VentX promotes tumor specific immunity and efficacy of immune checkpoint inhibitors.

Immune suppression within tumor microenvironments (TME) have been implicated in limited efficacy of immune check point inhibitors (ICIs) against solid tumors. Down-regulated VentX expression in tumor associated macrophages (TAMs) underlies phagocytotic anergic phenotype of TAMs, which govern immunological state of TME. In this study, using a tumor immune microenvironment enabling model system (TIME-EMS) of non-small cell lung cancer (NSCLC), we found that PD-1 antibody modestly activates cytotoxic T lymphocytes (CTLs) within the NSCLC-TME but not the status of TIME. We showed that the restoration of VentX expression in TAMs reignites the phagocytotic function of TAMs, which in turn, transforms TIME, activates CTLs in a tumor-specific manner and promotes efficacy of PD-1 antibody against NSCLC but not toxicity on normal lung epithelial cells. Supported by in vivo data on NSG-PDX models of primary human NSCLC, our study revealed potential venues to promote the efficacy of ICI against solid tumors through VentX-based mechanisms.

Long-term outcomes analysis of flap-based perineal reconstruction.

BACKGROUND: High-risk patients undergoing abdominoperineal resection and pelvic exenteration may benefit from immediate flap reconstruction. However, there is currently no consensus on the ideal flap choice or patient for whom this is necessary. This study aimed to evaluate the long-term outcomes of using pedicled gracilis flaps for pelvic reconstruction and to analyze predictors of postoperative complications. METHODS: This was a retrospective review of a single reconstructive surgeon's cases between January 2012 and June 2021 identifying patients who underwent perineal reconstruction secondary to oncologic resection. Preoperative and outcome variables were collected and analyzed to determine the risk of developing minor and major wound complications. RESULTS: A total of 101 patients were included in the study with most patients (n = 88) undergoing unilateral gracilis flap reconstruction after oncologic resection. The mean follow-up period was 75 months. Of 101 patients, 8 (7.9%) developed early major complications, and an additional 13 (12.9%) developed late major complications. Minor complications developed in 33 patients (32.7%) with most cases being minor wound breakdown requiring local wound care. Most patients (n = 92, 91.1%) did not develop donor site complications. Anal cancer was significantly associated with early major complications, whereas younger age and elevated body mass index were significant predictors of developing minor wound complications. CONCLUSIONS: This study builds on our previous work that demonstrated the long-term success rate of gracilis flap reconstruction after large pelvic oncologic resections. A few patients developed donor site complications, and perineal complications were usually easily managed with local wound care, thus making the gracilis flap an attractive alternative to abdominal-based flaps.

Evaluation of interdisciplinary care pathway implementation in older elective surgery patients.

BACKGROUND: The American College of Surgeons Geriatric Surgery Verification Program outlines best practices for surgical care in older adults. These recommendations have guided institutions to create workflows to better support needs specific to older surgical patients. This qualitative study explored clinician experiences to understand influences on implementation of frailty screening and an interdisciplinary care pathway in older elective colorectal surgery and neurosurgery patients. STUDY DESIGN: Semi-structured in-person and video-based interviews were conducted from July 2021 to March 2022 with clinicians caring for patients ≥70 years on the colorectal surgery and neurosurgery services. Interviews addressed familiarity with and beliefs about the intervention, intervention alignment with routine workflow and workflow adaptations, and barriers and facilitators to performing the intervention. Interviews were analyzed using the consolidated framework for implementation research (CFIR) to find themes related to ongoing implementation. RESULTS: Thirty-two clinicians participated (56.3% female, 58.8% White). Fifteen relevant CFIR constructs were identified. Key themes to implementation success included strong participant belief in effectiveness of the intervention and its advantage over standard care; the importance of training, reference materials, and champions; and the need for institution-level investment in resources to amplify the impact of the intervention on patients and expand the capacity to address their needs. CONCLUSION: Systematic evaluation found implementation of frailty screening and an interdisciplinary care pathway in elective colorectal surgery and neurosurgery patients to be supported by participating clinicians, yet sustainability of the intervention and further adoption across surgical services to better meet the needs of older patients would necessitate organizational resource allocation.

