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Supplemental Figures S1-S7

Pancreatic ductal adenocarcinoma (PDAC) has a prominent fibrotic stroma, which is a result of interactions between tumor, immune and pancreatic stellate cells (PSC), or cancer-associated fibroblasts (CAF). Targeting inflammatory pathways present within the stroma may improve access of effector immune cells to PDAC and response to immunotherapy. Heat shock protein-90 (Hsp90) is a chaperone protein and a versatile target in pancreatic cancer. Hsp90 regulates a diverse array of cellular processes of relevance to both the tumor and the immune system. However, to date the role of Hsp90 in PSC/CAF has not been explored in detail. We hypothesized that Hsp90 inhibition would limit inflammatory signals, thereby reprogramming the PDAC tumor microenvironment to enhance sensitivity to PD-1 blockade. Treatment of immortalized and primary patient PSC/CAF with the Hsp90 inhibitor XL888 decreased IL6, a key cytokine that orchestrates immune changes in PDAC at the transcript and protein level in vitro. XL888 directly limited PSC/CAF growth and reduced Jak/STAT and MAPK signaling intermediates and alpha-SMA expression as determined via immunoblot. Combined therapy with XL888 and anti–PD-1 was efficacious in C57BL/6 mice bearing syngeneic subcutaneous (Panc02) or orthotopic (KPC-Luc) tumors. Tumors from mice treated with both XL888 and anti–PD-1 had a significantly increased CD8+ and CD4+ T-cell infiltrate and a unique transcriptional profile characterized by upregulation of genes associated with immune response and chemotaxis. These data demonstrate that Hsp90 inhibition directly affects PSC/CAF in vitro and enhances the efficacy of anti–PD-1 blockade in vivo.

Background Incarcerated patients represent one of the most vulnerable populations in the United States healthcare system. Studying disparities in care they receive, however, has been difficult due to a history of abuse at the hands of medical researchers rendering this population excluded from most current medical research. Due to incarceration, these patients are frequently maintained in shackles and under constant guard when receiving healthcare. There is a paucity of literature on the influence these measures exert on healthcare workers and the care they provide. Our study aimed to measure surgical trainee's perception of health inequities and disparities in incarcerated individuals undergoing surgical care. Methods An anonymous cross-sectional survey was administered at our single institution to all general surgery trainees assessing perceptions in delivering care to incarcerated patients within our hospital system. The survey consisted of 10 items, nine of which were yes or no responses, and 1 open-ended text question. Survey results were averaged, and percentages were reported. Results Of all current general surgery residents (n = 60), 40 (66%) completed the survey. Almost all respondents (n = 39, 97.5%) have cared for a patient that was incarcerated or in police custody. Most respondents (n = 25, 62.5%) have operated on an incarcerated patient with an armed guard present in the operating room. Similarly, most respondents (n = 26, 65%) have cared for a patient intubated and sedated that was shackled to a bed. The majority of respondents (n = 30, 75%) recalled incidents where a trauma patient was actively questioned by law enforcement during the primary/secondary survey during initial trauma evaluation. At the time of hospital discharge, a quarter (n = 10, 25%) of respondents reported being unable to prescribe all of the medications that a non-imprisoned patient would receive with the same condition. In addition, 18 (45%) respondents felt they were unable to arrange outpatient follow-up with physical or occupational therapy and/or the patient's primary/consulting physician due to patient's incarcerated status. Strikingly, half of respondents (n = 19, 47.5%) believed that the incarcerated patient received substandard care, and the majority of respondents (n = 28, 72%) agreed that the holding areas for incarcerated patients in the emergency room provide substandard patient care. Conclusions The current status of caring for incarcerated patients within our system represents an urgent and needed area for quality improvement. Surgical trainees report difficulty caring for these patients, and they perceive these individuals receive substandard care. Though our cross-sectional study did not assess the origin of this disparity, the challenges trainees face in caring for incarcerated patients, from assessment to diagnosis and treatment, as well as in follow-up signals an area requiring further research and study.

Tumor markers are commonly utilized in the diagnostic evaluation, treatment decision making, and surveillance of appendiceal tumors. In this study, we aimed to determine the prognostic significance of elevated preoperative tumor markers in patients with pseudomyxoma peritonei secondary to low-grade appendiceal mucinous neoplasm who underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Using a multi-institutional database, eligible patients with measured preoperative tumor markers [carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), or cancer antigen 125 (CA-125)] were identified. Univariate and multivariate Cox-proportional hazards regression analysis assessed relationships between normal and elevated serum tumor markers with progression-free and overall survival in the context of multiple clinicopathologic variables. zTwo hundred and sixty-four patients met criteria. CEA was the most commonly measured tumor marker (97%). Patients who had any elevated tumor marker had a higher peritoneal carcinomatosis index (PCI) as compared to those with normal range markers. Elevated CEA and CA 19-9 levels were individually associated with longer inpatient length of stay, requirement for intraoperative transfusion, and incomplete cytoreduction. Utilization of neoadjuvant chemotherapy, increased PCI score, elevated CA 19-9 (p = 0.007), and CA-125 levels (p = 0.01) were predictive of decreased progression-free survival on univariate analysis. However, in a multivariate model, only elevated PCI was a statistically significant predictor of progression-free survival. Elevated preoperative tumor markers indicate a higher burden of disease but are not independently associated with survival in this retrospective multi-institutional cohort. Further prospective studies are needed to clarify the utility of these markers in this patient population.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is increasingly performed for peritoneal surface malignancies but remains associated with significant morbidity. Scant research is available regarding the impact of insurance status on postoperative outcomes.Patients undergoing CRS/HIPEC between 2000 and 2017 at 12 participating sites in the US HIPEC Collaborative were identified. Univariate and multivariate analyses were used to compare the baseline characteristics, operative variables, and postoperative outcomes of patients with government, private, or no insurance.Among 2268 patients, 699 (30.8%) had government insurance, 1453 (64.0%) had private, and 116 (5.1%) were uninsured. Patients with government insurance were older, more likely to be non-white, and comorbid (p 0.05). Patients with government (OR: 2.25, CI: 1.50-3.36, p 0.001) and private (OR: 1.69, CI: 1.15-2.49, p = 0.008) insurance had an increased risk of complications on univariate analysis. There was no independent relationship on multivariate analysis. An American Society of Anesthesiologists score of 3 or 4, peritoneal carcinomatosis index score15, completeness of cytoreduction score1, and nonhome discharge were factors independently associated with a postoperative complication.While there were differences in postoperative outcomes between the three insurance groups on univariate analysis, there was no independent association between insurance status and postoperative complications after CRS/HIPEC.

Pancreatic ductal adenocarcinoma (PDAC) has a prominent fibrotic stroma, which is a result of interactions between tumor, immune and pancreatic stellate cells (PSC), or cancer-associated fibroblasts (CAF). Targeting inflammatory pathways present within the stroma may improve access of effector immune cells to PDAC and response to immunotherapy. Heat shock protein-90 (Hsp90) is a chaperone protein and a versatile target in pancreatic cancer. Hsp90 regulates a diverse array of cellular processes of relevance to both the tumor and the immune system. However, to date the role of Hsp90 in PSC/CAF has not been explored in detail. We hypothesized that Hsp90 inhibition would limit inflammatory signals, thereby reprogramming the PDAC tumor microenvironment to enhance sensitivity to PD-1 blockade. Treatment of immortalized and primary patient PSC/CAF with the Hsp90 inhibitor XL888 decreased IL6, a key cytokine that orchestrates immune changes in PDAC at the transcript and protein level in vitro. XL888 directly limited PSC/CAF growth and reduced Jak/STAT and MAPK signaling intermediates and alpha-SMA expression as determined via immunoblot. Combined therapy with XL888 and anti–PD-1 was efficacious in C57BL/6 mice bearing syngeneic subcutaneous (Panc02) or orthotopic (KPC-Luc) tumors. Tumors from mice treated with both XL888 and anti–PD-1 had a significantly increased CD8+ and CD4+ T-cell infiltrate and a unique transcriptional profile characterized by upregulation of genes associated with immune response and chemotaxis. These data demonstrate that Hsp90 inhibition directly affects PSC/CAF in vitro and enhances the efficacy of anti–PD-1 blockade in vivo.

CRS/HIPEC is thought to confer a survival advantage for patients with malignant peritoneal mesothelioma (MPM). However, the impact of nonperitoneal organ resection is not clearly defined. We evaluated the impact of major organ resection (MOR) on postoperative outcomes and overall survival (OS). The US HIPEC collaborative database (2000–2017) was reviewed for MPM patients who underwent CRS/HIPEC. MOR was defined as total or partial resection of diaphragm, stomach, spleen, pancreas, small bowel, colon, rectum, kidney, ureter, bladder, and/or uterus. MOR was categorized as 0, 1, or 2+ organs. A total of 174 patients were identified. Median PCI was 16 (3–39). The distribution of patients with MOR-0, MOR-1, and MOR-2+ was 94, 45, and 35 patients, respectively. MOR-1 and MOR-2+ groups had a higher frequency of any complication compared with MOR-0 (57.8%, 74.3%, and 48.9%, respectively, p = 0.035), but Clavien 3/4 complications were similar. Median length of stay was slightly higher in the MOR-1 and MOR-2+ groups (10 and 11 days) compared with the MOR-0 cohort (9 days, p = 0.005). Incomplete cytoreduction, ASA class 4, and male gender were associated with increased mortality on unadjusted analysis; however, their impact on OS was attenuated on multivariable analysis. MOR was not associated with OS based on these data (MOR-1: HR 1.67, 95% CI 0.59–4.74; MOR-2+ : HR 0.77, 95% CI 0.22–2.69). MOR was not associated with an increase in major complications or worse OS in patients undergoing CRS/HIPEC for MPM and should be considered, if necessary, to achieve complete cytoreduction for MPM patients.

