreased invasion and migration ability of the cells, but not with proliferation and apoptosis. Intraperitoneal administration of siSYT13 significantly inhibited the growth of peritoneal nodules and prolonged survival in mice. In an analysis of 200 patients with gastric cancer, SYT13 expression in primary gastric cancer tissues was significantly greater in patients with peritoneal recurrence or metastasis. A high level of SYT13 expression in primary gastric cancer tissues was an independent risk factor for peritoneal recurrence. CONCLUSION: SYT13 expression in gastric cancer is associated with perioneal metatases and is a potential target for treatment.

Peritoneal Metastases from Gastrointestinal Cancer.

PURPOSE OF REVIEW: Peritoneal metastases may occur from a majority of cancers that occur within the abdomen or pelvis. When cancer spread to the peritoneal surfaces is documented, a decision regarding palliation vs. an aggressive approach using cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy must be made. The perioperative chemotherapy may be hyperthermic intraperitoneal chemotherapy (HIPEC) administered in the operating room or early postoperative intraperitoneal chemotherapy (EPIC) administered in the first 4 or 5 postoperative days. RECENT FINDINGS: This decision is dependent on a well-defined group of prognostic indicators. In addition to treatment, the clinical and pathologic features of a primary cancer can be used to select perioperative treatments that may prevent cancer cells within the abdomen and pelvis from progressing to established peritoneal metastases. In some clinical situations with appendiceal and colorectal cancers, the clinical or histopathologic features may indicate that second-look surgery plus perioperative chemotherapy should occur. Peritoneal metastases should always be considered for treatment or prevention.

Primary curative surgery and preemptive or adjuvant hyperthermic peritoneal chemotherapy in colorectal cancer patients at high risk to develop peritoneal carcinomatosis. A systematic review.

PURPOSE: Τo evaluate all available data on the effect of preemptive intervention in patients who have curative surgery for colorectal cancer (CRC) and are at high risk to develop peritoneal carcinomatosis (PC). METHODS: The authors conducted a systematic review of all published studies from January 2000 to July 2016. Twelve studies were eventually considered for analysis, and were divided in four categories, according to different approaches for adjuvant intra-peritoneal chemotherapy: a) hyperthermic intraperitoneal chemotherapy (HIPEC), during primary surgery for CRC; b) early postoperative intraperitoneal chemotherapy (EPIC), after primary surgery for CRC; c) early re-intervention (laparotomy or laparoscopy) and HIPEC; and d) as second look laparotomy and HIPEC + cytoreductive surgery (CRS), several months after primary surgery. RESULTS: Considering prophylactic HIPEC during primary surgery, the studies that were analysed showed a peritoneal recurrence rate of 0-12.9%, a 3- and 5-year disease free survival (DFS) of 67-97.5% and 54.8-84% respectively, and a 3- and 5-year overall survival (OS) of 67-100% and 84%, respectively. These oncological results are probably better than what is expected in patients at high risk to develop PC and have only adjuvant systemic chemotherapy. Because of the great heterogeneity in inclusion criteria (risk factors for PC) and methodology of intra-peritoneal chemotherapy (different timing, different techniques, different agents), a meta-analysis was not performed. CONCLUSIONS: At present and because of the insufficient available evidence, preemptive intervention at the immediate postoperative adjuvant setting is recommended only in the setting of a registered clinical trial.

Abortifacient metapristone (RU486 derivative) interrupts CXCL12/CXCR4 axis for ovarian metastatic chemoprevention.

Recent global epidemiological studies revealed the lower ovarian cancer death from long-term use of oral contraceptives. However, the underlying mechanism of action is not clear. Here, we use the abortifacient metapristone (RU486 derivative) to test the hypothesis that the contraceptives might interrupt CXCL12/CXCR4 chemokine axis to inhibit ovarian cancer metastasis. Metapristone at concentrations (

