Informing the development of antipsychotic-induced weight gain management guidance: patient experiences and preferences - qualitative descriptive study.

BACKGROUND: Antipsychotic-induced weight gain (AIWG) is a substantial contributor to high obesity rates in psychiatry. Limited management guidance exists to inform clinical practice, and individuals with experience of managing AIWG have had no or minimal input into its development. A lack of empirical research outlining patient values and preferences for management also exists. Recommendations addressing weight management in psychiatry may be distinctly susceptible to ideology and sociocultural values regarding intervention appropriateness and expectations of self-management, reinforcing the need for co-produced management guidance. This study is the first to ask: how do individuals conceptualise preferred AIWG management and how can this be realised in practice? AIMS: 1. Explore the management experiences of individuals with unwanted AIWG. 2. Elicit their values and preferences regarding preferred management. METHOD: Qualitative descriptive methodology informed study design. A total of 17 participants took part in semi-structured interviews. Data analysis was undertaken using reflexive thematic analysis. RESULTS: Participants reported that clinicians largely overestimated AIWG manageability using dietary and lifestyle changes. They also reported difficulties accessing alternative management interventions, including a change in antipsychotic and/or pharmacological adjuncts. Participants reported current management guidance is oversimplified, lacks the specificity and scope required, and endorses a 'one-size-fits-all' management approach to an extensively heterogenous side-effect. Participants expressed a preference for collaborative AIWG management and guidance that prioritises early intervention using the range of evidence-based management interventions, tailored according to AIWG risk, participant ability and participant preference. CONCLUSION: Integration of this research into guideline development will help ensure recommendations are relevant and applicable, and that individual preferences are represented.

The risk of developing pseudomyxoma peritonei from a non-perforated low grade appendiceal mucinous neoplasm found at appendicectomy.

INTRODUCTION: Low-grade appendiceal mucinous neoplasms (LAMNs) are classified as non-perforated (pTis, pT3) or perforated (pT4), and considered precursors of pseudomyxoma peritonei (PMP). This study aims to quantify the risk of developing PMP from pTis and pT3 LAMNs. MATERIALS AND METHODS: Retrospective analysis of a prospectively collected database identified LAMN patients referred to a specialist centre from 2004 to 2019. pT4 LAMNs and other appendix tumours were excluded. All patients had specialist review of their pathology, operation note, and a CT scan (at least 6 weeks post-operatively). Surveillance CTs were then performed at 6, 12, 24, 36, 48, & 60 months, with tumour markers (CEA, CA19-9, CA125). RESULTS: 193 pT3/pTis LAMN patients were included (pTis = 153, pT3 = 40). Median follow-up = 6.45 (3.91-22.13) years, M:F ratio = 1:1.57, and median age = 57 (23-83) years. Initial surgery included: appendicectomy (67 %), appendicectomy + visceral resection (6 %), and right hemicolectomy (27 %). R1 resections were identified in 5/193 patients (2.5 %). 3 R1 patients underwent re-operation (2 caecal pole excision and 1 ileocecectomy), none of which had residual tumour. 8/193 patients (4 %) were lost to follow up. None of the remaining 185 developed PMP. CONCLUSION: This is the largest reported series of pTis/pT3 LAMNs with standardised follow-up in the literature. LAMNs correctly classified as pT3/pTis (after careful specialist review of pathology, operation note, and a baseline post-operative CT) have negligible risk of developing PMP and should have low intensity surveillance. If completely excised, further surgery is not indicated. R1 resections should be considered on an individual basis at a specialist centre.

Preoperative chemotherapy response and survival in patients with colorectal cancer peritoneal metastases.