Background/objective Natural history and outcomes for truncal/extremity (TE) soft tissue sarcoma (STS) is derived primarily from studies investigating all histiotypes as one homogenous cohort. We aimed to define the recurrence rate (RR), recurrence patterns, and response to radiation of TE leiomyosarcomas (LMS). Methods Patients from the US Sarcoma Collaborative database with primary, high-grade TE STS were identified. Patients were grouped into LMS or other histology (non-LMS). Primary endpoints were locoregional recurrence-free survival (LR-RFS), distant-RFS (D-RFS), and disease specific survival (DSS). Results Of 1215 patients, 93 had LMS and 1122 non-LMS. In LMS patients, median age was 63 and median tumor size was 6 cm. In non-LMS patients, median age was 58 and median tumor size was 8 cm. In LMS patients, overall RR was 42% with 15% LR-RR and 29% D-RR. The 3yr LR-RFS, D-RFS, and DSS were 84%, 65%, and 76%, respectively. When considering high-risk (>5 cm and high-grade, n = 49) LMS patients, the overall RR was 45% with 12% LR-RR and 35% D-RR. 61% received radiation. The 3yr LR-RFS (78vs93%, p = 0.39), D-RFS (53vs63%, p = 0.27), and DSS (67vs91%, p = 0.17) were similar in those who did and did not receive radiation. High-risk, non-LMS patients had a similar overall RR of 42% with 15% LR-RR and 30% D-RR. 60% of non-LMS patients received radiation. There was an improved 3yr LR-RFS (82vs75%, p = 0.030) and DSS (77vs65%,p = 0.007) in non-LMS patients who received radiation. Conclusions In our cohort, patients with LMS have a low local recurrence rate (12–15%) and modest distant recurrence rate (29–35%). However, LMS patients had no improvement in local control or long-term outcomes with radiation. The value of radiation in these patients merits further investigation.

BACKGROUND. Patient age is a significant factor in preoperative selection for major abdominal surgery. The association of age, tumor biology, and postoperative outcomes in patients undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) remains ill-defined. METHODS. Retrospective analysis was performed for patients who underwent a CCR0/1 CRS/HIPEC from the US HIPEC Collaborative Database (2000–2017). Age was categorized into < 65 or ≥ 65 years. Primary outcome was postoperative major complications. Secondary outcomes were non-home discharge (NHD) and readmission. Analysis was stratified by disease histology: non-invasive (appendiceal LAMN/HAMN), and invasive (appendiceal/colorectal adenocarcinoma). RESULTS. Of 1090 patients identified, 22% were ≥ 65 (n = 240), 59% were female (n = 646), 25% had non-invasive (n = 276) and 51% had invasive (n = 555) histology. Median PCI was 13 (IQR 7–20). Patients ≥ 65 had a higher rate of major complications (37 vs 26%, p = 0.02), NHD (12 vs 5%, p < 0.01), and readmission (28 vs 22%, p = 0.05), compared to those < 65. For non-invasive histology, age ≥ 65 was not associated with major complications or NHD on multivariable analysis. For invasive histology, when accounting for PCI and CCR, age ≥ 65 was associated with major complications (OR 2.04, 95% CI 1.16–3.59, p = 0.01). When accounting for major complications, age ≥ 65 was associated with NHD (OR 2.54, 95% CI 1.08–5.98, p = 0.03). Age ≥ 65 was not predictive of readmission for any histology when accounting for major complications. CONCLUSIONS. Age ≥ 65 years is an independent predictor for postoperative major complications and non-home discharge for invasive histology, but not non-invasive histology. These data inform preoperative counseling, risk stratification, and early discharge planning.

Radiographic prediction of peritoneal carcinomatosis index (PCI) can improve patient selection for cytoreductive surgery. We aimed to determine the correlation of computed tomography (CT)-predicted PCI (CT-PCI) and magnetic resonance imaging (MRI)-predicted PCI (MRI-PCI) with intraoperative-PCI, and if a preoperative-PCI cutoff is associated with incomplete cytoreduction.Patients from the US HIPEC Collaborative (2000-2017) with appendiceal, colorectal, or peritoneal mesothelioma (PM) histology who underwent cytoreductive surgery were included. Pearson correlation coefficients were used to determine correlation between preoperative and intraoperative-PCI values. Fisher r-to-z transformation was used to compare correlations.A total of 488 patients were included. Of these, 34% had noninvasive appendiceal, 30% invasive appendiceal, 28% colorectal, and 8% PM histology. CT-PCI was correlated with intraoperative-PCI for patients with noninvasive and invasive appendiceal and colorectal histologies (r = 0.689, 0.554, and 0.571; all P .001), but not PM (r = 0.188; P = .295). MRI-PCI was correlated with intraoperative-PCI for all histologies (non-invasive appendiceal: r = 0.591; P = .002; invasive appendiceal: r = 0.848; P .001; colorectal: r = 0.729; P .001; PM: r = 0.890; P = .007). Comparing CT and MRI, correlations were similar in noninvasive appendiceal and colorectal histologies; MRI was better for invasive appendiceal and PM (P = .005 and P = .021, respectively). Twenty-eight (6%) patients underwent an incomplete cytoreduction (cytoreduction score, 2-3). PCI greater than 15 was associated with cytoreduction score of 2 to 3 for both CT and MRI (CT-PCI: odds ratio, 3.0; P = .033; MRI-PCI: odds ratio, 7.6; P = .071).In this multi-institutional cohort, CT and MRI-PCI correlate well with intraoperative-PCI. MRI appears to be superior for invasive appendiceal and peritoneal mesothelioma. External validation in a larger population is needed.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) results in significant morbidity and readmissions. Previous studies have been limited by single-institution design or lack of tumor details in the database used. The 12-institution US HIPEC Collaborative Database was queried between 1999 and 2017. Preoperative and intraoperative patient and tumor details were analyzed for associations with readmissions. A total of 2017 of 2372 cases were included in the analysis. The 30-day readmission rate was 15.9% (n = 321). Common indications for readmission included failure to thrive (29.9%), infection (23.6%), and ileus/bowel obstruction (15.1%). The readmitted cohort had more complications, including intra-abdominal abscess (21.2% vs 6.2%), ileus (28.0% vs 17.2%), anastomotic leak (11.2% vs 2.2%), enteric fistula (5.6% vs 1.5%), deep venous thrombosis (6.2% vs 2.5%), and pulmonary embolism (6.9% vs 2.5%). Factors independently associated with readmission (p < 0.05) included ECOG score ≥ 3 (OR 3.4), depression (OR 2.4), total parenteral nutrition (OR 3.6), low anterior resection or partial colectomy (OR 2.0), and stoma creation (OR 2.2). Factors not associated included neoadjuvant chemotherapy, peritoneal cancer index, and completeness of cytoreduction. Readmission rate between 31 and 90 days was 3.9% (n = 78). Independent predictors (p < 0.05) included operative time (OR 1.1), low anterior resection or partial colectomy (OR 1.7), and stoma creation (OR 2.2). In the largest study to date examining readmissions after CRS-HIPEC, 30-day readmission rate was 15.9%. Tumor factors failed to predict readmission, whereas preoperative functional status and depression along with individual cytoreductive procedures predicted readmission. Patients with these risk factors or postoperative complications may benefit from closer post-discharge monitoring.