NF-κB-regulated VentX expression mediates tumoricidal effects of chemotherapeutics at noncytotoxic concentrations.

Limited therapeutic efficacy and severe side effects represent the central hurdles facing cancer chemotherapy. Immune suppression within tumor immune microenvironments (TIME) has been implicated in chemoresistance. In this study, using a TIME-enabling model system (TIME-EMS), we demonstrate that the chemotherapeutic agent doxorubicin has cytocidal effects on tumor cells at high dosage but induces changes in the immune landscape of the TIME at low noncytotoxic concentrations via NF-κB-mediated induction of homeobox protein VentX expression in tumor-associated macrophages (TAMs). We demonstrated that VentX-regulated TAMs drastically promote tumor chemosensitivity >10-fold but exert little effect on chemotoxicity to normal cells through activating cytotoxic T lymphocytes in a tumor-specific manner. Supported by the in vivo synergy of VentX-regulated TAMs and low-dosage noncytotoxic doxorubicin, our data suggest a cell-death-independent immune mechanism for improving the therapeutic index of chemotherapeutic agents.

Survival Outcomes for Malignant Peritoneal Mesothelioma at Academic Versus Community Hospitals.

BACKGROUND: Malignant peritoneal mesothelioma is a rare disease with poor outcomes. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy is the cornerstone of therapy. We aim to compare outcomes of malignant peritoneal mesothelioma treated at academic versus community hospitals. METHODS: This was a retrospective cohort study using the National Cancer Database to identify patients with malignant peritoneal mesothelioma from 2004 to 2016. Patients were divided according to treating facility type: academic or community. Outcomes were assessed using log-rank tests, Cox proportional-hazard modeling, and Kaplan-Meier survival statistics. RESULTS: In total, 2682 patients with malignant peritoneal mesothelioma were identified. A total of 1272 (47.4%) were treated at an academic facility and 1410 (52.6%) were treated at a community facility. Five hundred forty-six (42.9%) of patients at academic facilities underwent debulking or radical surgery compared to 286 (20.2%) at community facilities. Three hundred sixty-six (28.8%) of patients at academic facilities received chemotherapy on the same day as surgery compared to 147 (10.4%) of patients at community facilities. Unadjusted 5-year survival was 29.7% (95% CI 26.7-32.7) for academic centers compared to 18.3% (95% CI 16.0-20.7) for community centers. In multivariable analysis, community facility was an independent predictor of increased risk of death (HR: 1.19, 95% CI 1.08-1.32, p = 0.001). CONCLUSIONS: We demonstrate better survival outcomes for malignant peritoneal mesothelioma treated at academic compared to community facilities. Patients at academic centers underwent surgery and received chemotherapy on the same day as surgery more frequently than those at community centers, suggesting that malignant peritoneal mesothelioma patients may be better served at experienced academic centers.

The Effect of Facility Volume on Survival Following Proctectomy for Rectal Cancer.

BACKGROUND: Prior studies assessing colorectal cancer survival have reported better outcomes when operations are performed at high-volume centers. These studies have largely been cross-sectional, making it difficult to interpret their estimates. We aimed to assess the effect of facility volume on survival following proctectomy for rectal cancer. METHODS: Using data from the National Cancer Database, we included all patients with complete baseline information who underwent proctectomy for non-metastatic rectal cancer between 2004 and 2016. Facility volume was defined as the number of rectal cancer cases managed at the treating center in the calendar year prior to the patient's surgery. Overall survival estimates were obtained for facility volumes ranging from 10 to 100 cases/year. Follow-up began on the day of surgery and continued until loss to follow-up or death. RESULTS: A total of 52,822 patients were eligible. Patients operated on at hospitals with volumes of 10, 30, and 50 cases/year had similar distributions of grade, clinical stage, and neoadjuvant therapies. 1-, 3-, and 5-year survival all improved with increasing facility volume. One-year survival was 94.0% (95% CI: 93.7, 94.3) for hospitals that performed 10 cases/year, 94.5% (95% CI: 94.2, 94.7) for 30 cases/year, and 94.8% (95% CI: 94.5, 95.0) for 50 cases/year. Five-year survival was 68.9% (95% CI: 68.0, 69.7) for hospitals that performed 10 cases/year, 70.8% (95% CI: 70.1, 71.5) for 30 cases/year, and 72.0% (95% CI: 71.2, 72.8) for 50 cases/year. CONCLUSIONS: Treatment at a higher volume facility results in improved survival following proctectomy for rectal cancer, though the small benefits are less profound than previously reported.