Peritoneal Involvement Is More Common Than Nodal Involvement in Patients With High-Grade Appendix Tumors Who Are Undergoing Prophylactic Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: Right hemicolectomy is routinely recommended in patients with histologic findings of high-grade appendix tumors after appendicectomy. Undetected peritoneal disease may be encountered at surgery. In high-grade appendix tumors with disease detected radiologically, complete cytoreduction may not be possible and outcomes poor. For these reasons, we adopted a policy of prophylactic cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. OBJECTIVE: The purpose of this study was to quantify the rates of peritoneal and nodal metastatic disease in patients with high-grade appendix tumors without obvious metastatic disease and to report the long-term outcomes of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in these patients. DESIGN: Data regarding peritoneal and nodal metastatic disease were extracted from surgical and histologic records. SETTINGS: The study was conducted at a high-volume tertiary referral center for peritoneal malignancy. PATIENTS: Patients referred with histologically high-grade appendix tumors at appendicectomy, without detectable metastatic spread, between January 1994 and September 2016 were included MAIN OUTCOME MEASURES:: A total of 62 patients with high-grade pathology at appendicectomy, without clinical or radiological peritoneal disease, underwent complete cytoreduction with hyperthermic intraperitoneal chemotherapy. RESULTS: Thirty-five (57%) of 62 patients had peritoneal disease (median peritoneal cancer index 5 (range, 1-28)). Eleven (31%) of 35 had microscopic peritoneal disease. Overall, 23 (37%) of 62 had peritoneal disease beyond the confines of a standard right hemicolectomy. Nine (15%) of 62 had nodal involvement. Mean overall and disease-free survival were 110.9 (95% CI, 94.8-127.0 mo) and 102.1 months (95% CI, 84.3-119.9 mo), with 5-year overall and disease-free survival of 83.2% and 76.0%. LIMITATIONS: The retrospective nature limits the interpretation of these results. CONCLUSIONS: Complete cytoreduction was achieved in all of the patients, with excellent long-term survival. The incidence of peritoneal spread (57%) compared with nodal involvement (15%) supports cytoreductive surgery and hyperthermic intraperitoneal chemotherapy as definitive treatment rather than prophylaxis in patients with high-grade appendix tumors, even without radiologically detectable disease. High-grade appendix tumors benefit from early aggressive operative management to deal with potential peritoneal and nodal spread and should be considered for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. See Video Abstract at http://links.lww.com/DCR/A360.

Strategies to prevent peritoneal carcinomatosis arising from colorectal cancer.

In the last decades, cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy became a curative option for peritoneal metastases in selected patients, otherwise considered for palliative therapy alone. Better knowledge of physiopathology of peritoneal spread and identification of predictive factors for peritoneal relapse prompted specialized centers to investigate the role of a 'proactive approach' in order to early detect peritoneal metastasis. These encouraging data could justify an active attitude in selected patients at high risk of peritoneal recurrence after curative resection of primary tumor. Selection criteria and the timing of complementary hyperthermic intraperitoneal chemotherapy remain important points of discussion. In this article, we will discuss treatment principles and future perspectives to early treat and, if possible, to prevent peritoneal dissemination after curative treatment of colorectal cancer.

No. 344-Opportunistic Salpingectomy and Other Methods of Risk Reduction for Ovarian/Fallopian Tube/Peritoneal Cancer in the General Population.