BackgroundPaucity of T cells in the immune privileged tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is a major reason that PDAC is refractory to immune checkpoint blockade.1 In this study, we show that human PDAC tumors over-express vasoactive intestinal peptide (VIP), an immunosuppressive neuropeptide, that inhibits effector T cell responses and regulates chemokine receptor expression on activated T cells.2 3 We thus hypothesized that pharmacological inhibition of VIP receptor signaling could enhance anti-tumor responses in PDAC.MethodsVIP levels in plasma were determined via VIP-specific enzyme immunoassay and confirmed with immunohistochemistry (IHC) of tissue sections. VIP receptor (VIP-R) signaling in C57BL/6 immunocompetent murine models of KPC, MT5 or Panc02 pancreatic cancer was inhibited by daily sub-cutaneous treatment with ANT008 or ANT308, two novel VIP-R antagonists with predicted high binding affinities to VIP receptors.4–7 Multiplex IHC or flow cytometry detected frequencies and phenotypes of intra-tumoral T cells across treatment groups.ResultsHuman PDAC tumors expressed VIP by immunohistochemistry, and PDAC patients had significantly elevated plasma VIP levels when compared to healthy volunteers (pConclusionsVIP-R antagonists represent a novel approach to treat PDAC. VIP and VIP-R sequences are highly conserved between humans and mice,8 and human T cells are activated in vitro following treatment with VIP-R antagonists. Thus, we predict comparable anti-tumor activity of the combination of VIP-R antagonist and anti-PD-1 MoAb in human PDAC patients. Further clinical development of this novel concept will require appropriate pre-clinical pharmacokinetic and toxicology studies.AcknowledgementsThe authors thank healthy volunteers and patients for blood and/or tissue samples. The authors also thank the shared resources at Emory University, namely the Emory Integrated Genomics Core (EIGC), Emory Flow Cytometry Core (EFCC), Cancer Animal Models Shared Resource (CAMS), Cancer Tissue Pathology Core (CTP), Biostatistics Shared Resource (BSR) and Integrated Cellular Imaging Core (ICI), that provided services or instruments at subsidized cost to conduct some of the reported experiments. BioRender was used to make figure 4A and 5C. This work was supported in part by Katz Foundation funding and Emory School of Medicine Dean's Imagine, Innovate and Impact (I3) venture award to Edmund K. Waller and NIH R01 CA207619 awarded to Susan N. Thomas. Part of the cost for the immunohistochemistry staining of tissues was covered by Winship Cancer Institute Development Discovery and Therapeutic Program Pilot funding to Sruthi Ravindranathan.Abstract 748 Figure 1VIP is over-expressed by PDAC. (A) VIP mRNA expression levels in various solid malignancies, as obtained from TCGA. (B) Representative images of human PDAC tumor stained with antibodies to VIP or CK19, showing VIP co-expression in islets (black arrow) and cancer epithelial cells (red arrow). Levels of VIP in (C) culture supernatants collected from murine and human PDAC cell lines cultured for 24 hours (n=3 per cell line) were compared to culture supernatants from B16F10 and D4M melanoma cells; (D) plasma of mice bearing melanoma or PDAC tumors (n=5) compared to plasma of non-tumor-bearing mice; (E) plasma of PDAC patients (n=19) compared to that from healthy volunteers (n=26). Statistical differences in C and D were performed by ANOVA followed by Dunnett's post-test and in E were performed by student's t-test. Error bars show mean ± SEM. *pAbstract 748 Figure 2VIP-R antagonists improve responses to anti-PD-1. KPC.Luc, MT5 or Panc02 cells were subcutaneously implanted in immunocompetent C57BL/6 mice. About one week after tumor implantation, when the tumors were palpable, mice were randomized into treatment groups and treated with VIP-R antagonist and/or anti-PD-1 as described in methods. (A) KPC.Luc, MT5 and Panc02 tumor volumes as measured by Vernier calipers on day 22 after subcutaneous tumor implantation. (B) Kaplan-Meier survival plots of C57BL/6 mice with subcutaneously implanted KPC.Luc, MT5 or Panc02 tumors stratified by treatment. Kaplan-Meier survival plots of (C) C57BL/6 mice receiving monoclonal CD4 and/or CD8 monoclonal antibodies (D) CD4KO or (E) CD8KO mice compared to wild-type CD57BL/6 mice with subcutaneously implanted KPC.Luc tumors, stratified by treatment. Statistical differences in A were calculated by ANOVA followed by Dunnett's post-test. Solid line shows mean with in each treatment group. Statistical differences in B-E are calculated via Log-rank test. *pAbstract 748 Figure 3Enhanced T cell response with combination therapy. mRNA expression in T cells isolated from subcutaneous KPC.Luc tumors in C57BL/6 mice treated with ANT008 and/or anti-PD-1 (n=3 per treatment group), were analyzed via Nanostring metabolism panel. Volcano plot showing differential expression of genes in T cells from (A) ANT008+ isotype IgG (IgG) vs scrambled peptide (Scram) + isotype IgG, (B) scrambled peptide +anti-PD-1 vs scrambled peptide + isotype IgG and (C) ANT008+anti-PD-1 vs scrambled peptide + isotype IgG (n=3 mice per treatment group). Genes that are associated with TCR activation and co-stimulation and are at levels significantly higher when compared to Scram+ isotype IgG (FDRAbstract 748 Figure 4Increased T cell density with combination therapy. KPC.Luc cells were orthotopically implanted in the tail of the pancreas of C57BL/6 mice and treated with ANT008 and/or anti-PD-1 with n=9, 10, 8 and 11 in scrambled+IgG, ANT008+IgG, scrambled+anti-PD-1 and ANT008+anti-PD-1, respectively. (A) Schematic showing orthotopic implantation of KPC.Luc cells and treatment strategy with ANT008 and/or anti-PD-1. (B) Waterfall plot showing % change in tumor flux on day 22 relative to day 7 prior to start of treatment. (C) Total flux as measured by IVIS bioluminescent imaging in the different treatment groups. Cross symbol represents mice that were euthanized before day 25 due to ulceration of the tumor and circle symbol represent mouse that were imaged on day 26 via MRI imaging shown in supplementary figure S5. (D) Bar graph showing weight of pancreas on day 25 when the mice were euthanized. 'Star' shaped data points indicate tumor free mice and dotted horizontal line represents the average weight of healthy pancreas from naïve mice. (E) Representative multiplex IHC images (right) showing pancreatic tumors stained for DAPI (blue), CD4 (yellow), CD8 (red) and Ki67 (cyan) and trichrome staining (left) with black arrows showing blue collagen stain in the tissue. XY plot showing the correlation between number of (F) CD4+ or (G) CD8+ T cells/mm2; and (H) Ki67+ CD4+ or (I) Ki67+ CD8+ T cells/mm2 with weight of the pancreas with n=4 to 6 mice per group. P values in panel D were calculated using student ANOVA followed by Dunnett's post hoc test (comparing each treatment group with Scram+IgG). Error bars show mean ± SEM. *pAbstract 748 Figure 5Increased T cell homing with combination therapy. KPC.Luc tumors were subcutaneously implanted in C57BL/6 mice and treated with VIP-R antagonist and/or anti-PD-1 checkpoint therapy for 10 days after the tumors were palpable. Tumor draining lymph nodes were then analyzed for percentage of (A) CXCR4+CD69+ and (B) CXCR4+Ki67+ cells in CD4+ (left) and CD8+ (right) subsets of T cells. In a separate experiment, on day 15 after subcutaneous implantation of KPC.Luc tumors, GFP+ T cells from enhanced GFP transgenic mice (C57BL/6 background) were adoptively transferred (via tail vein injections) and treated with ANT308± aPD-1 for 3 days. (C) Schematic showing GFP+ T cell transfer and treatment strategy in mice with subcutaneous KPC.Luc tumors. (D) Representative Hoescht (blue for nucleus) stained tumor tissues from tumors of each treatment group. Two regions of interest (ROI) in ANT308+aPD-1 treated tumors are shown at higher magnification. Statistical differences in A and B were determined via repeated measures ANOVA and Dunnett's post-test with n=4–5 mice per group. *pReferencesSahin IH, et al. Immunotherapy in pancreatic ductal adenocarcinoma: an emerging entity? Ann Oncol 2017;28(12):2950–2961.Gonzalez-Rey E, Anderson P, Delgado M. Emerging roles of vasoactive intestinal peptide: a new approach for autoimmune therapy. Ann Rheum Dis 2007;66(Suppl 3):p. iii70–6.Anderson P, Gonzalez-Rey E. Vasoactive intestinal peptide induces cell cycle arrest and regulatory functions in human T cells at multiple levels. Mol Cell Biol 2010;30(10):2537–51.Li JM, et al. VIPhyb, an antagonist of vasoactive intestinal peptide receptor, enhances cellular antiviral immunity in murine cytomegalovirus infected mice. PLoS One 2013;8(5):e63381.Moody TW, et al., VIP receptor antagonists and chemotherapeutic drugs inhibit the growth of breast cancer cells. Breast Cancer Res Treat 2001;68(1):55–64.Moody TW, et al. A vasoactive-Intestinal-Peptide antagonist inhibits nonsmall cell lung-cancer growth. Proceedings of the National Academy of Sciences of the United States of America 1993;90(10):4345–4349.Zia H, et al. Breast cancer growth is inhibited by vasoactive intestinal peptide (VIP) hybrid, a synthetic VIP receptor antagonist. Cancer Res 1996;56(15):3486–9.Sena M, et al. High conservation of upstream regulatory sequences on the human and mouse vasoactive intestinal peptide (VIP) genes. DNA Seq 1994;5(1):25–9.Ethics ApprovalAll experimental procedures involving mice were approved by the Institutional Animal Care and Use Committee (IACUC) at Emory University. De-identified blood samples from consented patients with PDAC (IRB 00087397) or healthy volunteers (IRB 00046063) were obtained with approval from Institutional Review Boards.

A paucity of effector T cells within tumors renders pancreatic ductal adenocarcinoma (PDAC) resistant to immune checkpoint therapies. While several under-development approaches target immune-suppressive cells in the tumor microenvironment, there is less focus on improving T cell function. Here we show that inhibiting vasoactive intestinal peptide receptor (VIP-R) signaling enhances anti-tumor immunity in murine PDAC models. In silico data mining and immunohistochemistry analysis of primary tumors indicate overexpression of the neuropeptide vasoactive intestinal peptide (VIP) in human PDAC tumors. Elevated VIP levels are also present in PDAC patient plasma and supernatants of cultured PDAC cells. Furthermore, T cells up-regulate VIP receptors after activation, identifying the VIP signaling pathway as a potential target to enhance T cell function. In mouse PDAC models, VIP-R antagonist peptides synergize with anti-PD-1 antibody treatment in improving T cell recruitment into the tumors, activation of tumor-antigen-specific T cells, and inhibition of T cell exhaustion. In contrast to the limited single-agent activity of anti-PD1 antibodies or VIP-R antagonist peptides, combining both therapies eliminate tumors in up to 40% of animals. Furthermore, tumor-free mice resist tumor re-challenge, indicating anti-cancer immunological memory generation. VIP-R signaling thus represents a tumor-protective immune-modulatory pathway that is targetable in PDAC.

Anastomotic failure (AF) after cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) remains a dreaded complication. Whether specific factors, including anastomotic technique, are associated with AF is poorly understood.Patients who underwent CRS-HIPEC including at least one bowel resection between 2000 and 2017 from 12 academic institutions were reviewed to determine factors associated with AF (anastomotic leak or enteric fistula).Among 1020 patients who met the inclusion criteria, the median age was 55 years, 43.9% were male, and the most common histology was appendiceal neoplasm (62.3%). The median Peritoneal Cancer Index was 14, and 93.2% of the patients underwent CC0/1 resection. Overall, 82 of the patients (8%) experienced an AF, whereas 938 (92.0%) did not. In the multivariable analysis, the factors associated with AF included male gender (odds ratio [OR], 2.2; p 0.01), left-sided colorectal resection (OR 10.0; p = 0.03), and preoperative albumin (OR 1.8 per g/dL; p = 0.02).Technical factors such as method (stapled vs hand-sewn), timing of anastomosis, and chemotherapy regimen used were not associated with AF (all p 0.05). Anastomotic failure was associated with longer hospital stay (23 vs 10 days; p 0.01), higher complication rate (90% vs 59%; p 0.01), higher reoperation rate (41% vs 9%; p 0.01), more 30-day readmissions (59% vs 22%; p 0.01), greater 30-day mortality (9% vs 1%; p 0.01), and greater 90-day mortality (16% vs 8%; p = 0.02) as well as shorter median overall survival (25.6 vs 66.0 months; p 0.01).Among patients undergoing CRS-HIPEC, AF is independently associated with postoperative morbidity and worse long-term outcomes. Because patient- and tumor-related, but not technical, factors are associated with AF, operative technique may be individualized based on patient considerations and surgeon preference.