Treatment guidelines provided by PRODIGE-7 recommend perioperative systemic chemotherapy before cytoreductive surgery (CRS) for colorectal cancer peritoneal metastases (CRPM). Toxicity with multimodal treatment needs to be better defined. Chemotherapy response and impact on survival have not been reported. We assessed CRPM patients who received systemic oxaliplatin/irinotecan before CRS (preoperative) with Mitomycin C (35 mg/m2, 90 min) or Oxaliplatin (368 mg/m2, 30 min) heated intraperitoneal chemotherapy (HIPEC). Secondary analysis was performed from a prospective database. Overall survival (OS) in chemotherapy responders (R) and nonresponders (NR) was compared. Toxicity was assessed by rate of adverse events (AEs). From April 2005 to April 2021, 436 patients underwent CRS + HIPEC; 125 (29%) received preoperative chemotherapy. The 112 (90%) received oxaliplatin (64, 57%) or irinotecan (48, 43%). R, defined as complete (CR) or partial response on preoperative imaging and/or postoperative histology, was seen in 71, 63% (53.8-72.3); 16, 14% (8.4-22.2) had CR. Median OS in R versus NR was 43.7 months (37.9-49.4) versus 23.9 (16.3-31.4) p = 0.007, HR 0.51 (0.31-0.84). OS multivariable analysis showed HR 0.48 (0.25-0.95), p = 0.03 for chemotherapy response corrected by peritoneal cancer index, completeness of cytoreduction score. CRS led to 21% grade 3-4 AEs versus 4% for preoperative chemotherapy. HIPEC grade 3-4 AEs were 0.5%. Preoperative chemotherapy response is an independent predictor for OS in CRPM.

Cytoreductive surgery plus hyperthermic intraoperative peritoneal chemotherapy for people with peritoneal metastases from colorectal, ovarian or gastric origin: A systematic review of randomized controlled trials.

BACKGROUND: There is uncertainty in the relative benefits and harms of hyperthermic intraoperative peritoneal chemotherapy (HIPEC) when added to cytoreductive surgery (CRS) +/- systemic chemotherapy or systemic chemotherapy alone in people with peritoneal metastases from colorectal, gastric, or ovarian cancers. METHODS: We searched randomized controlled trials (RCTs) in the medical literature until April 14, 2022 and applied methods used for high-quality systematic reviews. FINDINGS: We included a total of eight RCTs (seven RCTs included in quantitative analysis as one RCT did not provide data in an analyzable format). All comparisons other than ovarian cancer contained only one trial. For gastric cancer, there is high uncertainty about the effect of CRS + HIPEC + systemic chemotherapy. For stage III or greater epithelial ovarian cancer undergoing interval cytoreductive surgery, CRS + HIPEC + systemic chemotherapy probably decreases all-cause mortality compared to CRS + systemic chemotherapy. For colorectal cancer, CRS + HIPEC + systemic chemotherapy probably results in little to no difference in all-cause mortality and may increase the serious adverse events proportions compared to CRS +/- systemic chemotherapy, but probably decreases all-cause mortality compared to fluorouracil-based systemic chemotherapy alone. INTERPRETATION: The role of CRS + HIPEC in gastric peritoneal metastases is uncertain. CRS + HIPEC should be standard of care in women with stage III or greater epithelial ovarian cancer undergoing interval CRS. CRS + systemic chemotherapy should be standard of care for people with colorectal peritoneal metastases, with HIPEC given only as part of a RCT focusing on subgroups and regimes. PROSPERO REGISTRATION: CRD42019130504.

Enhanced bacterial cancer therapy delivering therapeutic RNA interference of c-Myc.

BACKGROUND: Bacterial cancer therapy was first trialled in patients at the end of the nineteenth century. More recently, tumour-targeting bacteria have been harnessed to deliver plasmid-expressed therapeutic interfering RNA to a range of solid tumours. A major limitation to clinical translation of this is the short-term nature of RNA interference in vivo due to plasmid instability. To overcome this, we sought to develop tumour-targeting attenuated bacteria that stably express shRNA by virtue of integration of an expression cassette within the bacterial chromosome and demonstrate therapeutic efficacy in vitro and in vivo. RESULTS: The attenuated tumour targeting Salmonella typhimurium SL7207 strain was modified to carry chromosomally integrated shRNA expression cassettes at the xylA locus. The colorectal cancer cell lines SW480, HCT116 and breast cancer cell line MCF7 were used to demonstrate the ability of these modified strains to perform intracellular infection and deliver effective RNA and protein knockdown of the target gene c-Myc. In vivo therapeutic efficacy was demonstrated using the Lgr5creERT2Apcflx/flx and BlgCreBrca2flx/flp53flx/flx orthotopic immunocompetent mouse models of colorectal and breast cancer, respectively. In vitro co-cultures of breast and colorectal cancer cell lines with modified SL7207 demonstrated a significant 50-95% (P < 0.01) reduction in RNA and protein expression with SL7207/c-Myc targeted strains. In vivo, following establishment of tumour tissue, a single intra-peritoneal administration of 1 × 106 CFU of SL7207/c-Myc was sufficient to permit tumour colonisation and significantly extend survival with no overt toxicity in control animals. CONCLUSIONS: In summary we have demonstrated that tumour tropic bacteria can be modified to safely deliver therapeutic levels of gene knockdown. This technology has the potential to specifically target primary and secondary solid tumours with personalised therapeutic payloads, providing new multi-cancer detection and treatment options with minimal off-target effects. Further understanding of the tropism mechanisms and impact on host immunity and microbiome is required to progress to clinical translation.

