Development of a prediction model for recurrence in patients with colorectal peritoneal metastases undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.

INTRODUCTION: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) improves survival outcomes for selected patients with colorectal peritoneal metastases (PM), but recurrence rates are high. The aim of this study was to develop a tool to predict recurrence in patients with colorectal PM that undergo CRS-HIPEC. MATERIALS AND METHODS: For this retrospective cohort study, data of patients that underwent CRS-HIPEC for colorectal PM from four Dutch HIPEC centers were used. Exclusion criteria were perioperative systemic therapy and peritoneal cancer index (PCI) ≥20. Nine previously identified factors were considered as predictors: gender, age, primary tumor characteristics (location, nodal stage, differentiation, and mutation status), synchronous liver metastases, preoperative Carcino-Embryonal Antigen (CEA), and peritoneal cancer index (PCI). The prediction model was developed using multivariable Cox regression and validated internally using bootstrapping. The performance of the model was evaluated by discrimination and calibration. RESULTS: In total, 408 patients were included. During the follow-up, recurrence of disease occurred in 318 patients (78%). Significant predictors of recurrence were PCI (HR 1.075, 95% CI 1.044-1.108) and primary tumor location (left sided HR 0.719, 95% CI 0.550-0.939). The prediction model for recurrence showed fair discrimination with a C-index of 0.64 (95% CI 0.62, 0.66) after internal validation. The model was well-calibrated with good agreement between the predicted and observed probabilities. CONCLUSION: We developed a prediction tool that could aid in the prediction of recurrence in patients with colorectal PM who undergo CRS-HIPEC.

Referral rate of patients with incidental gallbladder cancer and survival: outcomes of a multicentre retrospective study.

BACKGROUND: Treatment outcomes of incidental gallbladder cancer generally stem from tertiary referral centres, while many patients are initially diagnosed and managed in secondary care centres. Referral patterns of patients with incidental gallbladder cancer are poorly reported. This study aimed to evaluate incidental gallbladder cancer treatment in secondary centres, rates of referral to tertiary centres and its impact on survival. METHODS: Medical records of patients with incidental gallbladder cancer diagnosed between 2000 and 2019 in 27 Dutch secondary centres were retrospectively reviewed. Patient characteristics, surgical treatment, tumour characteristics, referral pattern and survival were assessed. Predictors for overall survival were determined using multivariable Cox regression. RESULTS: In total, 382 patients with incidental gallbladder cancer were included. Of 243 patients eligible for re-resection (pT1b-pT3, M0), 131 (53.9%) were referred to a tertiary centre. The reason not to refer, despite indication for re-resection, was not documented for 52 of 112 non-referred patients (46.4%). In total, 98 patients underwent additional surgery with curative intent (40.3%), 12 of these in the secondary centre. Median overall survival was 33 months (95% c.i. 24 to 42 months) in referred patients versus 17 months (95% c.i. 3 to 31 months) in the non-referred group (P = 0.019). Referral to a tertiary centre was independently associated with improved survival after correction for age, ASA classification, tumour stage and resection margin (HR 0.60, 95% c.i. 0.38 to 0.97; P = 0.037). CONCLUSION: Poor incidental gallbladder cancer referral rates were associated with worse survival. Age, performance status, resection margin or tumour stage should not preclude referral of a patient with incidental gallbladder cancer to a tertiary centre.

Towards Equal Access to Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy and Survival in Patients with Isolated Colorectal Peritoneal Metastases: A Nationwide Population-Based Study.