BACKGROUND: While sub-2 cm pancreatic neuroendocrine tumors (NETs) are often observed, small bowel-NETs undergo resection and lymphadenectomy regardless of size. Aim was to define the natural history of duodenal (D-NETs), determine the role of resection, and define the factors associated with overall survival (OS) after resection. METHODS: National Cancer Database (2004-2014) was queried for the patients with nonmetastatic/nonfunctional D-NETs. Local resection (LR): local excision/polypectomy/excisional biopsy. Anatomic resection (AR): radical surgery. Tumor size was divided into less than 1cm, 1 to 2 cm, and ≥2 cm. Propensity score weighting was used to create balanced resection and no-resection cohorts. The primary endpoint was OS. RESULTS: Among 5502 patient, the median age was 65 years. The median follow-up was 49 months. The median tumor size was 0.8 cm. Resection was performed in 72% (n = 3954; LR: 61%, AR: 39%). Lymph node (LN) resection was performed in 26% (43% had metastasis). A total of 74% had negative margins. Resection and no-resection cohorts were propensity score weighted for age/sex/race/Charlson-Deyo score/tumor grade (all independently associated with OS on multivariable analysis). Resection was associated with improved median OS compared to no resection in all sizes (2 cm: median not reached vs 90 months; all P < .01). Subset analysis of each resection size cohort demonstrated that neither type of resection, LN retrieval, LN positivity, or margin status was associated with OS (all P > .05). CONCLUSION: Patients with nonmetastatic and nonfunctional D-NETS should be considered for resection regardless of tumor size. Given the lack of prognostic value, the resection type and extent of LN retrieval should be tailored to each patient’s clinical picture and safety profile.

Objective:Despite heterogeneous biology, similar surveillance schemas are utilized after resection of all pancreatic neuroendocrine tumors (PanNETs). Given concerns regarding excess radiation exposure and financial burden, our aim was to develop a prognostic score for disease recurrence to guide individually tailored surveillance strategies.Methods:All patients with primary nonfunctioning, nonmetastatic well/moderately differentiated PanNETs who underwent curative-intent resection at 9-institutions from 2000 to 2016 were included (n = 1006). A Recurrence Risk Score (RRS) was developed from a randomly selected derivation cohort comprised of 67% of patients and verified on the validation-cohort comprised of the remaining 33%.Results:On multivariable analysis, patients within the derivation cohort (n = 681) with symptomatic tumors (jaundice, pain, bleeding), tumors >2cm, Ki67 >3%, and lymph node (LN) (+) disease had increased recurrence. Each factor was assigned a score based on their weighted odds ratio that formed a RRS of 0 to 10: symptomatic = 1, tumor >2cm = 2, Ki67 3% to 20% = 1, Ki67 >20% = 6, LN (+) = 1. Patients were grouped into low-(RRS = 0-2; n = 247), intermediate-(RRS = 3-5; n = 204), or high (RRS = 6-10; n = 9)-risk groups. At 24 months, 33% of high RRS recurred, whereas only 2% of low and 14% of intermediate RRS recurred. This persisted in the validation cohort (n = 325).Conclusions:This international, novel, internally validated RRS accurately stratifies recurrence-free survival for patients with resected PanNETs. Given their unique recurrence patterns, surveillance intervals of 12, 6, and 3 months are proposed for low, intermediate, and high RRS patients, respectively, to minimize radiation exposure and optimize cost/resource utilization.

Appendiceal adenocarcinoma with signet ring cells (SCA) is associated with worse overall survival (OS), and it is unclear whether cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) should be pursued in this patient population. We assessed the prognostic implications of signet ring cells in patients with appendiceal adenocarcinoma and peritoneal carcinomatosis undergoing CRS-HIPEC.The US HIPEC Collaborative, a 12-center, multi-institutional database of patients undergoing CRS-HIPEC, was reviewed for patients with SCA. Univariate and multivariate analyses were performed.Of 514 patients undergoing CRS-HIPEC for appendiceal adenocarcinoma, 125 (24%) had SCA. The SCA and non-SCA groups had similar baseline characteristics. SCA had worse OS compared with non-SCA (32.0 vs 91.4 months, p 0.001). In univariate analysis for only SCA cases, there was worse OS in patients with poorly differentiated tumors, positive lymph nodes, LVI, PCI 20, or incomplete cytoreduction (CC-2/3). However, multivariate analysis showed only positive lymph nodes (HR 1.14 [95% CI 1.00-1.31], p = 0.04), poor differentiation (5.60 [1.29-24.39], p = 0.02), and incomplete cytoreduction (4.90 [1.11-12.70], p = 0.03) were independently associated with decreased OS for SCA.While signet cells are a negative prognostic feature, they should not be a contraindication to CRS-HIPEC in patients with well-moderately differentiated tumors with negative lymph nodes, where complete cytoreduction can be achieved.

Objective Our aim was to compare outcomes in patients who underwent unplanned excisions (UE) of soft-tissue sarcomas (STS) against patients with planned excisions (PE). Methods The retrospective 7-institution US Sarcoma Collaborative database was used. Patients with curative-intent resection of truncal/extremity STS between 2000 and 2016 were included. Propensity score weighting analysis (PSWA) was performed. Endpoints were locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and disease-specific survival (DSS). Results One thousand five hundred and ninety-six patients were included. Eighty-two percent (n = 1315) underwent PE and 18% (n = 281) underwent UE. Compared with PE, patients with UE were younger with smaller tumors with similar tumor grade. Unmatched analysis revealed PE was associated with worse DMFS (hazard ratio [HR] 1.95, P = .009) and DSS (HR 1.78, P = .039), but not LRFS compared with UE. On PSWA, UE had earlier LRFS (3-year LRFS: 80.5% vs 89.8%, P = .039), but not DMFS or DSS. By grade, patients with high-grade tumors and UE had worse LRFS (1-year LRFS: 90% vs 94%, P = .015), but similar DMFS and DSS compared with PE. In low-grade patients, UE and PE had similar LRFS, DMFS, or DSS. Conclusions UE of STS is not associated with worse prognosis compared to PE, though UE is associated with earlier locoregional recurrence in patients with high-grade tumors. Multimodality therapy is needed to achieve improved outcomes in these patients.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are highly vascular neoplasms treated similarly, irrespective of tumor location. The expression of pro-angiogenic factors (STAT3, VEGF, and HIF-1α) and their association with adverse pathologic factors and disease recurrence following resection remains unclear. All patients with non-metastatic GEP-NETs who underwent curative-intent resection from 2000 to 2013 were included. Immunohistochemistry was performed for pro-angiogenic factors, Ki-67 index, and CD31 using tissue microarrays made in triplicate by a pathologist blinded to other clinicopathologic variables. Primary outcome was a 3-year recurrence-free survival (3-yrRFS); secondary outcomes were correlation of pro-angiogenic factors with Ki-67 index, adverse pathologic factors, and CD31 expression, a marker of microvascular density. Of 144 GEP-NETs resected, STAT3 expression was high in 12 (8%) and low in 132 (92%) pts. High STAT3 expression was associated with worse 3-yrRFS compared to low expression (55% vs 84%; p = 0.003). High VEGF expression had a 3-yrRFS of 76% vs 82% for low expression (p = 0.09). HIF-1α expression was not associated with RFS. Ki-67 ≥ 3% was associated with worse 3-yrRFS (≥ 3%: 51% vs median: 75% vs CD31 < median: 86%; p = 0.04). High STAT3 expressing tumors were more likely to have a Ki-67 ≥ 3% (42% vs 7%; p

The clinical relevance of primary tumor sidedness is not fully understood in colon cancer patients with peritoneal metastasis treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). This was a retrospective cohort study of a multi-institutional database of patients with peritoneal surface malignancy at 12 participating high-volume academic centers from the US HIPEC Collaborative. Overall, 336 patients with colon primary tumors who underwent curative-intent CRS with or without HIPEC were identified; 179 (53.3%) patients had right-sided primary tumors and 157 (46.7%) had left-sided primary tumors. Patients with right-sided tumors were more likely to be older, male, have higher Peritoneal Cancer Index (PCI), and have a perforated primary tumor, but were less likely to have extraperitoneal disease. Patients with complete cytoreduction (CC-0/1) had a median disease-free survival (DFS) of 11.5 months (95% confidence interval [CI] 7.6–15.3) versus 13.1 months (95% CI 9.5–16.8) [p = 0.158] and median overall survival (OS) of 30 months (95% CI 23.5–36.6) versus 45.4 months (95% CI 35.9–54.8) [p = 0.028] for right- and left-sided tumors; respectively. Multivariate analysis revealed that right-sided primary tumor was an independent predictor of worse DFS (hazard ratio [HR] 1.75, 95% CI 1.19–2.56; p =0.004) and OS (HR 1.72, 95% CI 1.09–2.73; p = 0.020). Right-sided primary tumor was an independent predictor of worse DFS and OS. Relevant clinicopathologic criteria, such as tumor sidedness and PCI, should be considered in patient selection for CRS with or without HIPEC, and guide stratification for clinical trials.

