Factors Predicting Readmission and Mortality in Patients Admitted for Malignant Bowel Obstruction.

INTRODUCTION: Malignant bowel obstruction (MBO) is a common complication of patients with advanced malignancies and has poor prognosis. Currently, there are limited guidelines for MBO management or predicting outcomes for these patients. OBJECTIVE: To identify patient factors associated with readmission and mortality after hospital admission for MBO. PARTICIPANTS: A 5-year retrospective review was performed from 2017 to 2022 at a single tertiary institution to evaluate patients admitted for MBO. All patients had advanced cancer of gastrointestinal or gynecologic primary. Patient demographics, socioeconomic factors, tumor characteristics, and inpatient outcomes were collected. Multivariable analyses were performed to determine variables predicting hospital readmission for recurrent MBO and 90-day mortality. RESULTS: 210 patients were included. Mean age was 61 years, 28% were male, and 19% did not primarily speak English. 35% of patients lived over 50 miles from the hospital. On multivariable analysis, non-English speaking patients exhibited increased risk of readmission for MBO (OR = 2.82, P = .039). Older age was associated with decreased risk for MBO readmission (OR = .96, P = .007). Ascites was associated with increased mortality (OR = 2.17, P = .043). Earlier palliative care (PC) consultation predicted decreased readmission (OR = .24, P < .001) yet increased mortality at 90 days (OR = 3.20, P = .003). CONCLUSION: Patient age, primary language, and PC consult were predictors for MBO readmission, which may impact 90-day mortality. Given the palliative nature of MBO, modifiable factors such as PC consultation and multidisciplinary goals of care discussions should be prioritized in order to reduce readmissions and focus on quality of life (QOL) for this patient population.

Natural history of undifferentiated pleomorphic sarcoma: Experience from the US Sarcoma Collaborative.

BACKGROUND: Undifferentiated pleomorphic sarcoma (UPS) is a relatively rare but aggressive neoplasm. We sought to utilize a multi-institutional US cohort of sarcoma patients to examine predictors of survival and recurrence patterns after resection of UPS. METHODS: From 2000 to 2016, patients with primary UPS undergoing curative-intent surgical resection at seven academic institutions were retrospectively reviewed. Epidemiologic and clinicopathologic factors were reviewed by site of origin. Overall survival (OS), recurrence-free survival (RFS), time-to-locoregional (TTLR), time-to-distant recurrence (TTDR), and patterns of recurrence were analyzed. RESULTS: Of the 534 UPS patients identified, 53% were female, with a median age of 60 and median tumor size of 8.5 cm. The median OS, RFS, TTLR, and TTDR for the entire cohort were 109, 49, 86, and 46 months, respectively. There were no differences in these survival outcomes between extremity and truncal UPS. Compared with truncal, extremity UPS were more commonly amenable to R0 resection (87% vs. 75%, p = 0.017) and less commonly associated with lymph node metastasis (1% vs. 6%, p = 0.031). R0 resection and radiation treatment, but not site of origin (extremity vs. trunk) were independent predictors of OS and RFS. TTLR recurrence was shorter for UPS resected with a positive margin and for tumors not treated with radiation. CONCLUSION: For patients with resected extremity and truncal UPS, tumor size >5 cm and positive resection margin are associated with worse survival OS and RFS, irrespectively the site of origin. R0 surgical resection and radiation treatment may help improve these survival outcomes.

Improved Postoperative Pain Management Outcomes After Implementation of Enhanced Recovery After Surgery (ERAS) Protocol for Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (CRS-HIPEC).