BACKGROUND: Before 2016, patients with isolated synchronous colorectal peritoneal metastases (PMCRC) diagnosed in expert centers had a higher odds of undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) and better overall survival (OS) than those diagnosed in referring centers. Nationwide efforts were initiated to increase awareness and improve referral networks. METHODS: This nationwide study aimed to evaluate whether the between-center differences in odds of undergoing CRS-HIPEC and OS have reduced since these national efforts were initiated. All patients with isolated synchronous PMCRC diagnosed between 2009 and 2021 were identified from the Netherlands Cancer Registry. Associations between hospital of diagnosis and the odds of undergoing CRS-HIPEC, as well as OS, were assessed using multilevel multivariable regression analyses for two periods (2009-2015 and 2016-2021). RESULTS: In total, 3948 patients were included. The percentage of patients undergoing CRS-HIPEC increased from 17.2% in 2009-2015 (25.4% in expert centers, 16.5% in referring centers), to 23.4% in 2016-2021 (30.2% in expert centers, 22.6% in referring centers). In 2009-2015, compared with diagnosis in a referring center, diagnosis in a HIPEC center showed a higher odds of undergoing CRS-HIPEC (odds ratio [OR] 1.64, 95% confidence interval [CI] 1.02-2.67) and better survival (hazard ratio [HR] 0.80, 95% CI 0.66-0.96). In 2016-2021, there were no differences in the odds of undergoing CRS-HIPEC between patients diagnosed in HIPEC centers versus referring centers (OR 1.27, 95% CI 0.76-2.13) and survival (HR 1.00, 95% CI 0.76-1.32). CONCLUSION: Previously observed differences in odds of undergoing CRS-HIPEC were no longer present. Increased awareness and the harmonization of treatment for PMCRC may have contributed to equal access to care and a similar chance of survival at a national level.

Predicting futility of upfront surgery in perihilar cholangiocarcinoma: Machine learning analytics model to optimize treatment allocation.

BACKGROUND: While resection remains the only curative option for perihilar cholangiocarcinoma, it is well known that such surgery is associated with a high risk of morbidity and mortality. Nevertheless, beyond facing life-threatening complications, patients may also develop early disease recurrence, defining a "futile" outcome in perihilar cholangiocarcinoma surgery. The aim of this study is to predict the high-risk category (futile group) where surgical benefits are reversed and alternative treatments may be considered. METHODS: The study cohort included prospectively maintained data from 27 Western tertiary referral centers: the population was divided into a development and a validation cohort. The Framingham Heart Study methodology was used to develop a preoperative scoring system predicting the "futile" outcome. RESULTS: A total of 2271 cases were analyzed: among them, 309 were classified within the "futile group" (13.6%). American Society of Anesthesiology (ASA) score ≥ 3 (OR 1.60; p = 0.005), bilirubin at diagnosis ≥50 mmol/L (OR 1.50; p = 0.025), Ca 19-9 ≥ 100 U/mL (OR 1.73; p = 0.013), preoperative cholangitis (OR 1.75; p = 0.002), portal vein involvement (OR 1.61; p = 0.020), tumor diameter ≥3 cm (OR 1.76; p < 0.001), and left-sided resection (OR 2.00; p < 0.001) were identified as independent predictors of futility. The point system developed, defined three (ie, low, intermediate, and high) risk classes, which showed good accuracy (AUC 0.755) when tested on the validation cohort. CONCLUSIONS: The possibility to accurately estimate, through a point system, the risk of severe postoperative morbidity and early recurrence, could be helpful in defining the best management strategy (surgery vs. nonsurgical treatments) according to preoperative features.

Persistent and new-onset symptoms after cholecystectomy in patients with uncomplicated symptomatic cholecystolithiasis: A post hoc analysis of 2 prospective clinical trials.