A Case of Microsatellite Instability-High Colon Cancer in a Young Woman With Familial Adenomatous Polyposis.

Two major molecular pathways of colorectal carcinogenesis, chromosomal instability (CIN) and microsatellite instability (MSI), are considered to be mutually exclusive. Distinguishing CIN from MSI-high tumors has considerable therapeutic implications, because patients with MSI-high tumors can derive considerable benefit from immune checkpoint inhibitors, and tumors that evolved through the CIN pathway do not respond to these agents. Familial adenomatous polyposis (FAP) is a genetic syndrome that is defined by a mutation in the APC gene and is thought to lead to carcinogenesis through the CIN pathway. Here, we report a case of a young woman with FAP who was treated for medulloblastoma as a child and developed advanced MSI-high colon cancer as a young adult. Her response to second-line immunotherapy enabled resection of her colon cancer, and she is free of disease >10 months after surgery. This case highlights the potential for overlap between the CIN and MSI carcinogenic pathways and associated therapeutic implications.

The Association Between Sex and Survival for Anal Squamous Cell Carcinoma.

BACKGROUND: The incidence of anal squamous cell carcinoma (SCC) is rising, despite the introduction of a vaccine against human papillomavirus (HPV), the most common etiology of anal SCC. The rate of anal SCC is higher among women and sex-based survival differences may exist. We aimed to examine the association between sex and survival for stage I-IV anal SCC. MATERIALS AND METHODS: The National Cancer Database was used to identify patients with stage I-IV anal SCC from 2004-2016. Outcomes were assessed utilizing log rank tests, Kaplan-Meier statistics, and Cox proportional-hazard modeling. Subgroup analyses by disease stage and by HPV status were performed. Outcomes of interest were median, 1-, and 5-year survival by sex. RESULTS: There were 31,185 patients with stage I-IV anal SCC. 10,714 (34.3%) were male and 20,471 (65.6%) were female. 1- and 5- year survival was 90.2% (95% CI 89.8 - 90.7) and 67.7% (95% CI 66.9 - 68.5) for females compared to 85.8% (95% CI 85.1 - 86.5) and 55.9% (95% CI 54.7 - 57.0) for males. In subgroup analysis, females demonstrated improved unadjusted and adjusted survival for all stages of disease. Female sex was an independent predictor of improved survival (HR 0.68, 95% CI 0.65 - 0.71, P < 0.001). CONCLUSIONS: We demonstrate better overall survival for females compared to males for stage I-IV anal SCC. It is not clear why women have a survival advantage over men, though exposure to prominent risk factors may play a role. High-risk men may warrant routine screening for anal cancer.

Spatially organized multicellular immune hubs in human colorectal cancer.

Immune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. To understand the rules governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd individuals. Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across tumors. To discover hubs of interacting malignant and immune cells, we identified expression programs in different cell types that co-varied across tumors from affected individuals and used spatial profiling to localize coordinated programs. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage and an MMRd-enriched immune hub within the tumor, with activated T cells together with malignant and myeloid cells expressing T cell-attracting chemokines. By identifying interacting cellular programs, we reveal the logic underlying spatially organized immune-malignant cell networks.

Perioperative Code Status Discussions: How Are We Doing?

Approximately 15% of patients with a code status of do-not-resuscitate (DNR) or do-not-intubate (DNI) present for surgery. Despite professional guidelines requiring discussions with patients regarding perioperative resuscitation, it is unclear whether these recommendations are consistently followed. Our review of 158 patient encounters with established DNR/DNI code status found that code status discussions (CSDs) were documented only 70% of the time, and code status orders were inconsistently entered to reflect those discussions. We present solutions to improve CSD documentation, including refining perioperative workflows, simplifying code status choices, optimizing electronic health record order entry, and a supplementary consent form to facilitate code status review.

Surgical Management of Small Bowel Lymphoma.