BACKGROUND: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) for patients with peritoneal carcinomatosis is promising but has potential for significant morbidity and prolonged hospitalization. Enhanced Recovery After Surgery (ERAS) is a standardized protocol designed to optimize perioperative care. This study describes trends in epidural and opioid use after implementing ERAS for CRS-HIPEC at a tertiary academic center. METHODS: A retrospective analysis of patients undergoing CRS-HIPEC from January 2020 to September 2023 was conducted. ERAS was implemented in February 2022. Medication and outcomes data were compared before and after ERAS initiation. All opioids were converted to morphine milligram equivalents (MMEs). RESULTS: A total of 136 patients underwent CRS-HIPEC: 73 (54%) pre- and 63 (46%) post-ERAS. Epidural usage increased from 63% pre-ERAS to 87% post-ERAS (p = 0.001). Compared with those without epidurals, patients with epidurals had decreased total 7-day oral and intravenous (IV) opioid requirements (45 MME vs. 316 MME; p < 0.001). There was no difference in 7-day opioid totals between pre- and post-ERAS groups. After ERAS, more patients achieved early ambulation (83% vs. 53%; p < 0.001), early diet initiation (81% vs. 25%; p < 0.001), and early return of bowel function (86% vs. 67%; p = 0.012). CONCLUSIONS: ERAS implementation for CRS-HIPEC was associated with increased epidural use, decreased oral and IV opioid use, and earlier bowel function return. Our study demonstrates that epidural analgesia provides adequate pain control while significantly decreasing oral and IV opioid use, which may promote gastrointestinal recovery postoperatively. These findings support the implementation of an ERAS protocol for effective pain management in patients undergoing CRS-HIPEC.

Preoperative CA 19-9 Predicts Disease Progression in Colorectal Peritoneal Metastases Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: An Analysis from the US HIPEC Collaborative.

INTRODUCTION: Patients with colorectal peritoneal metastases (CRPM) are increasingly treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). Unfortunately, data identifying preoperative risk factors for poor oncologic outcomes after this procedure are limited. We aimed to determine the prognostic value of preoperative CEA, CA 125, and CA 19-9 on disease progression after CRS/HIPEC. METHODS: Patients with CRPM treated with curative intent CRS/HIPEC from 12 participating sites in the United States from 2000 to 2017 were identified. Progression-free survival (PFS), defined as disease progression or recurrence, was the primary outcome. RESULTS: In 279 patients who met inclusion criteria, the rate of disease progression was 63.8%, with a median PFS of 11 months (interquartile range [IQR] 5-20). Elevated CA 19-9 was associated with dismal PFS at 2 years (8.9% elevated vs. 30% not elevated, p < 0.01). In 113 patients who underwent upfront CRS/HIPEC, CA 19-9 emerged as the sole tumor marker independently predictive of worse PFS (hazard ratio [HR] 2.88, p = 0.048). In the subgroup of patients who had received neoadjuvant therapy (NAT), no variable was independently predictive of PFS. CA 19-9 levels over 37 U/ml were highly specific for accelerated disease progression after CRS/HIPEC. Lastly, there was no association between PFS and elevated CEA or CA 125. CONCLUSIONS: Elevated CA 19-9 is associated with decreased PFS in patients with CRPM. While traditionally CEA is the main tumor marker assessed in colon cancer, we found that CA 19-9 may better inform preoperative risk stratification for poor oncologic outcomes in patients with CRPM. However, prospective studies are required to confirm this association.

PIPAC for Gastrointestinal Malignancies.

The peritoneum is a common site of metastases for gastrointestinal tumors that predicts a poor outcome. In addition to decreased survival, peritoneal metastases (PMs) can significantly impact quality of life from the resulting ascites and bowel obstructions. The peritoneum has been a target for regional therapies due to the unique properties of the blood-peritoneum barrier. Cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) have become accepted treatments for limited-volume peritoneal disease in appendiceal, ovarian, and colorectal malignancies, but there are limitations. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) improves drug distribution and tissue penetration, allowing for a minimally invasive application for patients who are not CRS/HIPEC candidates based on high disease burden. PIPAC is an emerging treatment that may convert the patient to resectable disease, and may increase survival without major morbidity, as indicated by many small studies. In this review, we discuss the rationale and benefits of PIPAC, as well as sentinel papers describing its application for gastric, colorectal, appendiceal, and pancreatobiliary PMs. While no PIPAC device has yet met FDA approval, we discuss next steps needed to incorporate PIPAC into neoadjuvant/adjuvant treatment paradigms, as well as palliative settings. Data on active clinical trials using PIPAC are provided.

GITR and TIGIT immunotherapy provokes divergent multicellular responses in the tumor microenvironment of gastrointestinal cancers.