BACKGROUND: Laparoscopic cholecystectomy is the gold standard for treating biliary colic in patients with gallstones, but post-cholecystectomy abdominal pain is commonly reported. This study investigates which symptoms are likely to persist and which may develop after a cholecystectomy. METHODS: Patients from 2 previous prospective trials who underwent laparoscopic cholecystectomy for symptomatic cholecystolithiasis were included. Patients completed questionnaires on pain and gastrointestinal symptoms before surgery and at 6 months follow-up. The prevalence of persistent and new-onset abdominal symptoms was evaluated. RESULTS: A total of 820 patients received cholecystectomy and were included, 75.4% female (n = 616/820) mean age 49.4 years (standard deviation 13.7). At baseline, 74.1% (n = 608/820) of patients met all criteria for biliary colic. Cholecystectomy successfully resolved biliary colic in 94.8% (n = 327/345) of patients, but 36.5% (n = 299/820) of patients reported persistent abdominal pain after 6 months of follow-up. The prevalence of most abdominal symptoms reduced significantly. Symptoms such as flatulence (17.8%, n = 146/820) or restricted eating (14.5%, n = 119/820) persisted most often. New-onset symptoms were frequent bowel movements (9.6%, n = 79/820), bowel urgency (8.5%, n = 70/820), and new-onset diarrhea (8.4%, 69/820). CONCLUSION: Postcholecystectomy symptoms are mainly flatulence, frequent bowel movements, and restricted eating. Newly reported symptoms are mainly frequent bowel movements, bowel urgency, and diarrhea. The present findings give clinical guidance in informing, managing, and treating patients with symptoms after cholecystectomy.

A mixed-methods study to define Textbook Outcome for the treatment of patients with uncomplicated symptomatic gallstone disease with hospital variation analyses in Dutch trial data.

BACKGROUND: International consensus on the ideal outcome for treatment of uncomplicated symptomatic gallstone disease is absent. This mixed-method study defined a Textbook Outcome (TO) for this large group of patients. METHODS: First, expert meetings were organised with stakeholders to design the survey and identify possible outcomes. To reach consensus, results from expert meetings were converted in a survey for clinicians and for patients. During the final expert meeting, clinicians and patients discussed survey outcomes and a definitive TO was formulated. Subsequently, TO-rate and hospital variation were analysed in Dutch hospital data from patients with uncomplicated gallstone disease. RESULTS: First expert meetings returned 32 outcomes. Outcomes were distributed in a survey among 830 clinicians from 81 countries and 645 Dutch patients. Consensus-based TO was defined as no more biliary colic, no biliary and surgical complications, and the absence or reduction of abdominal pain. Analysis of individual patient data showed that TO was achieved in 64.2% (1002/1561). Adjusted-TO rates showed modest variation between hospitals (56.6-74.9%). CONCLUSION: TO for treatment of uncomplicated gallstone disease was defined as no more biliary colic, no biliary and surgical complications, and absence or reduction of abdominal pain.TO may optimise consistent outcome reporting in care and guidelines for treating uncomplicated gallstone disease.

Patients with Clinically Suspected Gallstone Disease: A More Selective Ultrasound May Improve Treatment Related Outcomes.

This study aimed to quantify the confirmation of gallstones on ultrasound (US) in patients with suspicion of gallstone disease. To aid general practitioners (GPs) in diagnostic workup, a model to predict gallstones was developed. A prospective cohort study was conducted in two Dutch general hospitals. Patients (≥18 years) were eligible for inclusion when referred by GPs for US with suspicion of gallstones. The primary outcome was the confirmation of gallstones on US. A multivariable regression model was developed to predict the presence of gallstones. In total, 177 patients were referred with a clinical suspicion of gallstones. Gallstones were found in 64 of 177 patients (36.2%). Patients with gallstones reported higher pain scores (VAS 8.0 vs. 6.0, p < 0.001), less frequent pain (21.9% vs. 54.9%, p < 0.001), and more often met criteria for biliary colic (62.5% vs. 44.2%, p = 0.023). Predictors for the presence of gallstones were a higher pain score, frequency of pain less than weekly, biliary colic, and an absence of heartburn. The model showed good discrimination between patients with and without gallstones (C-statistic 0.73, range: 0.68-0.76). Clinical diagnosis of symptomatic gallstone disease is challenging. The model developed in this study may aid in the selection of patients for referral and improve treatment related outcomes.