OBJECTIVE: This guideline reviews the potential benefits of opportunistic salpingectomy to prevent the development of high grade serous cancers (HGSC) of the ovary/fallopian tube/peritoneum based on current evidence supporting the fallopian tube origin of disease. INTENDED USERS: Gynaecologists, obstetricians, family doctors, registered nurses, nurse practitioners, residents, and health care providers. TARGET POPULATION: Adult women (18 and older): OPTIONS: Women considering hysterectomy who wish to retain their ovaries in situ have traditionally also retained their fallopian tubes. In addition, women undergoing permanent surgical sterilization have usually undergone tubal ligation using various methods rather than undergoing surgical removal of the entire fallopian tube. EVIDENCE: For the sections "Evidence Supporting the Hypothesis That HGSC Originates in the Fallopian Tube" and "Current Literature on the Effects and Safety of Opportunistic Salpingectomy," relevant studies were searched in PubMed, Medline, and the Cochrane Systematic Reviews using the following terms, either alone or in combination, with the search limited to English language materials: "high grade serous cancers ovary," "fallopian tube," "peritoneum," "opportunistic salpingectomy," "epithelial ovarian cancers," "origin," "tubal carcinoma in situ," "BRCA mutation," "prophylactic salpingectomy," "inflammation," "clear cell," and "endometrioid." The initial search was performed in March 2015 with a final literature search in March 2016. Relevant evidence was selected for inclusion in the following order: meta-analyses, systematic reviews, guidelines, randomized controlled trials, prospective cohort studies, observational studies, non-systematic reviews, case series, and reports. The total number of studies identified was 458, and 56 studies were included in this review. For the section "Other Factors Influencing the Risk of Developing "Ovarian" Cancers" a general Medline search was carried out using the terms "ovarian neoplasm" and "prevention." The search included papers published from December 2005 to March 2016. Meta-analyses were preferentially selected except where no such review was found. Additional searches for each subheading were also conducted (e.g., "ovarian neoplasm" and "tubal ligation.") Additional significant articles were identified through cross-referencing the identified reviews. For the search for "ovarian neoplasm" and "prevention," 10 meta-analyses were identified. For the search for "ovarian neoplasm" and "tubal ligation," an additional 4 meta-analyses were identified. VALIDATION METHODS: The content and recommendations were drafted and agreed on by the principal authors. The Executive and Board of the Society of Gynecologic Oncology of Canada reviewed the content and submitted comments for consideration, and the Board of the SOGC approved the final draft for publication. The quality of evidence was rated using the criteria described in the Grading of Recommendations Assessment, Development and Evaluation methodology framework (Table 1). The interpretation of strong and weak recommendations is described in Table 2. The summary of findings is available on request. BENEFITS, HARMS, AND/OR COSTS: The addition of opportunistic salpingectomy to a planned hysterectomy or permanent sterilization did not increase rates of hospital readmission (OR 0.91, 95% CI 0.75 to 1.10 and OR 0.8, 95% CI 0.56 to 1.21, respectively) or blood transfusions (OR 0.86, 95% CI 0.67 to 1.10 and OR 0.75, 95% CI 0.32 to 1.73, respectively) but did increase the overall operating time (by 16 minutes and 10 minutes, respectively) in a retrospective review of 43 931 women. The risk of repeat surgery for tubal pathology among women with retained fallopian tubes after hysterectomy was at least doubled (OR 2.13, 95% CI 1.88 to 2.42 in a population-based study of 170 000 women). If general gynaecologists were to consider removal of fallopian tubes at the time of every hysterectomy and sterilization procedure with referral of all patients with HGSC for hereditary cancer counselling and genetic testing, experts project a potential reduction in the rate of HGSC by 40% over the next 20 years. GUIDELINE UPDATE: Evidence will be reviewed 5 years after publication to decide whether all or part of the guideline should be updated. However, if important new evidence is published prior to the 5-year cycle, the review process may be accelerated for a more rapid update of some recommendations. SPONSORS: This guideline was developed with resources funded by the Society of Gynecologic Oncology of Canada and SOGC. SUMMARY STATEMENTS: RECOMMENDATIONS.

Occult and subsequent cancer incidence following risk-reducing surgery in BRCA mutation carriers.

OBJECTIVE: To report the frequency and features of occult carcinomas and the incidence of subsequent cancers following risk-reducing salpingo-oophorectomy (RRSO) in BRCA mutation carriers. METHODS: 257 consecutive women with germline BRCA mutations who underwent RRSO between January 1, 2000 and December 31, 2014 were identified in an Institutional Review Board approved study. All patients were asymptomatic with normal physical exams, CA 125 values, and imaging studies preoperatively, and had at least 12months of follow-up post-RRSO. All patients had comprehensive adnexal sectioning performed. Patient demographics and clinico-pathologic characteristics were extracted from medical and pathology records. RESULTS: The cohort included 148 BRCA1, 98 BRCA2, 6 BRCA not otherwise specified (NOS), and 5 BRCA1 and 2 mutation carriers. Occult carcinoma was seen in 14/257 (5.4%) of patients: 9 serous tubal intraepithelial carcinomas (STIC), 3 tubal cancers, 1 ovarian cancer, and 1 endometrial cancer. Three patients (1.2%) with negative pathology at RRSO subsequently developed primary peritoneal serous carcinoma (PPSC), and 2 of 9 patients (22%) with STIC subsequently developed pelvic serous carcinoma. 110 women (43%) were diagnosed with breast cancer prior to RRSO, and 14 of the remaining 147 (9.5%) developed breast cancer following RRSO. Median follow-up of the cohort was 63months. CONCLUSION: In this cohort, 5.4% of asymptomatic BRCA mutation carriers had occult carcinomas at RRSO, 86% of which were tubal in origin. The risk of subsequent PPSC for women with benign adnexa at RRSO is low; however, the risk of pelvic serous carcinoma among women with STIC is significantly higher.