Minimizing perioperative fluid administration is a key component of enhanced recovery after surgery protocols (ERAS). Acute kidney injury (AKI) is a major cause of morbidity and mortality in hospitalized patients. Our aim was to assess the association of ERAS with the incidence and severity of AKI in patients undergoing elective colorectal surgery. In this single-study retrospective review, patients undergoing colorectal surgery from 2013 to 2017 were included. Primary endpoint was postoperative AKI. Secondary outcomes were hospital length of stay (LOS) and 30-day readmission. Baseline demographics and procedure types were similar between both groups. AKI was higher in the ERAS versus non-ERAS group (23 vs 9%; P = 0.002). Factors associated with increased risk of AKI on univariate regression included presence of preoperative cardiovascular risk factors (hazard ratio (HR) 3.5; 95% CI 1.3–9.7; P < 0.01), more complex colorectal operations (HR 5.1; 95% CI 1.6–16.1; P < 0.01), and management with an ERAS pathway (HR 2.9; 95% CI 1.5–5.8; P < 0.01). On multi-variable analysis, ERAS remained a significant risk factor for developing AKI (HR 3.44; 95% CI 1.5–7.7; P < 0.01). ERAS patients had a shorter hospital LOS (3.9 vs 5.9 days, P < 00.1) compared with non-ERAS patients, with no difference in 30-day readmission rates (11.5 vs 10.7%; P = 0.98). Although the incidence of AKI is higher in patients treated with ERAS protocols, the majority represent minor elevations in baseline serum creatinine and did not affect the reduction in hospital LOS associated with ERAS. Given the potential association of AKI, however, with increased long-term morbidity and mortality, ERAS protocols should be optimized to prevent postoperative AKI.

BACKGROUND The three-delays model describes delays in seeking, reaching, and receiving care for vulnerable populations needing treatment. The dominant delay for patients with gastric adenocarcinoma (GAC) is unknown. We aimed to define patients with GAC who reached and received care at our regional safety-net hospital (Grady Memorial Hospital [GMH]) and our neighboring quaternary referral hospital (Emory University Hospital [EUH]). METHODS Clinicopathologic data from National Cancer Database (NCDB) participating academic centers were compared with GMH from 2004 to 2014. Outcomes of patients undergoing surgery at GMH were compared to those at EUH. RESULTS At presentation, compared to NCDB centers (n = 69 662), GMH patients (n = 154) were more often black (85.1 vs 17.2%; P

BackgroundPostoperative complications (POCs) are associated with worse oncologic outcomes in various cancer histologies. The impact of POCs on thesurvivalof patients withappendiceal or colorectal cancer after cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) is unknown.MethodsThe US HIPEC Collaborative (2000-2017) was reviewed for patients who underwent CCR0/1 CRS/HIPEC for appendiceal/colorectal cancer. The analysis was stratified by noninvasive appendiceal neoplasm versus invasive appendiceal/colorectal adenocarcinoma. The POCs were grouped into infectious, cardiopulmonary, thromboembolic, and intestinal dysmotility. The primary outcomes were overall survival (OS) and recurrence-free survival (RFS).ResultsOf the 1304 patients, 33% had noninvasive appendiceal neoplasm (n = 426), and 67% had invasive appendiceal/colorectal adenocarcinoma (n = 878). In the noninvasive appendiceal cohort, POCs were identified in 55% of the patients (n = 233). The 3-year OS and RFS did not differ between the patients who experienced a complication and those who did not (OS, 94% vs 94%, p = 0.26; RFS, 68% vs 60%, p = 0.15). In the invasive appendiceal/colorectal adenocarcinoma cohort, however, POCs (63%; n = 555) were associated with decreased 3-year OS (59% vs 74%; p

Background Pancreatic ductal adenocarcinoma (PDAC), the fourth leading cause of cancer related death in the U.S, has a 5-year survival rate of only 10%.1 The paucity of T cells in the immune privileged tumor microenvironment (TME) is a major limitation in developing an effective immunotherapy against PDAC.2The cancer genome atlas (TCGA) shows that human PDAC tumors express high levels of vasoactive intestinal peptide (VIP), an immunosuppressive neuropeptide (figure 1A), that inhibits effector T cell responses.3 4 We hypothesized that paracrine secretion of VIP in the TME is a targetable mediator of immune paralysis in PDAC, and that pharmacological inhibition of VIP receptor signaling could enhance anti-tumor responses in PDAC. Methods VIP levels in plasma or cell culture supernatant was determined via VIP-specific enzyme immunoassay. Luciferase transfected KPC (KPC.luc) cells were injected subcutaneously or orthotopically into the pancreas of C57BL/6, CD4KO, or CD8KO mice from Jackson Laboratories. C57BL/6 mice T cell subsets in were depleted post tumor implantation with anti-CD4 and/or anti-CD8 antibodies. Tumor-bearing mice were treated daily with ANT008, a novel VIP receptor antagonist peptide, and/or anti-PD1 monoclonal antibody (MoAb) for 10 days, starting 7-10 days after implantation. T cells isolated from peripheral blood of PDAC patients were expanded 9 days ex vivo in anti-CD3 MoAb coated plates with 30U/ml IL-2 and either control peptide (scrambled VIP sequence) or ANT008. Survival by VIP and VIP receptor expression from the TCGA was clinically correlated. Results Increased human and mouse PDAC expression correlates with elevated blood levels (figure 1). While the PDAC cancer cell lines express VIP receptors, ANT008 does not have direct cytotoxic effect on cell growth in vitro (figure 2). However, in orthotopic KPC model, treatment with ANT008 & anti-PD-1 significantly decreased tumor growth rate and burden (figure 3) while increasing the intratumoral levels of CD4 and CD8 proliferating T cells (figure 4) via a T cell dependent mechanism (figure 5). Additionally, in ex vivo cultures of T cells isolated from PDAC patients, ANT008 improved the effector properties of T cells via decreasing expression levels of co-inhibitory molecules and decreasing frequency of regulatory T cells (figure 6). Clinically, VIPR1 receptor expression, but not VIP, provides a survival benefit (figure 7). Conclusions VIP is a targetable mechanism of immune escape in PDAC. Inhibiting VIP receptor signaling improves effector properties of T cells and synergistically improves the anti-tumor response to checkpoint inhibitors in mouse PDAC models. References Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin2020;70(1):7-30. Sahin IH, et al. Immunotherapy in pancreatic ductal adenocarcinoma: an emerging entity?Ann Oncol 2017;28(12):2950-2961. Gonzalez-Rey E, Anderson P, Delgado M. Emerging roles of vasoactive intestinal peptide: a new approach for autoimmune therapy. Ann Rheum Dis 2007;66(Suppl 3):iii70-6. Anderson P, Gonzalez-Rey E. Vasoactive intestinal peptide induces cell cycle arrest and regulatory functions in human T cells at multiple levels. Mol Cell Biol 2010;30(10):2537-51.

Background Both pancreatic ductal adenocarcinoma (PDAC) and metastatic colorectal cancer (mCRC) have yet to widely benefit from T cell-targeted immunotherapy and have universally poor prognoses. Thus, enhancing the activity of immunotherapy is a high priority. Our laboratory recently reported that heat shock protein-90 (Hsp90) inhibition enhances the efficacy of PD-1 blockade in preclinical models of PDAC.1 Mechanistically, Hsp90 inhibitors can limit activation of cancer associated fibroblasts (CAF) and promote infiltration of T cells when combined with PD-1 blockade. Based on these data, we are conducting a Phase Ib/II clinical trial to evaluate the combination of XL888 (Hsp90 inhibitor) and pembrolizumab in patients with metastatic pancreatic and colorectal cancers. We hypothesize that this combination will be safe and elicit pronounced microenvironmental changes, leading to enhanced efficacy. Methods During the phase II portion, PDAC or mCRC patients (n=16 each) were randomized to receive a three week lead in with either pembrolizumab or pembrolizumab and XL888. Paired biopsies were obtained at baseline and at week two on treatment. A comprehensive panel of immunologic correlatives studies is being conducted to examine treatment-induced alterations in the tumor microenvironment and peripheral blood. Results As of August 23rd, 2020, paired liver biopsy specimens from sites of metastasis have been successfully obtained from a total of 15 patients (n=7 PDAC and n=8 mCRC). These specimens underwent single cell mass cytometry (CyTOF) analysis to assess immunophenotypic markers of T and myeloid cells. Using this approach, we have generated a comprehensive view of the immune landscape at baseline and following treatment. These data will be validated by immunohistochemical analysis of FFPE biopsy specimens obtained in parallel at the time of CyTOF analysis. In addition to these correlative studies, using immortalized and primary CAF from PDAC patients, we have shown XL888 dampens production of IL-6 and other cytokines in vitro. The impact of XL888 on systemic cytokines and chemokines (n=48 total) in the peripheral blood from patients enrolled in the clinical trial is therefore also being assessed. Conclusions Our correlative analysis of paired biopsies and peripheral blood from a novel clinical trial of XL888 and pembrolizumab will allow for further mechanistic insight into treatment-induced immune modulation. These data will also serve to validate whether alterations of CAF phenotype, cytokine and chemokine release, and T cell infiltration observed preclinically are mirrored in patients. Trial Registration This clinical trial is underway and registered with the ID NCT03095781. Ethics Approval The study was approved by Emory University’s Ethics Board, approval IRB00087397. Reference Zhang Y, Ware MB, Zaidi M, Ruggieri AN, Olson B, Komar H, Farren MR, Nagaraju GP, Zhang C, Chen Z, Sarmiento J, Ahmed R, Maithel SK, El-Rayes BF, Lesinski GB. Heat shock protein-90 inhibition alters activation of pancreatic stellate cells and enhances the efficacy of PD-1 blockade in pancreatic cancer. Molecular Cancer Therapeutics 2020.