BACKGROUND: Primary small bowel non-Hodgkin's lymphoma is a rare disease representing 2% of small intestine malignancies. There is limited data delineating the optimal treatment for these heterogeneous tumors. We aim to examine relationships between different treatment modalities and surgical outcomes in patients with small bowel lymphoma. MATERIALS AND METHODS: Patients diagnosed with stage I-III small bowel lymphoma in 2004-2015 who underwent surgery were identified in the National Cancer Database. Two cohorts were created based on systemic chemotherapy treatment status. The primary outcome was overall survival. An adjusted Cox proportional hazards model was used to evaluate the impact of treatment strategy on survival. RESULTS: 2283 patients met inclusion criteria Of these patients, 826 patients (36%) underwent surgical resection alone, and 1457 patients (64%) underwent resection with systemic chemotherapy. Chemotherapy was associated with improved overall survival in unadjusted (5-year overall survival, 55% versus 70%) and adjusted analysis (HR 0.54, 95% CI 0.47-0.63, p < 0.001). DISCUSSION: Patients with small bowel lymphoma have a low five-year overall survival after surgery. Chemotherapy is associated with improved survival, although one third of patients do not receive this therapy. Several other clinical factors are identified that are also associated with overall survival, including histology subtype, margin status, age, and medical comorbidities. This information can help with prognostication and potentially aid in treatment decision-making.

Lymph Node Positivity in T1/T2 Rectal Cancer: a Word of Caution in an Era of Increased Incidence and Changing Biology for Rectal Cancer.

BACKGROUND: The evaluation of lymph nodes in rectal cancer dictates treatment. The goals of this study are to characterize the contemporary rate of lymph node metastasis in early stage rectal cancer and to re-investigate histologic factors that predict positive lymph nodes. MATERIALS AND METHODS: Using the National Cancer Database, we identified patients with clinical stage I rectal adenocarcinoma. Multivariable logistic regression was used to determine risk factors for lymph node positivity. RESULTS: 12.2% of patients with T1 tumors and 18.0% of patients with T2 tumors had positive lymph nodes. For T1 tumors, positive lymph nodes were present in 9.3% with neither poor differentiation nor lymphovascular invasion (LVI), 17.3% with poor differentiation alone, 34.7% with LVI alone, and 45.0% with both poor differentiation and LVI. For T2 tumors, positive lymph nodes were present in 11.7% with neither poor differentiation nor LVI, 25.3% with poor differentiation alone, 47.3% with LVI alone, and 41.5% with both poor differentiation and LVI. LVI was an independent predictor of positive lymph nodes (OR;4.75,95%CI;3.17-7.11,p < 0.001) for T1 and (OR;6.20,95%CI;4.53-8.51,p < 0.001) T2 tumors. CONCLUSIONS: T1/T2 tumors have higher rates of positive lymph nodes when poor differentiation and LVI are present. These results should be taken into consideration prior to surgical treatment.

Surgical resection improves overall survival of patients with small bowel leiomyosarcoma.

PURPOSE: Small bowel leiomyosarcoma (SB LMS) is a rare disease with few studies characterizing its outcomes. This study aims to evaluate surgical outcomes for patients with SB LMS. METHODS: The National Cancer Database was queried from 2004 to 2016 to identify patients with SB LMS who underwent surgical resection. The primary outcome was overall survival. RESULTS: A total of 288 patients with SB LMS who had undergone surgical resection were identified. The median age was 63, and the majority of patients were female (56%), White (82%), and had a Charlson comorbidity score of zero (76%). Eighty-one percent of patients had negative margins following surgical resection. Fourteen percent of patients had metastatic disease at the time of diagnosis. Nineteen percent of patients received chemotherapy and 3% of patients received radiation. One-year overall survival was 77% (95% CI: 72-82%) and 5-year overall survival was 43% (95% CI: 36-49%). Higher grade (HR: 1.98, 95% CI: 1.10-3.55, p = 0.02) and metastatic disease at diagnosis (HR: 2.57, 95% CI: 1.45-4.55, p = 0.001) were independently associated with higher risk of death. CONCLUSION: SB LMS is a rare disease entity, with treatment centering on complete surgical resection. Our results demonstrate that overall survival is higher than previously thought. Timely diagnosis to allow for complete surgical resection is key, and investigation into the possible role of chemotherapy or radiation therapy is needed.