Genomic attributes of airway commensal bacteria and mucosa.

Microbial communities at the airway mucosal barrier are conserved and highly ordered, in likelihood reflecting co-evolution with human host factors. Freed of selection to digest nutrients, the airway microbiome underpins cognate management of mucosal immunity and pathogen resistance. We show here the initial results of systematic culture and whole-genome sequencing of the thoracic airway bacteria, identifying 52 novel species amongst 126 organisms that constitute 75% of commensals typically present in heathy individuals. Clinically relevant genes encode antimicrobial synthesis, adhesion and biofilm formation, immune modulation, iron utilisation, nitrous oxide (NO) metabolism and sphingolipid signalling. Using whole-genome content we identify dysbiotic features that may influence asthma and chronic obstructive pulmonary disease. We match isolate gene content to transcripts and metabolites expressed late in airway epithelial differentiation, identifying pathways to sustain host interactions with microbiota. Our results provide a systematic basis for decrypting interactions between commensals, pathogens, and mucosa in lung diseases of global significance.

Predicting antipsychotic-induced weight gain in first episode psychosis - A field-wide systematic review and meta-analysis of non-genetic prognostic factors.

BACKGROUND: Whether non-genetic prognostic factors significantly influence the variable prognosis of antipsychotic-induced weight gain (AIWG) has not yet been systematically explored. METHODS: Searches for both randomized and non-randomized studies were undertaken using four electronic databases, two trial registers, and via supplemental searching methods. Unadjusted and adjusted estimates were extracted. Meta-analyses were undertaken using a random-effects generic inverse model. Risk of bias and quality assessments were undertaken using Quality in Prognosis Studies (QUIPS) and Grading of Recommendations Assessment, Development and Evaluation (GRADE), respectively. RESULTS: Seventy-two prognostic factors were assessed across 27 studies involving 4426 participants. Only age, baseline body mass index (BMI), and sex were suitable for meta-analysis. Age (b=-0.044, 95%CI -0.157-0.069), sex (b=0.236, 95%CI -0.086-0.558), and baseline BMI (b=-0.013 95%CI -0.225-0.200) were associated with nonsignificant effects on AIWG prognosis. The highest quality GRADE rating was moderate in support of age, trend of early BMI increase, antipsychotic treatment response, unemployment, and antipsychotic plasma concentration. Trend of early BMI increase was identified as the most clinically significant prognostic factor influencing long-term AIWG prognosis. CONCLUSIONS: The strong prognostic information provided by BMI trend change within 12 weeks of antipsychotic initiation should be included within AIWG management guidance to highlight those at highest risk of worse long-term prognosis. Antipsychotic switching and resource-intensive lifestyle interventions should be targeted toward this cohort. Our results challenge previous research that several clinical variables significantly influence AIWG prognosis. We provide the first mapping and statistical synthesis of studies examining non-genetic prognostic factors of AIWG and highlight practice, policy, and research implications.

RAS Mutation Status Should Not Be Used to Predict Outcome from Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Colorectal Peritoneal Metastases.