Clinicopathological and Molecular Insights into Gallbladder Cancer.

Although gallbladder cancer (GBC) is rare, it is one of the few cancers with a higher mortality rate than incidence, accounting for 1 [...].

Treatment patterns and survival in older adults with unresected nonmetastatic biliary tract cancers.

INTRODUCTION: The optimal treatment for unresected nonmetastatic biliary tract cancer (uBTC) is not well-established. The objective of this study was to analyze the treatment patterns and compare the differences in overall survival (OS) between different treatment strategies amongst older adults with uBTC. MATERIALS AND METHODS: We identified patients aged ≥65 years with uBTC using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database (2004-2015). Treatments were classified into chemotherapy, chemoradiotherapy, and radiotherapy. The primary outcome was OS. The differences in OS were analyzed using Kaplan-Meier curves and multivariable Cox proportional hazard regression. RESULTS: A total of 4352 patients with uBTC were included. The median age was 80 years and median OS was 4.1 months. Most patients (67.3%, n = 2931) received no treatment, 19.1% chemotherapy (n = 833), 8.1% chemoradiotherapy (n = 354), and 5.4% radiotherapy alone (n = 234). Patients receiving no treatment were older and had more comorbidities. Chemotherapy was associated with significantly longer OS than no treatment in uBTC (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.79-0.95), but no difference was found in the subgroups of intrahepatic cholangiocarcinoma (iCCA; HR 0.87, 95% CI 0.75-1.00) and gallbladder carcinoma (GBC; HR 1.09, 95% CI 0.86-1.39). In the sensitivity analyses, capecitabine-based chemoradiotherapy showed significantly longer OS in uBTC compared to chemotherapy (adjusted HR 0.71, 95% CI 0.53-0.95). DISCUSSION: A minority of older patients with uBTC receive systemic treatments. Chemotherapy was associated with longer OS compared to no treatment in uBTC, but not in the subgroups of iCCA and GBC. The efficacy of chemoradiotherapy, especially in perihilar cholangiocarcinoma using capecitabine-based chemoradiotherapy, may be further evaluated in prospective clinical trials.

The diagnostic value of staging laparoscopy in gallbladder cancer: a nationwide cohort study.

BACKGROUND: Disseminated disease (DD) is often found at (re-)exploration in gallbladder cancer (GBC) patients. We aimed to assess the yield of staging laparoscopy (SL) and identify predictors for DD. METHODS: This retrospective study included patients from all Dutch academic centres with primary GBC (pGBC) and incidentally diagnosed GBC (iGBC) planned for (re-)resection. The yield of SL was determined. In iGBC, predictive factors for DD were assessed. RESULTS: In total, 290 patients were included. Of 183 included pGBC patients, 143 underwent laparotomy without SL, and 42 (29%) showed DD perioperatively. SL, conducted in 40 patients, identified DD in eight. DD was found in nine of 32 patients who underwent laparotomy after SL. Of 107 included iGBC patients, 100 underwent laparotomy without SL, and 19 showed DD perioperatively. SL, conducted in seven patients, identified DD in one. Cholecystitis (OR = 4.25; 95% CI 1.51-11.91) and primary R1/R2 resection (OR = 3.94; 95% CI 1.39-11.19) were independent predictive factors for DD. CONCLUSIONS: In pGBC patients, SL may identify DD in up to 20% of patients and should be part of standard management. In iGBC patients, SL is indicated after primary resection for cholecystitis and after initial R1/R2 resection due to the association of these factors with DD.

Oncological Safety and Potential Cost Savings of Routine vs Selective Histopathological Examination After Appendectomy: Results of the Multicenter, Prospective, Cross-Sectional FANCY Study.