BACKGROUND Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis can be performed in two ways: Open or closed abdominal technique. AIM To evaluate the impact of HIPEC method on post-operative and long-term survival outcomes. METHODS Patients undergoing CRS with HIPEC from 2000-2017 were identified in the United States HIPEC collaborative database. Post-operative, recurrence, and overall survival outcomes were compared between those who received open vs closed HIPEC. RESULTS Of the 1812 patients undergoing curative-intent CRS and HIPEC, 372 (21%) patients underwent open HIPEC and 1440 (79%) underwent closed HIPEC. There was no difference in re-operation or severe complications between the two groups. Closed HIPEC had higher rates of 90-d readmission while open HIPEC had a higher rate of 90-d mortalities. On multi-variable analysis, closed HIPEC technique was not a significant predictor for overall survival (hazards ratio: 0.75, 95% confidence interval: 0.51-1.10, P = 0.14) or recurrence-free survival (hazards ratio: 1.39, 95% confidence interval: 1.00-1.93, P = 0.05) in the entire cohort. These findings remained consistent in the appendiceal and the colorectal subgroups. CONCLUSION In this multi-institutional analysis, the HIPEC method was not independently associated with relevant post-operative or long-term outcomes. HIPEC technique may be left to the discretion of the operating surgeon.

Prognostication based on preoperative clinical factors is lacking in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). This study aims to determine the value of preoperative tumor markers as predictors of progression-free survival (PFS) and overall survival (OS) for patients with peritoneal carcinomatosis from a primary mucinous adenocarcinoma of the appendix (MACA). We queried the United States HIPEC Collaborative, a database of patients with peritoneal carcinomatosis treated with CRS/HIPEC at twelve institutions between 2000 and 2017, identifying 409 patients with MACA. Multivariate analysis was used to identify independent predictors of disease progression. Subgroup analysis was conducted to evaluate the impact of tumor grade on the predictive value of tumor markers. CA19-9 [HR 2.44, CI 1.2–3.4] emerged as an independent predictor of PFS while CEA [HR 4.98, CI 1.06–23.46] was independently predictive of OS (p

While recent studies have introduced the composite measure of a textbook outcome (TO) for measuring postoperative outcomes, the incidence of a TO has not been characterized among patients undergoing cytoreductive surgery (CRS) for peritoneal surface malignancies (PSM).All patients who underwent CRS ± hyperthermic intraperitoneal chemotherapy (HIPEC) between 1999 and 2017 from 12 institutions were included. A TO was defined as the absence of any of the following criteria: completeness of cytoreduction1, reoperation within 90-days, readmission within 90-days, mortality within 90-days, any grade ≥2 complication, hospital stay75th percentile, and non-home discharge.Among 1904 patients who underwent CRS, only 30.9% achieved a TO while 69.1% failed to achieve a TO most commonly because of postoperative complications. On multivariable analysis, factors associated with achieving a TO were age65 years (OR: 1.5), albumin ≥3.5 g/dl (OR: 5.7), receipt of HIPEC (OR: 4.5), PCI ≤14 (OR: 2.2), intravenous fluid volume ≤10,000 ml (OR: 2.1), blood loss ≤1000 ml (OR: 4.2) and operative time7 h (OR: 1.9); while receipt of neoadjuvant therapy (OR: 0.7) and liver resection (OR: 0.4) were associated with not achieving a TO (all p 0.05). TO was associated with improved overall survival (median 159 months vs 56 months, p 0.01) even after controlling for confounders on Cox regression (hazard ratio: 2.5, p 0.01).Among patients undergoing CRS ± HIPEC for PSM, failure to achieve a TO is common and independently associated with worse overall survival.

Background BTC is an aggressive disease exacerbated by inflammation and immune suppression. Expansion of immunosuppressive cells occurs in biliary tract cancer (BTC), yet the role of BTC-derived cytokines in this process is unclear. Methods Activated signalling pathways and cytokine production were evaluated in a panel of human BTC cell lines. Human peripheral blood mononuclear cells (PBMCs) were cultured with BTC supernatants, with and without cytokine neutralising antibodies, and analysed by flow cytometry or immunoblot. A human BTC tissue microarray (TMA, n = 69) was stained for IL-6, GM-CSF, and CD33+S100a9+ cells and correlated with clinical outcomes. Results Immunomodulatory factors (IL-6, GM-CSF, MCP-1) were present in BTC supernatants. BTC supernatants expanded CD33dimCD11b+HLA-DRlow/− myeloid-derived suppressor cells (MDSCs) from human PBMCs. Neutralisation of IL-6 and GM-CSF in BTC supernatants inhibited activation of STAT3/5, respectively, in PBMCs, with heterogeneous effects on MDSC expansion in vitro. Staining of a BTC TMA revealed a positive correlation between IL-6 and GM-CSF, with each cytokine and more CD33+S100a9+ cells. Increased CD33+S100a9+ staining positively correlated with higher tumour grade, differentiation and the presence of satellite lesions. Conclusion BTC-derived factors promote suppressive myeloid cell expansion, and higher numbers of CD33+S100a9+ cells in resectable BTC tumours correlates with more aggressive disease.

BackgroundWhile parenchymal hepatic metastases were previously considered a contraindication to cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC), liver resection (LR) is increasingly performed with CRS/HIPEC.MethodsPatients from the US HIPEC Collaborative (2000-2017) with invasive appendiceal or colorectal adenocarcinoma undergoing primary, curative intent CRS/HIPEC with CC0-1 resection were included. LR was defined as a formal parenchymal resection. Primary endpoints were postoperative complications and overall survival (OS).ResultsA total of 658 patients were included. About 83 (15%) underwent LR of colorectal (58%) or invasive appendiceal (42%) metastases. LR patients had more complications (81% vs. 60%; p = .001), greater number of complications (2.3 vs. 1.5; p

BACKGROUND Variations in care have been demonstrated both within and among institutions in many clinical settings. By standardizing perioperative practices, Enhanced Recovery After Surgery (ERAS) pathways reduce variation in perioperative care. We sought to characterize the variation in cytoreductive surgery (CRS)/heated intraperitoneal chemotherapy (HIPEC) perioperative practices among experienced US medical centers. METHODS Data from the US HIPEC Collaborative represents a retrospective multi-institutional cohort study of CRS and CRS/HIPEC procedures performed from 12 major academic institutions. Patient characteristics and perioperative practices were reported and compared. Institutional variation was analyzed using hierarchical mixed-effects linear (continuous outcomes) or logistic (binary outcomes) regression models. RESULTS A total of 2372 operations were included. CRS/HIPEC was performed most commonly for appendiceal histologies (64.2%). The rate of complications (overall 56.3%, range: 31.8-70.9) and readmissions (overall 20.6%, range: 8.9-33.3) varied by institution (P

Pancreatic ductal adenocarcinoma (PDAC) is exceptionally resistant to immune checkpoint inhibition (ICI). We previously reported that elevated systemic interleukin-6 (IL-6) and increased numbers of T cells positive for circulating cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) correlate with worse overall survival in patients with PDAC. We postulated that combined blockade of IL-6 and CTLA-4 would significantly enhance anti-tumor immune responses to PDAC. Dual blockade of IL-6 and CTLA-4 in immune competent mice bearing subcutaneously injected pancreatic tumors significantly inhibited tumor growth, accompanied by overwhelming T cell infiltration. Therapeutic efficacy was confirmed in an orthotopic murine model of pancreatic cancer and T cell depletion studies unveiled a unique dependence on CD4+ T cells for anti-tumor activity of dual IL-6 and CTLA-4 blockade. In vitro studies utilizing T cells from a TRP-1 transgenic mouse as an antigen-specific model system demonstrate this combination therapy elicits increased IFN-γ production by activated CD4+ T cells. Additionally, IFN-γ stimulation of pancreatic tumor cells in vitro profoundly increased tumor cell production of CXCR3 specific chemokines (CXCL10 and CXCL9). Further studies blocking CXCR3 in the presence of combined IL-6 and CTLA-4 blockade prevented orthotopic tumor regression, demonstrating a dependence on the CXCR3 axis for anti-tumor efficacy. We also found combination therapy increased intratumoral CD4+ T cells and elicited systemic changes in T-helper subsets. These data represent the first report of IL-6 and CTLA-4 blockade as a means to regress pancreatic tumors with defined operative mechanisms of efficacy. Given these results, this therapeutic combination has potential for immediate clinical translation.One Sentence SummaryBlockade of interleukin-6 in pancreatic cancer enhances CTLA-4 immune checkpoint inhibition to regress tumors in a CD4+ T cell and CXCR3-dependent manner.