BACKGROUND: Genetic biomarkers guide systemic anti-cancer treatment (SACT) in metastatic colorectal cancer. It has been suggested they have a role in selecting patients with colorectal peritoneal metastases (CRPM) for cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). This study aims to quantify the effect of mutation status on overall survival (OS), adjusting for confounders such as pre-operative systemic anticancer treatment (SACT). PATIENTS AND METHODS: Retrospective analysis of patients undergoing CRS/HIPEC for CRPM at a national peritoneal tumour centre (2004-2017) was performed. Demographics, treatment history and operative data were extracted. Known biomarker gene mutation status was noted including: KRAS, NRAS, BRAF, PIK3CA and MMR. Cox regression analysis and Kaplan-Meier curves were used to determine overall survival. RESULTS: One hundred ninety-five patients were included. Median follow-up time was 34.7 months (range 5.4-184.9 months) and median OS was 38.7 months (95% CI 32.4-44.9 months). Biomarker status was as follows: KRAS (n = 114), NRAS (n = 85), BRAF (n = 44), PIK3CA (n = 15) and MMR (n = 21). Mutation rates were 45.6%, 3.5%, 13.6%, 13.3% and 14.3%, respectively. Seventy-four per cent underwent complete cytoreduction (CC = 0), 81% received SACT pre-CRS/HIPEC and 65% post-CRS/HIPEC. RAS (p = 0.21) or BRAF (p = 0.109) mutation status did not predict OS. Nodal involvement, extramural vascular invasion, Peritoneal Cancer Index (PCI) score, CC score, SACT post-HIPEC and NRAS mutation were significant negative predictors of OS in univariate analysis (p < 0.05). Multivariate Cox regression confirmed CC-score > 1 (HR: 7.599, 95% CI 3.402-16.974, p < 0.0001) as a negative predictor of OS. RAS mutation status did not affect outcome (HR: 1.682, 95% CI 0.995-2.843, p = 0.052). CONCLUSIONS: RAS mutation status should not in isolation be used to select patients for CRS/HIPEC.

Patterns and Timing of Recurrence following CRS and HIPEC in Colorectal Cancer Peritoneal Metastasis.

INTRODUCTION: Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (CRS/HIPEC) is an established treatment of Colorectal Peritoneal Metastases (CRPM). This study aims to determine the timing and patterns of recurrent disease on imaging following complete CRS/HIPEC. METHODS: Retrospective analysis of a national peritoneal tumour service database identified CRPM patients with complete CRS/HIPEC(CC0) from 2005 to-2018. Patients with<2 years follow-up or and those where post-operative histology from the CRS/HIPEC procedure did not confirm CRPM from their original colorectal cancer were excluded. Time to recurrence was measured from surgery to first radiologically illustrated recurrence. CT was the primary modality used, supplemented by PET-CT or MRI if required. Outcomes of interest were survival data (including overall survival (OS), disease-free survival (DFS) and peritoneal-recurrence free survival (PRFS)), timing and patterns of recurrent disease. RESULTS: 146 of the 176 patients identified were eligible for inclusion. Median OS for all study patients was 45.2 months (95% CI 38-53 months), median DFS was 11.7 months (95% CI 9-14 months), and median PRFS was 25.2 months (95% CI 14.7-30 months). Recurrent disease was seen in 112 cases (77%), radiologically classified as intraperitoneal in 50 patients (44%), single site systemic in 21 patients (19%) and multi-site in 41 patients (37%). CT detection rate for disease recurrence was 88%. Subgroup analyses showed that PCI ≥12, positive nodal primary disease and synchronous peritoneal disease were associated with worse outcomes. CONCLUSION: Patients selected for CRS/HIPEC for CRPM have an OS > 45 months, with the majority recurring systemically within a year. Peritoneal recurrence is a later event after several years. Surveillance programs in this group should be most intensive in the first 2 years after surgery, using CT with oral and intravenous contrast.

Endoscopic full-thickness resection of well-differentiated T2 neuroendocrine tumors in the duodenal bulb: a case series.