OBJECTIVE: To investigate the oncological safety and potential cost savings of selective histopathological examination after appendectomy. BACKGROUND: The necessity of routine histopathological examination after appendectomy has been questioned, but prospective studies investigating the safety of a selective policy are lacking. METHODS: In this multicenter, prospective, cross-sectional study, inspection and palpation of the (meso)appendix was performed by the surgeon in patients with suspected appendicitis. The surgeon's opinion on additional value of histopathological examination was reported before sending all specimens to the pathologist. Main outcomes were the number of hypothetically missed appendiceal neoplasms with clinical consequences benefiting the patient (upper limit two-sided 95% confidence interval below 3:1000 considered oncologically safe) and potential cost savings after selective histopathological examination. RESULTS: Seven thousand three hundred thirty-nine patients were included. After a selective policy, 4966/7339 (67.7%) specimens would have been refrained from histopathological examination. Appendiceal neoplasms with clinical consequences would have been missed in 22/4966 patients. In 5/22, residual disease was completely resected during additional surgery. Hence, an appendiceal neoplasm with clinical consequences benefiting the patient would have been missed in 1.01:1000 patients (upper limit 95% confidence interval 1.61:1000). In contrast, twice as many patients (10/22) would not have been exposed to potential harm due to re-resections without clear benefit, whereas consequences were neither beneficial nor harmful in the remaining seven. Estimated cost savings established by replacing routine for selective histopathological examination were €725,400 per 10,000 patients. CONCLUSIONS: Selective histopathological examination after appendectomy for suspected appendicitis is oncologically safe and will likely result in a reduction of pathologists' workload, less costs, and fewer re-resections without clear benefit.

Development and External Validation of a Model to Predict Overall Survival in Patients With Resected Gallbladder Cancer.

OBJECTIVE: The aim of this study was to develop and validate a clinical prediction model to predict overall survival in patients with nonmetastatic, resected gallbladder cancer (GBC). BACKGROUND: Although several tools are available, no optimal method has been identified to assess survival in patients with resected GBC. METHODS: Data from a Dutch, nation-wide cohort of patients with resected GBC was used to develop a prediction model for overall survival. The model was internally validated and a cohort of Australian GBC patients who underwent resection was used for external validation. The performance of the American Joint Committee on Cancer (AJCC) staging system and the present model were compared. RESULTS: In total, 446 patients were included; 380 patients in the development cohort and 66 patients in the validation cohort. In the development cohort median survival was 22 months (median follow-up 75 months). Age, T/N classification, resection margin, differentiation grade, and vascular invasion were independent predictors of survival. The externally validated C-index was 0.75 (95%CI: 0.69-0.80), implying good discriminatory capacity. The discriminative ability of the present model after internal validation was superior to the ability of the AJCC staging system (Harrell C-index 0.71, [95%CI: 0.69-0.72) vs. 0.59 (95% CI: 0.57-0.60)]. CONCLUSION: The proposed model for the prediction of overall survival in patients with resected GBC demonstrates good discriminatory capacity, reasonable calibration and outperforms the authoritative AJCC staging system. This model can be a useful tool for physicians and patients to obtain information about survival after resection and is available from https:// gallbladderresearch.shinyapps.io/Predict_GBC_survival/.

Comprehensive clinicopathological and genomic profiling of gallbladder cancer reveals actionable targets in half of patients.