Pancreatic ductal adenocarcinoma (PDAC) has dismal 5-year survival (

Pancreatic ductal adenocarcinoma (PDAC) is unresponsive to immune checkpoint therapy largely due to a paucity of T cells within the tumor microenvironment (TME) and abundant immunosuppressive signaling pathways. In this study we show that human PDAC tumors over-express vasoactive intestinal peptide (VIP), an immunosuppressive neuropeptide that suppresses T cell effector properties and promotes the generation of regulatory T cells (Tregs). Therefore, we treated tumor-bearing mice with VIP receptor peptide antagonists and measured T cell homing, activation, and anti-tumor responses in preclinical murine models of PDAC. Pharmacological inhibition of VIP receptor (VIP-R) signaling using daily subcutaneous injections of peptide antagonists had no discernable toxicity in healthy and tumor-bearing mice. Treatment with VIP-R antagonists in combination with anti-PD-1 checkpoint blockade significantly decreased tumor burden, and improved survival in subcutaneous and orthotopic murine PDAC models. Combination therapy significantly enhanced T cell activation and proliferation and decreased frequencies of Tregs within the TME. Anti-tumor responses were T cell dependent, as the combination therapy failed to improve survival in CD4 or CD8 deficient mice using knock-out strains and antibody depletion. Furthermore, combination therapy significantly increased frequencies of tumor specific T cells (measured with a tetramer reagent) and provided protective immunity against tumor rechallenge. Combination therapy led to significant increases in the infiltration of adoptively transferred GFP+ T cells into PDAC tumors and decreased CXCR4 expression levels on T cells. Encouragingly, peptide-based VIP-R antagonists enhanced the in vitro activation of human T cells isolated from peripheral blood of PDAC patients. Human T cells cultured with VIP-R antagonists had increased proliferation, activation, and decreased proportions of T regs and exhausted T cells co-expressing PD-1, Tim-3 and Lag-3. Taken together, our findings show that VIP is a targetable mechanism of immune escape in PDAC. Inhibiting VIP receptor signaling improves T cell effector properties and synergistically improves anti-tumor responses to checkpoint inhibitors in mouse PDAC models. Additionally, as the VIP sequence is identical between human and mice, and since VIP-R antagonists have similar effects on human and murine T cells in culture, clinical translation is highly feasible. Citation Format: Sruthi Ravindranathan, Passang Tenzin, Jian Ming Li, Rohan Dhamsania, Michael Ware, Mohammad Zaidi, Shuhua Wang, Jingru Zhu, Maria Cardenas, Yuan Liu, Gaurav Joshi, Sanjeev Gumber, Brian Robinson, Anish Sen-Majumdar, Shanmuganathan Chandrakasan, Haydn Kissick, Alan Frey, Susan Thomas, Bassel El-Rayes, Gregory Lesinski, Edmund K. Waller. Inhibiting vasoactive intestinal peptide receptor signaling elicits T cell dependent anti-tumor response of pancreatic ductal adenocarcinoma to immune checkpoint therapy [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-072.

BackgroundPancreatic ductal adenocarcinoma (PDAC) has yet to widely benefit from T cell-targeted immunotherapy and displays universally poor prognosis. Thus, enhancing the activity of immunotherapy is a high priority. Our laboratory recently reported that heat shock protein-90 (Hsp90) inhibition enhances the efficacy of PD-1 blockade in murine models of PDAC (Zhang Y. et al., Mol Cancer Ther, 2020). Hsp90 inhibitors can limit activation of cancer associated fibroblasts (CAF) and promote infiltration of T cells when combined with PD-1 blockade in preclinical systems.MethodsBased on these data, we are conducting a Phase Ib/II clinical trial to evaluate the combination of XL888 (Hsp90 inhibitor) and pembrolizumab in patients with metastatic pancreatic cancer. We hypothesize that this combination will be safe and elicit pronounced microenvironmental changes, leading to enhanced efficacy of checkpoint blockade in a tumor type that is otherwise refractory to this approach. During the phase II portion patients were randomized to receive a three week lead in with either pembrolizumab or pembrolizumab and XL888. Paired biopsies and blood samples were obtained at baseline and at week two on treatment and CyTOF was used to assess changes in circulating and tumor infiltrating immune populations. Further, CyTOF profiling of circulating immune cells was performed to assess impacts of XL888 on over thirty phenotypically defined immune populations (figure 1).ResultsAs of June 2021, paired liver biopsy specimens from sites of metastasis have been successfully obtained from a total of 8 patients and paired peripheral blood mononuclear cell samples have been analyzed in 24 patients. Our CyTOF analysis illustrated a surprising increase in myeloid cell populations within the tumor following treatment. Analysis of circulating immune cells illustrated a decrease in natural killer cells and Th17 populations following treatment while naïve B cells were increased. These data will be validated by immunohistochemical analysis of FFPE biopsy specimens obtained in parallel at the time of CyTOF analysis. The impact of XL888 on systemic cytokines and chemokines (n=48 total) in the peripheral blood from patients enrolled in the clinical trial is therefore being assessed as a potential mechanism to explain this observation.Abstract 403 Figure 1Clinical trial and correlative analysis schema. Patients were randomized to receive either pembrolizumab alone or in combination with the HSP90 inhibitor XL888 for a two week cycle prior to crossover to the combination arm. Plasma, peripheral blood mononuclear cells (PBMC), and biopsies were assayed to evaluate immunomodulatory effects of the therapies.ConclusionsClinical data from this trial indicates that this combination is safe in patients. As clinical data matures, changes in soluble and cellular biomarkers will be correlated with response to elucidate mechanisms of response or resistance to this combination therapy.Trial RegistrationThis clinical trial is underway and registered with the ID NCT03095781Ethics ApprovalThe study was approved by Emory University’s Ethics Board, approval IRB00087397.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

BACKGROUND: The path of the biliopancreatic limb for reconstruction of the pancreatic anastomosis during pancreatoduodenectomy for pancreatic ductal adenocarcinoma can be trans-mesocolon or through the ligament of Treitz. Even after curative intent pancreatoduodenectomy, incidence of recurrence in the surgical bed remains high and may lead to obstruction of the biliopancreatic limb. However, the association between path of jejunal limb and incidence of biliopancreatic limb obstruction has not been studied. Primary aim was to determine whether path of reconstruction predisposes to biliopancreatic limb obstruction in the setting of local recurrence. METHODS: Patients who underwent pancreatoduodenectomy for pancreatic ductal adenocarcinoma (2008–2018) from a single institution were identified. As disease recurrence is the predominant cause of biliopancreatic limb obstruction, analysis was limited to patients with known recurrence at date of last follow-up. Given a known median time to recurrence of 8 to 10 months after resection for pancreatic ductal adenocarcinoma, analysis was further limited to patients with at least 8 months of follow-up. Primary outcome was incidence of biliopancreatic limb obstruction. RESULTS: Among the 517 patients identified, 182 were included. Median age was 65 years; 51% were male. Median follow-up was 22 months. Path of reconstruction was trans-mesocolon in 35% (n = 64) and through ligament of Treitz in 65% (n = 118). There was no difference between the two groups in clinicopathologic factors including age, tumor differentiation, grade, T-stage, N-stage, LVI, or PNI (all p > 0.05). Importantly, there was no difference in retroperitoneal margin positivity between groups (transmesocolon 8% vs ligament of Treitz 10%, p = 0.79). Both groups had similar post-operative outcomes including median length-of-stay (trans-mesocolon 6 days vs ligament of Treitz 6 days, p = 0.89) and median follow-up (trans-mesocolon 21 months vs ligament of Treitz 23 months, p = 0.68). Biliopancreatic limb obstruction was detected in 8% (n = 14) of which 14% (n = 2) were in the trans-mesocolon group and 86% (n = 12) were in the ligament of the Treitz group. Therefore, incidence of biliopancreatic limb obstruction was 3.1% in the trans-mesocolon group and 10.4% in the ligament of the Treitz group resulting in an absolute risk increase of 7.3%, risk ratio of 3.4, and relative risk increase of 2.3. There was no difference in median time to biliopancreatic limb obstruction between the groups (17.6 months vs 18.5 months, p = 1.0). Biliopancreatic limb obstruction was caused by locally recurrent pancreatic ductal adenocarcinoma in 93% (n = 13) and kinking of the duodenojejunal anastomosis in 7% (n = 1). Intervention was performed in 71% (n = 10) and included surgical bypass in 29% (n = 4), percutaneous drain in 21% (n = 3), and endoscopic/surgical decompression in 21% (n = 3). CONCLUSION: Biliopancreatic limb obstruction is a known complication after pancreatoduodenectomy for pancreatic ductal adenocarcinoma due to local recurrence in the surgical bed. This study shows that path of jejunal limb through the ligament of Treitz may be associated with a higher incidence of biliopancreatic limb obstruction compared with trans-mesocolon as the position of the biliopancreatic limb in the surgical bed may be more predisposed to obstruction after local recurrence. Larger studies are needed; however, given this potential risk of subsequent obstruction, these data suggest that the reconstruction paths may not be equivalent when performing pancreatoduodenectomy for pancreatic ductal adenocarcinoma.

Background Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is an increasingly utilized strategy for patients with peritoneal surface malignancies (PSM). Methods The US HIPEC Collaborative was retrospectively reviewed to compare the indications and perioperative outcomes of patients who underwent CRS ± HIPEC between 2000 and 2012 (P1) versus 2013–2017 (P2). Results Among 2,364 patients, 39% were from P1 and 61% from P2. The most common primary site was appendiceal (64%) while the median PCI was 13 and most patients had CCR 0 (60%) or 1 (25%). Over time, median estimated blood loss, need for transfusion, and length of hospital stay decreased. While the incidence of any (55% vs. 57%; p = 0.426) and Clavien III/IV complications did not change over time, there was a decrease in 90-day mortality (5% vs. 3%; p = 0.045). Conclusion CRS-HIPEC is increasingly performed for PSM at high-volume centers. Despite improvements in some perioperative outcomes and a reduction in postoperative mortality, morbidity rates remain high.