Background and Aims: Endoscopic therapies have moved to the forefront in the removal of small, well-differentiated duodenal neuroendocrine tumors (NETs). Classic procedures used to address small tumors, especially those less than 1 cm in diameter, are banding without resection, ligation endoscopic mucosal resection, or endoscopic submucosal dissection. Endoscopic full-thickness resection (EFTR) is a procedure developed recently that allows for sealing off of the tissue surrounding the tumor before full-thickness removal. Although surgical resection is typically recommended for NETs measuring 2 cm and larger, this may not always be possible given patients' ages or comorbidities. We present the cases of 3 patients with well-differentiated NETs of the duodenal bulb measuring greater than 2 cm who were poor candidates for surgery and were thus offered EFTR for excision of their tumors. Methods: Three patients with well-differentiated, stage II NETs of the duodenal bulb underwent chromoendoscopy and narrow-band imaging, EUS, prophylactic dilation of the upper esophageal sphincter and pylorus, and EFTR using an over-the-scope clip system. Results: In each case, there was no residual mass seen on endoscopy, Ga-68 Dotatate positron emission tomography-CT imaging, or biopsy up to 1 year after the procedure. Two of the 3 cases had normal chromogranin A levels at all follow-up points, and the third case had chromogranin A levels that trended down to a near-normal level of 145 ng/mL. Conclusions: Three patients with NETs of the duodenal bulb who were poor surgical candidates underwent successful EFTR using a full-thickness resection device. At 1-year follow-up, they have no evidence of disease recurrence on imaging and pathology after EFTR.

Patient Sentiments Influencing Management Strategy for Single-sided Deafness.

OBJECTIVE: Assess opinions that influence treatment choice for single sided deafness (SSD). STUDY DESIGN: Retrospective chart review. SETTING: Tertiary neurotology referral center. PATIENTS: Patients with SSD were recruited between December 2020 and February 2021. Included patients were self-selected by voluntary completion of the study questionnaire. MAIN OUTCOME MEASURES: Tinnitus Handicap Inventory (THI), Hearing Handicap Inventory for Adults (HHIA), and a questionnaire containing 25 areas of inquiry relevant to management strategy decision making. RESULTS: In comparison to the surgical management group, patients opting for nonsurgical amplification were significantly more concerned about device visibility (p = 0.005, 1.32 ±â€Š0.22 versus 2.67 ±â€Š0.37), undergoing surgery (p = 0.017, 1.64 ±â€Š0.23 versus 2.89 ±â€Š0.51), and the thought of harboring an implanted device (p = 0.003, 1.46 ±â€Š0.22 versus 2.82 ±â€Š0.35). Patients with a major hearing handicap (grade 2-4) placed significantly less emphasis on out-of-pocket costs (p = 0.049, 2.38 ±â€Š0.17 versus 2.94 ±â€Š0.21) and were less concerned about experiencing discomfort from the device (p = 0.033, 3.13 ±â€Š0.11 versus 3.56 ±â€Š0.16) or ease of device use (p = 0.040, 3.20 ±â€Š0.13 versus 3.63 ±â€Š0.13) when compared with the minor handicap group. CONCLUSIONS: Lingering concerns about device visibility, undergoing surgery, and harboring an implanted device underscore the need for thorough patient counseling during SSD device selection consultations. These efforts should aim to address esthetic and surgical risk concerns while emphasizing the potential for improvements in quality of life.

Improving clinical care for women with endometriosis: qualitative analysis of women's and health professionals' views.

PURPOSE: Endometriosis is a chronic condition where endometrial-like cells proliferate outside the uterus causing pain and disability. Limited treatments are available but symptom management is essential for social and economic participation. The aim was to compare women's and health professionals' perceptions of quality of endometriosis health care and opportunities for improvements. METHODS: Women participated in closed moderated online discussion groups and health professionals in semi-structured telephone interviews. Discussion group text and interview transcripts were thematically analyzed using the Framework Analysis approach. RESULTS: Forty-six women, 12 general practitioners (GPs), and 1 gynecologist participated. Endometriosis can have debilitating consequences. However, women reported that healthcare providers may dismiss symptoms, lack essential knowledge and provide inconsistent advice; treatments are seldom successful or without adverse side-effects. Health professionals acknowledged limitations in expertise, persistent myths, and challenges in achieving best practice. Enhancing collaborative care skills, individualized treatment plans, and local referral pathways to multi-disciplinary care may improve satisfaction with endometriosis care-giving and receiving. CONCLUSIONS: This is the first comparison of patient and practitioner perceptions of endometriosis in primary healthcare. Models of multi-disciplinary, collaborative care need to be developed and evaluated against consumer-informed measures of women's wellbeing, quality of life and satisfaction with symptom management and health care.