A multi-center analysis of cumulative inpatient opioid use in colorectal surgery patients.

BACKGROUND: There are little data on risk factors for increased inpatient opioid use and its relationship with persistent opioid use after colorectal surgery. METHODS: We identified colorectal surgery patients across five collaborating institutions. Patient comorbidities, surgery data, and outcomes were captured in the American College of Surgeons National Surgical Quality Improvement Program. We recorded preoperative opioid exposure, inpatient opioid use, and persistent use 90-180 days after surgery. RESULTS: 1646 patients were analyzed. Patients receiving ≥250 MMEs (top quartile) were included in the high use group. On multivariable analysis, age <65, emergent surgery, inflammatory bowel disease, and postoperative complications, but not prior opioid exposure, were predictive of high opioid use. Patients in the top quartile of use had an increased risk of persistent opioid use (19.8% vs. 9.7%, p < 0.001), which persisted on multivariable analysis (OR 1.48; p = 0.037). CONCLUSIONS: We identified risk factors for high inpatient use that can be used to identify patients that may benefit from opioid sparing strategies. Furthermore, high postoperative inpatient use was associated with an increased risk of persistent opioid use.

VentX expression in tumor-associated macrophages promotes phagocytosis and immunity against pancreatic cancers.

Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy that has no effective treatment. The tumor microenvironment (TME) of PDA employs a multitude of immune derangement strategies to protect PDA from immune elimination. Tumor-associated macrophages (TAMs) have been implicated in the pathogenesis of immune suppression of the PDA TME; however, its underlying mechanisms remained largely unknown. Using primary patient samples, our studies showed that, in comparison with macrophages isolated from normal pancreatic tissues, the phagocytosis activity of the PDA TAMs was significantly reduced. We found that the expression of homeobox protein VentX, a master regulator of macrophage plasticity, was significantly decreased in the PDA TAMs. We demonstrated that VentX was required for phagocytosis and that restoration of VentX expression in PDA TAMs promoted phagocytosis through the regulation of the signaling cascades involved in the process. Using an ex vivo culture model of primary human PDA, we showed that VentX-modulated TAMs transformed the PDA TME from a protumor milieu to an antitumor microenvironment by rectifying differentiation, proliferation, and activation of PDA-infiltrating immune cells. Using NSG-PDX models of primary human PDAs, we showed that VentX-modulated TAMs exerted strong inhibition on PDA tumorigenesis in vivo. Taken together, our data revealed a central mechanism underlying immune evasion of PDA and a potential novel venue to improve PDA prognosis.

The Effect of Surgical Trainee Education on Opioid Prescribing: An International Evaluation.

INTRODUCTION: Up to 6% of opioid naive patients who undergo surgery become chronic opioid users. The aim of this study was to determine if formal opioid prescribing education of general surgery residents is associated with decreased opioid prescribing postoperatively. METHODS: We surveyed surgery residents at 3 general surgery programs in the United States and 1 in Israel. Residents were divided into 2 groups based on whether or not they received formal opioid prescribing education. RESULTS: Of those surveyed, 107 (50%) responded. 45% of residents had formal opioid prescribing education, which included instructional videos, current literature, and hospital guidelines. For the 4 operations analyzed, residents who received no formal teaching prescribed a higher number of opioids (lumpectomy p = 0.001, open inguinal hernia repair p = 0.004, laparoscopic appendectomy p = 0.007, thyroidectomy p = 0.002). The largest difference in opioid prescribing was seen in "high prescribers," defined as residents prescribing 15 or more opioid pills. For thyroidectomy, 24.4% of residents without formal education prescribed 20 or more oxycodone 5mg pills compared to 0% of residents with formal education. The Israeli cohort was less likely to receive a pain focused education and was also less likely to prescribe opioids to their patients for all 4 procedures evaluated. CONCLUSIONS: Although a minority of general surgery residents are receiving an opioid prescribing education, a formal educational program was associated with significantly decreased opioid prescribing. There is a need for a generalizable educational opioid program for surgery residents.