The role of neoadjuvant chemotherapy (NCT) for high-risk soft tissue sarcoma (STS) is questioned. This study aimed to define which patients may experience a survival advantage with NCT. All the patients from the U.S. Sarcoma Collaborative database (2000–2016) who underwent curative-intent resection of high-grade, primary truncal/extremity STS size 5 cm or larger were included in this study. The primary end points were recurrence-free survival (RFS) and overall survival (OS). Of the 4153 patients, 770 were included in the study. The median tumor size was 10 cm, and 669 of the patients (87%) had extremity tumors. The most common histology was undifferentiated pleomorphic sarcoma (UPS), found in 42% of the patients. Of the 770 patients, 216 (28%) received NCT. The patients who received NCT had deeper, larger tumors (p

Management of2-cm pancreatic neuroendocrine tumors is controversial. Although often indolent, the oncologic heterogeneity of these tumors particularly related to lymph node metastases poses challenges when deciding between resection versus surveillance.We analyzed all patients who underwent resection of primary nonfunctional2-cm with curative-intent at 8 institutions of the US Neuroendocrine Tumor Study Group from 2000 to 2016. Pancreatic neuroendocrine tumors with poor differentiation and Ki-6720% were excluded. Our primary aim was to create a lymph node risk score that predicted lymph node metastases accurately for2-cm pancreatic neuroendocrine tumors, utilizing readily available preoperative data.Of 695 patients with resected pancreatic neuroendocrine tumors, 309 were2 cm. Of these small pancreatic neuroendocrine tumors, 25% were proximal (head/uncinate), 23% had a Ki-673%, and only 8% were moderately differentiated. Also, only 9% of all2-cm pancreatic neuroendocrine tumors were lymph node (+). Indeed lymph node positivity was associated with worse 5-year recurrence-free survival compared with lymph node (-) disease (80% vs 96%; P = .007). Factors known preoperatively to be associated with lymph node metastases were proximal location (odds ratio 4.0; P = .002) and Ki-67 ≥3% (odds ratio 2.7; P = .05). Moderate differentiation was not associated with lymph node (+) disease. Location and Ki-67 were assigned a value weighted by their odds ratio: (distal= 1, proximal= 4, and Ki-673% = 1 and Ki-67 ≥ 3% = 3), which formed a lymph node risk score ranging 1-7. Scores were categorized into low (1-2), intermediate (3-4), and high (5-7) risk groups. Incidence of lymph node metastases increased progressively based on risk group, with low = 3.2%, intermediate = 13.8%, and high = 20.5%. Only 3.4% of pancreatic neuroendocrine tumors with a Ki-673% in the distal pancreas were lymph node (+) compared with 21.4% of pancreatic neuroendocrine tumors with a Ki-67 ≥ 3% in the head/uncinate.This simple and novel lymph node risk score utilizes readily available preoperative factors (tumor location and Ki-67) to stratify risk of lymph node metastases accurately s for2-cm pancreatic neuroendocrine tumors and may help guide management strategy.

BACKGROUND: Both minimally invasive surgery (MIS) and open approaches for distal pancreatectomy are acceptable. MIS options include total laparoscopic/robotic (TLR) and hand-assist laparoscopy (HAL). When considering safety profile and specimen quality, the optimal approach is unknown. METHODS: Patients who underwent distal pancreatectomy from 2010–2018 at two major academic institutions were included. Converted procedures were categorized into final approach. Ninety-day perioperative/pathologic outcomes of MIS and open were compared. Subset analyses between TLR vs HAL and HAL vs open were performed. Intent-to-treat analysis was performed. RESULTS: Among 1006 patients, resection was performed by MIS in 35% (n = 352), open in 65%(n = 654). MIS had similar patient comorbidity profile as open but had increased operative time (183 vs 162 min; p < 0.01), lower estimated-blood-loss (EBL; 131 vs 341 mL; p < 0.01), fewer intraoperative blood transfusions (1.4 vs 5%; p < 0.01), shorter LOS (5.2 vs 7.2 days; p < 0.01). Tumor size was smaller (3.2 vs 4.4 cm; p < 0.01) with lower lymph node (LN) yield (14 vs 16; p < 0.01). When comparing HAL (n = 109) to TLR (n = 243), despite increased prior abdominal operations (60 vs 43%; p = 0.008), HAL had shorter operative time (167 vs 191 min; p < 0.01), similar length-of-stay (LOS; 5.4 vs 5.1 days; p = 0.27), and readmission rate (15 vs 13%; p = 0.47). When comparing HAL to open, the advantages of TLR approach persisted including lower EBL (171 vs 342 mL; p < 0.01), and shorter LOS (5.4 vs 7.2 days; p < 0.01). Although HAL had smaller tumors, it had a similar LN yield (16 vs 16; p = 0.80), and higher R0-rate (97 vs 83%; p < 0.01). CONCLUSION: Hand-assist laparoscopy is safe and feasible for distal pancreatectomy as operative time, complication profile, lymph node yield, and R0-rates are similar to open procedures, while maintaining the associated the advantages of a total laparoscopic/robotic approach with reduced blood loss and shorter length-of-stay.

BACKGROUND. No guidelines exist for surveillance following cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) for appendiceal and colorectal cancer. The primary objective was to define the optimal surveillance frequency after CRS/HIPEC. METHODS. The U.S. HIPEC Collaborative database (2000–2017) was reviewed for patients who underwent a CCR0/1 CRS/HIPEC for appendiceal or colorectal cancer. Radiologic surveillance frequency was divided into two categories: low-frequency surveillance (LFS) at q6–12mos or high-frequency surveillance (HFS) at q2–4mos. Primary outcome was overall survival (OS). RESULTS. Among 975 patients, the median age was 55 year, 41% were male: 31% had non-invasive appendiceal (n = 301), 45% invasive appendiceal (n = 435), and 24% colorectal cancer (CRC; n = 239). With a median follow-up time of 25 mos, the median time to recurrence was 12 mos. Despite less surveillance, LFS patients had no decrease in median OS (non-invasive appendiceal: 106 vs. 65 mos, p < 0.01; invasive appendiceal: 120 vs. 73 mos, p = 0.02; colorectal cancer [CRC]: 35 vs. 30 mos, p = 0.8). LFS patients had lower median PCI scores compared with HFS (non-invasive appendiceal: 10 vs. 19; invasive appendiceal: 10 vs. 14; CRC: 8 vs. 11; all p < 0.01). However, on multivariable analysis, accounting for PCI score, LFS was still not associated with decreased OS for any histologic type (non-invasive appendiceal: hazard ratio [HR]: 0.28, p = 0.1; invasive appendiceal: HR: 0.73, p = 0.42; CRC: HR: 1.14, p = 0.59). When estimating annual incident cases of CRS/HIPEC at 375 for noninvasive appendiceal, 375 invasive appendiceal and 4410 colorectal, LFS compared with HFS for the initial two postoperative years would potentially save $13–19 M/year to the U.S. healthcare system. CONCLUSIONS. Low-frequency surveillance after CRS/HIPEC for appendiceal or colorectal cancer is not associated with decreased survival, and when considering decreased costs, may optimize resource utilization.

Background For patients with peritoneal carcinomatosis undergoing cytoreductive surgery with heated intraperitoneal chemotherapy (CRS/HIPEC), incomplete cytoreduction (CCR2/3) confers morbidity without survival benefit. The aim of this study is to identify preoperative factors which predict CCR2/3. Methods All patients who underwent curative-intent CRS/HIPEC of low/high-grade appendiceal, colorectal, or peritoneal mesothelioma cancers in the 12-institution US HIPEC Collaborative from 2000 to 2017 were included (n = 2027). The primary aim is to create an incomplete-cytoreduction risk score (ICRS) to predict CCR2/3 CRS utilizing preoperative data. ICRS was created from a randomly selected cohort of 50% of patients (derivation cohort) and verified on the remaining patients (validation cohort). Results Within our derivation cohort (n = 998), histology was low-grade appendiceal neoplasms in 30%, high-grade appendiceal tumor in 41%, colorectal tumor in 22%, and peritoneal mesothelioma in 8%. CCR0/1 was achieved in 816 patients and CCR 2/3 in 116 patients. On multivariable analysis, preoperative factors associated with incomplete cytoreduction were male gender [odds ratio (OR) 3.4, p = 0.007], presence of ascites (OR 2.8, p = 0.028), cancer antigen (CA)-125 ≥ 40 U/mL (OR 3.4, p = 0.012), and carcinoembryonic antigen (CEA) ≥ 4.2 ng/mL (OR 3.2, p = 0.029). Each preoperative factor was assigned a score of 0 or 1 to form an ICRS from 0 to 4. Scores were grouped as zero (0), low (1-2), or high (3-4). Incidence of CCR2/3 progressively increased by risk group from 1.6% in zero to 13% in low and 39% in high. When ICRS was applied to the validation cohort (n = 1029), this relationship was maintained. Conclusion The incomplete cytoreduction risk score incorporates preoperative factors to accurately stratify the risk of CCR2/3 resection in CRS/HIPEC. This score should not be used in isolation, however, to exclude patients from surgery.

Given the ubiquity of laparoscopic cholecystectomy in the modern era, the incidence of incidentally diagnosed gallbladder cancers (GBCs) is rising. This unique clinical scenario poses specific challenges regarding the role of staging, re-resection, and adjuvant treatment for patients with this disease. This review will address these controversies with the latest published data.

Background The goals of resection of functional neuroendocrine tumors (NETs) are two-fold: Oncological benefit and symptom control. The interaction between the two is not well understood. Methods All patients with functional NETs of the pancreas, duodenum, and ampulla who underwent curative-intent resection between 2000 and 2016 were identified. Using Cox regression analysis, factors associated with reduced recurrence-free survival (RFS) were identified. Results Two-hundred and thirty patients underwent curative-intent resection. Fifty-three percent were insulinomas, 35% gastrinomas, and 12% were other types. Twenty-one percent had a known genetic syndrome, 23% had lymph node (LN) positivity, 80% underwent an R0 resection, and 14% had no postoperative symptom improvement (SI). Factors associated with reduced RFS included noninsulinoma histology, the presence of a known genetic syndrome, LN positivity, R1 margin, and lack of SI. On multivariable analysis, only the failure to achieve SI following resection was associated with reduced RFS. Considering only those patients with an R0 resection, failure to achieve SI was associated with worse 3-year RFS compared with patients having SI (36% vs 80%; P = 0.006). Conclusions Failure to achieve symptomatic improvement after resection of functional NETs is associated with worse RFS. These patients may benefit from short-interval surveillance imaging postoperatively to assess for earlier radiographical disease recurrence.