BACKGROUND: Understanding the mechanistic effects of novel immunotherapy agents is critical to improving their successful clinical translation. These effects need to be studied in preclinical models that maintain the heterogenous tumor microenvironment (TME) and dysfunctional cell states found in a patient's tumor. We investigated immunotherapy perturbations targeting co-stimulatory molecule GITR and co-inhibitory immune checkpoint TIGIT in a patient-derived ex vivo system that maintains the TME in its near-native state. Leveraging single-cell genomics, we identified cell type-specific transcriptional reprogramming in response to immunotherapy perturbations. METHODS: We generated ex vivo tumor slice cultures from fresh surgical resections of gastric and colon cancer and treated them with GITR agonist or TIGIT antagonist antibodies. We applied paired single-cell RNA and TCR sequencing to the original surgical resections, control, and treated ex vivo tumor slice cultures. We additionally confirmed target expression using multiplex immunofluorescence and validated our findings with RNA in situ hybridization. RESULTS: We confirmed that tumor slice cultures maintained the cell types, transcriptional cell states and proportions of the original surgical resection. The GITR agonist was limited to increasing effector gene expression only in cytotoxic CD8 T cells. Dysfunctional exhausted CD8 T cells did not respond to GITR agonist. In contrast, the TIGIT antagonist increased TCR signaling and activated both cytotoxic and dysfunctional CD8 T cells. This included cells corresponding to TCR clonotypes with features indicative of potential tumor antigen reactivity. The TIGIT antagonist also activated T follicular helper-like cells and dendritic cells, and reduced markers of immunosuppression in regulatory T cells. CONCLUSIONS: We identified novel cellular mechanisms of action of GITR and TIGIT immunotherapy in the patients' TME. Unlike the GITR agonist that generated a limited transcriptional response, TIGIT antagonist orchestrated a multicellular response involving CD8 T cells, T follicular helper-like cells, dendritic cells, and regulatory T cells. Our experimental strategy combining single-cell genomics with preclinical models can successfully identify mechanisms of action of novel immunotherapy agents. Understanding the cellular and transcriptional mechanisms of response or resistance will aid in prioritization of targets and their clinical translation.

The Role of Prophylactic and Adjuvant Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Prevention of Peritoneal Metastases in Advanced Colorectal Cancer.

Hyperthermic intraperitoneal chemotherapy (HIPEC) is a locoregional therapy that may be combined with cytoreductive surgery (CRS) to treat patients with colorectal cancer and peritoneal metastases (PM). In recent years, three randomized controlled trials (RCTs) have investigated the role of prophylactic or adjuvant HIPEC in preventing the development of PM in patients with high-risk colorectal cancer: PROPHYLOCHIP and COLOPEC evaluated adjuvant HIPEC, and HIPECT4 studied concurrent HIPEC and CRS. Although PROPHYLOCHIP and COLOPEC were negative trials, a great deal may be learned from their methodology, outcome measures, and patient selection criteria. HIPECT4 is the first RCT to show a clinical benefit of HIPEC in high-risk T4 colorectal cancer, demonstrating improved locoregional disease control with the addition of HIPEC to CRS with no increase in the rate of complications. This review critically examines the strengths and limitations of each major trial and discusses their potential impact on the practice of HIPEC. Several additional ongoing clinical trials also seek to investigate the role of HIPEC in preventing PM in advanced colorectal cancer.

Impact of Successful Implementation of an Enhanced Recovery After Surgery Protocol for Patients Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) are complex operations for the treatment of peritoneal metastases. Enhanced recovery after surgery (ERAS) protocols are intended to standardize preoperative, intraoperative, and postoperative pathways, with the goal of improving patient care. This study describes feasibility and outcomes after implementing an ERAS protocol for CRS/HIPEC at a tertiary academic center. METHODS: A single-institution experience of CRS/HIPEC was reviewed from January 2020 to March 2023. Patients were categorized according to whether they underwent CRS/HIPEC before or after ERAS initiation. Outcomes and protocol adherence were evaluated. RESULTS: A total of 115 CRS/HIPEC operations were included-74 before and 41 after ERAS implementation. Median age was younger in the post-ERAS group, whereas sex, comorbidities, peritoneal carcinomatosis index, operation performed, and operative time were similar between groups. The most common primary cancer sites were gynecologic (40%), appendiceal (24%), and colorectal (22%). Adherence to all postoperative ERAS components was 76%. More post-ERAS patients ambulated by postoperative day (POD) 1 (90% vs. 54%; p < 0.001), tolerated liquid diet by POD 2 (88% vs. 32%; p < 0.001), and had foley removed by POD 3 (86% vs. 43%; p < 0.001). There was a trend toward decreased length of stay in the post-ERAS cohort (7 vs. 8 days; p = 0.092), with no difference in major complications, intensive care unit admission, or 30-day readmission. CONCLUSIONS: Despite the heterogeneity of CRS/HIPEC operations, implementing an ERAS protocol for our patients was feasible and resulted in postoperative outcomes and adherence comparable with that of other major abdominal surgeries. This supports the potential for success in ERAS programs for CRS/HIPEC patients.