Comparison of mortality risk in patients with cirrhosis and COVID-19 compared with patients with cirrhosis alone and COVID-19 alone: multicentre matched cohort.

OBJECTIVE: Comorbid conditions are associated with poor prognosis in COVID-19. Registry data show that patients with cirrhosis may be at high risk. However, outcome comparisons among patients with cirrhosis+COVID-19 versus patients with COVID-19 alone and cirrhosis alone are lacking. The aim of this study was to perform these comparisons. DESIGN: A multicentre study of inpatients with cirrhosis+COVID-19 compared with age/gender-matched patients with COVID-19 alone and cirrhosis alone was performed. COVID-19 and cirrhosis characteristics, development of organ failures and acute-on-chronic liver failure (ACLF) and mortality (inpatient death+hospice) were compared. RESULTS: 37 patients with cirrhosis+COVID-19 were matched with 108 patients with COVID-19 and 127 patients with cirrhosis from seven sites. Race/ethnicity were similar. Patients with cirrhosis+COVID-19 had higher mortality compared with patients with COVID-19 (30% vs 13%, p=0.03) but not between patients with cirrhosis+COVID-19 and patients with cirrhosis (30% vs 20%, p=0.16). Patients with cirrhosis+COVID-19 versus patients with COVID-19 alone had equivalent respiratory symptoms, chest findings and rates of intensive care unit transfer and ventilation. However, patients with cirrhosis+COVID-19 had worse Charlson Comorbidity Index (CCI 6.5±3.1 vs 3.3±2.5, p<0.001), lower presenting GI symptoms and higher lactate. Patients with cirrhosis alone had higher cirrhosis-related complications, maximum model for end-stage liver disease (MELD) score and lower BiPAP/ventilation requirement compared with patients with cirrhosis+COVID-19, but CCI and ACLF rates were similar. In the entire group, CCI (OR 1.23, 95% CI 1.11 to 1.37, p<0.0001) was the only variable predictive of mortality on multivariable regression. CONCLUSIONS: In this multicentre North American contemporaneously enrolled study, age/gender-matched patients with cirrhosis+COVID-19 had similar mortality compared with patients with cirrhosis alone but higher than patients with COVID-19 alone. CCI was the only independent mortality predictor in the entire matched cohort.

Effect of a brief scenario-tailored educational program on parents' risk knowledge, perceptions, and decisions to administer prescribed opioids: a randomized controlled trial.

ABSTRACT: This randomized, controlled trial evaluated whether a brief educational program (ie, Scenario-Tailored Opioid Messaging Program [STOMP]) would improve parental opioid risk knowledge, perceptions, and analgesic efficacy; ensure safe opioid use decisions; and impact prescription opioid use after surgery. Parent-child dyads (n = 604) who were prescribed an opioid for short-term use were randomized to routine instruction (Control) or routine plus STOMP administered preoperatively. Baseline and follow-up surveys assessed parents' awareness and perceived seriousness of adverse opioid effects, and their analgesic efficacy. Parents' decisions to give an opioid in hypothetical scenarios and total opioid doses they gave to children at home were assessed at follow-up. Scenario-Tailored Opioid Messaging Program parents gained enhanced perceptions of opioid-related risks over time, whereas Controls did not; however, risk perceptions did not differ between groups except for addiction risk. Scenario-Tailored Opioid Messaging Program parents exhibited marginally greater self-efficacy compared to Controls (mean difference vs controls = 0.58 [95% confidence interval 0.08-1.09], P = 0.023). Scenario-Tailored Opioid Messaging Program parents had a 53% lower odds of giving an opioid in an excessive sedation scenario (odds ratio 0.47 [95% confidence interval 0.28-0.78], P = 0.003), but otherwise made similar scenario-based opioid decisions. Scenario-Tailored Opioid Messaging Program was not associated with total opioid doses administered at home. Instead, parents' analgesic efficacy and pain-relief preferences explained 7%, whereas child and surgical factors explained 22% of the variance in opioid doses. Scenario-tailored education enhanced parents' opioid risk knowledge, perceptions, and scenario-based decision-making. Although this may inform later situation-specific decision-making, our research did not demonstrate an impact on total opioid dosing, which was primarily driven by surgical and child-related factors.