Gallbladder cancer (GBC) is a rare, highly aggressive malignancy with a 5-year survival rate of 5-10% in advanced cases, highlighting the need for more effective therapies. The aim of this study was to identify potentially actionable therapeutic targets for GBC. Specimens and clinicopathological data of 642 GBC patients, diagnosed between 2000 and 2019 were collected using the Dutch Pathology Registry (PALGA) and the Netherlands Cancer Registry. All cases were histologically reviewed and a subset was subjected to a comprehensive next generation sequencing panel. We assessed mutations and gene amplifications in a panel of 54 actionable genes, tumor-mutational burden (TMB), and microsatellite instability (MSI). Additionally, the entire cohort was screened for HER2, PD-L1, pan-TRK, and p53 expression with immunohistochemistry. Histopathological subtypes comprised biliary-type adenocarcinoma (AC, 69.6%), intestinal-type AC (20.1%) and other subtypes (10.3%). The median total TMB was 5.5 mutations/Mb (range: 0-161.1) and 17.7% of evaluable cases had a TMB of >10 mutations/Mb. MSI was observed in two cases. Apart from mutations in TP53 (64%), tumors were molecularly highly heterogeneous. Half of the tumors (50%) carried at least one molecular alteration that is targetable in other tumor types, including alterations in CDKN2A (6.0% biallelically inactivated), ERBB2 (9.3%) and PIK3CA (10%). Immunohistochemistry results correlated well with NGS results for HER2 and p53: Pearson r = 0.82 and 0.83, respectively. As half of GBC patients carry at least one potentially actionable molecular alteration, molecular testing may open the way to explore targeted therapy options for GBC patients.

Recurrence patterns predict survival after resection of colorectal liver metastases.

BACKGROUND: Effective treatment of colorectal liver metastases (CRLM) is challenging because recurrence occurs in many patients after curative-intent resection. This study evaluates the recurrence patterns after resection of CRLM and its association with survival. METHODS: A retrospective review of prospectively collected data of patients with CRLM managed with curative-intent resection from January 2007 to December 2017 was performed. The main outcomes and measures were the timing of recurrence, initial sites of recurrence, overall survival and recurrence-free survival. Early recurrence was defined as the detection of any organ recurrence ≤6 months from resection of CRLM. RESULTS: A cohort of 194 patients was included for analysis. After a median follow-up of 85.3 months, 145 patients (74.7%) were diagnosed with recurrence. The median overall survival was 67.6 months (95% CI 50.4-80.2) and the 5-year overall survival was 54.1%. After initial recurrence was detected, the median survival was 28.9 months (95% CI 23.6-37.8) months and the 5-year overall survival was 28.8%. Early recurrence occurred in 58 patients (29.9%). Initial recurrence patterns included: liver only in 53 patients (36.5%), multiple sites in 48 patients (33.1%), lung only in 30 patients (20.7%), and other single extrahepatic sites in 14 patients (9.6%). Early recurrence and initial multi-site recurrence were independent predictors of worse overall survival for patients who develop recurrence after resection of CLRM. CONCLUSION: The timing and initial sites of recurrence are prognostic factors in determining survival after curative-intent resection of CRLM.

Multimodal CEA-targeted fluorescence and radioguided cytoreductive surgery for peritoneal metastases of colorectal origin.

In patients with colorectal peritoneal metastases scheduled for cytoreductive surgery, accurate preoperative estimation of tumor burden and subsequent intraoperative detection of all tumor deposits remains challenging. In this study (ClinicalTrials.gov NCT03699332) we describe the results of a phase I clinical trial evaluating [111In]In-DOTA-labetuzumab-IRDye800CW, a dual-labeled anti-carcinoembryonic antigen (anti-CEA) antibody conjugate that enables both preoperative imaging and intraoperative radioguidance and fluorescence imaging. Primary study outcomes are safety and feasibility of this multimodal imaging approach. Secondary outcomes are determination of the optimal dose, correlation between tracer uptake and histopathology and effects on clinical strategy. Administration of [111In]In-DOTA-labetuzumab-IRDye800CW is well-tolerated and enables sensitive pre- and intraoperative imaging in patients who receive 10 or 50 mg of the tracer. Preoperative imaging revealed previously undetected lymph node metastases in one patient, and intraoperative fluorescence imaging revealed four previously undetected metastases in two patients. Alteration of clinical strategy based on multimodal imaging occurred in three patients. Thus, multimodal image-guided surgery after administration of this dual-labeled tracer is a promising approach that may aid in decision making before and during cytoreductive surgical procedures.