Impact of Sodium Thiosulfate on Prevention of Nephrotoxicities in HIPEC: An Ancillary Evaluation of Cisplatin-Induced Toxicities in Ovarian Cancer.

PURPOSE: Hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin confers a survival benefit in epithelial ovarian cancer (EOC) but is associated with renal toxicity. Sodium thiosulfate (ST) is used for nephroprotection for HIPEC with cisplatin, but standard HIPEC practices vary. METHODS: A prospective, nonrandomized, clinical trial evaluated safety outcomes of HIPEC with cisplatin 75 mg/m2 during cytoreductive surgery (CRS) in patients with EOC (n = 34) and endometrial cancer (n = 6). Twenty-one patients received no ST (nST), and 19 received ST. Adverse events (AEs) were reported according to CTCAE v.5.0. Serum creatinine (Cr) was collected preoperatively and postoperatively (Days 5-8). Progression-free survival (PFS) was followed. Normal peritoneum was biopsied before and after HIPEC for whole transcriptomic sequencing to identify RNAseq signatures correlating with AEs. RESULTS: Forty patients had HIPEC at the time of interval or secondary CRS. Renal toxicities in the nST group were 33% any grade AE and 9% grade 3 AEs. The ST group demonstrated no renal AEs. Median postoperative Cr in the nST group was 1.1 mg/dL and 0.5 mg/dL in the ST group (p = 0.0001). Median change in Cr from preoperative to postoperative levels were + 53% (nST) compared with - 9.6% (ST) (p = 0.003). PFS did not differ between the ST and nST groups in primary or recurrent EOC patients. Renal AEs were associated with downregulation of metabolic pathways and upregulation of immune pathways. CONCLUSIONS: ST significantly reduces acute renal toxicity associated with HIPEC with cisplatin in ovarian cancer patients. As nephrotoxicity is high in HIPEC with cisplatin, nephroprotective agents should be considered.

Neighborhood-Level Socioeconomic Disadvantage Predicts Outcomes in Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Malignancy.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) improves survival in select patients with peritoneal metastases (PM), but the impact of social determinants of health on CRS/HIPEC outcomes remains unclear. PATIENTS AND METHODS: A retrospective review was conducted of a multi-institutional database of patients with PM who underwent CRS/HIPEC in the USA between 2000 and 2017. The area deprivation index (ADI) was linked to the patient's residential address. Patients were categorized as living in low (1-49) or high (50-100) ADI residences, with increasing scores indicating higher socioeconomic disadvantage. The primary outcome was overall survival (OS). Secondary outcomes included perioperative complications, hospital/intensive care unit (ICU) length of stay (LOS), and disease-free survival (DFS). RESULTS: Among 1675 patients 1061 (63.3%) resided in low ADI areas and 614 (36.7%) high ADI areas. Appendiceal tumors (n = 1102, 65.8%) and colon cancer (n = 322, 19.2%) were the most common histologies. On multivariate analysis, high ADI was not associated with increased perioperative complications, hospital/ICU LOS, or DFS. High ADI was associated with worse OS (median not reached versus 49 months; 5 year OS 61.0% versus 28.2%, P < 0.0001). On multivariate Cox-regression analysis, high ADI (HR, 2.26; 95% CI 1.13-4.50; P < 0.001), cancer recurrence (HR, 2.26; 95% CI 1.61-3.20; P < 0.0001), increases in peritoneal carcinomatosis index (HR, 1.03; 95% CI 1.01-1.05; P < 0.001), and incomplete cytoreduction (HR, 4.48; 95% CI 3.01-6.53; P < 0.0001) were associated with worse OS. CONCLUSIONS: Even after controlling for cancer-specific variables, adverse outcomes persisted in association with neighborhood-level socioeconomic disadvantage. The individual and structural-level factors leading to these cancer disparities warrant further investigation to improve outcomes for all patients with peritoneal malignancies.