Early Adaptation of Colorectal Cancer Cells to the Peritoneal Cavity Is Associated with Activation of "Stemness" Programs and Local Inflammation.

PURPOSE: At diagnosis, colorectal cancer presents with synchronous peritoneal metastasis in up to 10% of patients. The peritoneum is poorly characterized with respect to its superspecialized microenvironment. Our aim was to describe the differences between peritoneal metastases and their matched primary tumors excised simultaneously at the time of surgery. Also, we tested the hypothesis of these differences being present in primary colorectal tumors and having prognostic capacity. EXPERIMENTAL DESIGN: We report a comprehensive analysis of 30 samples from peritoneal metastasis with their matched colorectal cancer primaries obtained during cytoreductive surgery. We tested and validated the prognostic value of our findings in a pooled series of 660 colorectal cancer primary samples with overall survival (OS) information and 743 samples with disease-free survival (DFS) information from publicly available databases. RESULTS: We identified 20 genes dysregulated in peritoneal metastasis that promote an early increasing role of "stemness" in conjunction with tumor-favorable inflammatory changes. When adjusted for age, gender, and stage, the 20-gene peritoneal signature proved to have prognostic value for both OS [adjusted HR for the high-risk group (vs. low-risk) 2.32 (95% confidence interval, CI, 1.69-3.19; P < 0.0001)] and for DFS [adjusted HR 2.08 (95% CI, 1.50-2.91; P < 0.0001)]. CONCLUSIONS: Our findings indicated that the activation of "stemness" pathways and adaptation to the peritoneal-specific environment are key to early stages of peritoneal carcinomatosis. The in silico analysis suggested that this 20-gene peritoneal signature may hold prognostic information with potential for development of new precision medicine strategies in this setting.

Cytoreductive surgery (CRS) with hyperthermic intraoperative peritoneal chemotherapy (HIPEC) versus standard of care (SoC) in people with peritoneal metastases from colorectal, ovarian or gastric origin: protocol for a systematic review and individual participant data (IPD) meta-analyses of effectiveness and cost-effectiveness.

INTRODUCTION: There is uncertainty about whether cytoreductive surgery (CRS)+hyperthermic intraoperative peritoneal chemotherapy (HIPEC) improves survival and/or quality of life compared with standard of care (SoC) in people with peritoneal metastases who can withstand major surgery. PRIMARY OBJECTIVES: To compare the relative benefits and harms of CRS+HIPEC versus SoC in people with peritoneal metastases from colorectal, ovarian or gastric cancers eligible to undergo CRS+HIPEC by a systematic review and individual participant data (IPD) meta-analysis. SECONDARY OBJECTIVES: To compare the cost-effectiveness of CRS+HIPEC versus SoC from a National Health Service (NHS) and personal social services perspective using a model-based cost-utility analysis. METHODS AND ANALYSIS: We will perform a systematic review of literature by updating the searches from MEDLINE, Embase, Cochrane library, Science Citation Index as well as trial registers. Two members of our team will independently screen the search results and identify randomised controlled trials comparing CRS+HIPEC versus SoC for inclusion based on full texts for articles shortlisted during screening. We will assess the risk of bias in the trials and obtain data related to baseline prognostic characteristics, details of intervention and control, and outcome data related to overall survival, disease progression, health-related quality of life, treatment related complications and resource utilisation data. Using IPD, we will perform a two-step IPD, that is, calculate the adjusted effect estimate from each included study and then perform a random-effects model meta-analysis. We will perform various subgroup analyses, meta-regression and sensitivity analyses. We will also perform a model-based cost-utility analysis to assess whether CRS+HIPEC is cost-effective in the NHS setting. ETHICS AND DISSEMINATION: This project was approved by the UCL Research Ethics Committee (Ethics number: 16023/001). We aim to present the findings at appropriate international meetings and publish the review, irrespective of the findings, in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42019130504.