cGLRs Join Their Cousins of Pattern Recognition Receptor Family to Regulate Immune Homeostasis.

Pattern recognition receptors (PRRs) recognize danger signals such as PAMPs/MAMPs and DAMPs to initiate a protective immune response. TLRs, NLRs, CLRs, and RLRs are well-characterized PRRs of the host immune system. cGLRs have been recently identified as PRRs. In humans, the cGAS/STING signaling pathway is a part of cGLRs. cGAS recognizes cytosolic dsDNA as a PAMP or DAMP to initiate the STING-dependent immune response comprising type 1 IFN release, NF-κB activation, autophagy, and cellular senescence. The present article discusses the emergence of cGLRs as critical PRRs and how they regulate immune responses. We examined the role of cGAS/STING signaling, a well-studied cGLR system, in the activation of the immune system. The following sections discuss the role of cGAS/STING dysregulation in disease and how immune cross-talk with other PRRs maintains immune homeostasis. This understanding will lead to the design of better vaccines and immunotherapeutics for various diseases, including infections, autoimmunity, and cancers.

Targeting cGAS/STING signaling-mediated myeloid immune cell dysfunction in TIME.

Myeloid immune cells (MICs) are potent innate immune cells serving as first responders to invading pathogens and internal changes to cellular homeostasis. Cancer is a stage of altered cellular homeostasis that can originate in response to different pathogens, chemical carcinogens, and internal genetic/epigenetic changes. MICs express several pattern recognition receptors (PRRs) on their membranes, cytosol, and organelles, recognizing systemic, tissue, and organ-specific altered homeostasis. cGAS/STING signaling is a cytosolic PRR system for identifying cytosolic double-stranded DNA (dsDNA) in a sequence-independent but size-dependent manner. The longer the cytosolic dsDNA size, the stronger the cGAS/STING signaling activation with increased type 1 interferon (IFN) and NF-κB-dependent cytokines and chemokines' generation. The present article discusses tumor-supportive changes occurring in the tumor microenvironment (TME) or tumor immune microenvironment (TIME) MICs, specifically emphasizing cGAS/STING signaling-dependent alteration. The article further discusses utilizing MIC-specific cGAS/STING signaling modulation as critical tumor immunotherapy to alter TIME.

Bias Issues in Colorectal Cancer Management: A Review.

Based on census data, over one-third of the US population identifies as a racial or ethnic minority. This group of racial and ethnic minorities is more likely to develop cancer and die from it when compared with the general population of the USA. These disparities are most pronounced in the African American community. Despite overall CRC rates decreasing nationally and within certain racial and ethnic minorities in the USA, there continue to be disparities in incidence and mortality when compared with non-Hispanic Whites. The disparities in CRC incidence and mortality are related to systematic racism and bias inherent in healthcare systems and society. Disparities in CRC management will continue to exist until specific interventions are implemented in the context of each racial and ethnic group. This review's primary aim is to highlight the disparities in CRC among African Americans in the USA. For surgeons, understanding these disparities is formative to creating change and improving the quality of care, centering equity for all patients.

Outcomes of the First Virtual General Surgery Certifying Exam of the American Board of Surgery.

OBJECTIVE: To Study the Outcomes of the First Virtual General Surgery Certifying Exam of the American Board of Surgery. SUMMARY OF BACKGROUND DATA: The ABS General Surgery CE is normally an in-person oral examination. Due to the COVID-19 outbreak, the ABS was required to reschedule these. After 2 small pilots, the CE's October administration represented the first large-scale remote virtual exam. The purpose of this report is to compare the outcomes of this virtual and the previous in-person CEs. METHODS: CE candidates were asked to provide feedback on their experience via a survey. The passing rate was compared to the 1025 candidates who took the 2019-2020 in-person CEs. RESULTS: Of the 308 candidates who registered for the virtual CE, 306 completed the exam (99.4%) and 188 completed the survey (61.4%). The majority had a very positive experience. They rated the virtual CE as very good/excellent in security (90%), ease of exam platform (77%), audio quality (71%), video quality (69%), and overall satisfaction (86%). Notably, when asked their preference, 78% preferred the virtual exam. There were no differences in the passing rates between the virtual or in-person exams. CONCLUSIONS: The first virtual CE by the ABS was completed using available internet technology. There was high satisfaction, with the majority preferring the virtual platform. Compared to past in-person CEs, there was no difference in outcomes as measured by passing rates. These data suggest that expansion of the virtual CE may be desirable.

Landmark Series on Disparities in Surgical Oncology: Melanoma.

BACKGROUND: Although the lifetime risk of melanoma is disproportionately higher in whites, blacks have a poorer overall survival with an absolute survival difference of 25%. Significant progress has been made in melanoma treatment in the past decade; however, these successes may not be available or accessible to all segments of the population. METHODS: In this review, we highlight important studies in melanoma as well as informative retrospective studies from databases and nonmelanoma cancers where appropriate. RESULTS: There are no level I evidence-based studies on disparities in melanoma, and most likely there will never be, but the studies presented herein and clinical experience demonstrate that disparities in clinical outcomes from melanoma exists. CONCLUSIONS: By becoming aware of the disparities, we can help mitigate them by engagement, education, and corrective and empowering actions through awareness campaigns, appropriate clinical trial design, encouraging participation in clinical trials, increasing the diversity of providers, and advocacy.

Health-Related Quality of Life After Cytoreductive Surgery/HIPEC for Mucinous Appendiceal Cancer: Results of a Multicenter Randomized Trial Comparing Oxaliplatin and Mitomycin.

BACKGROUND: This study evaluated health-related quality of life (HRQOL) using patient-reported outcomes in subjects with mucinous appendiceal neoplasms who underwent cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) as part of a randomized trial comparing mitomycin with oxaliplatin. METHODS: In this prospective multicenter study, 121 mucinous appendiceal cancer patients, with evidence of peritoneal dissemination who underwent CRS, were randomized to receive mitomycin (divided 40 mg) or oxaliplatin (200 mg/m2) for HIPEC. The Functional Assessment of Cancer Therapy Neurotoxicity (FACT-G/NTX) questionnaire was utilized to assess HRQOL. The Trial Outcome Index (TOI) is a summary index responsive to changes in physical/functional outcomes. Repeated measures mixed models with an unstructured variance matrix were applied to assess changes in HRQOL longitudinally. RESULTS: Baseline questionnaire compliance was 95.9%. Baseline physical well-being (PWB) was independently associated with overall survival (hazard ratio 0.79, 95% confidence interval 0.66-0.96; p = 0.017). The TOI was significantly lower in the mitomycin group compared with the oxaliplatin arm at 12 weeks (p = 0.044; score difference 6.35) and 24 weeks after surgery (p = 0.049; score difference 5.61). At 12 weeks after surgery, declines from baseline were significant in the TOI (p = 0.004; score decline 8.99), PWB (p < 0.001; score decline 2.83), and FWB (p < 0.001; score decline 3.42) in the mitomycin group but not the oxaliplatin group. CONCLUSIONS: Compared with mitomycin, HIPEC perfusion with oxaliplatin results in significantly better physical and functional outcomes. With similar survival outcomes and complication rates, oxaliplatin should be considered as the chemoperfusion agent of choice in mucinous appendiceal cancer patients undergoing CRS/HIPEC.

Immune Effects of M51R Vesicular Stomatitis Virus Treatment of Carcinomatosis From Colon Cancer.

BACKGROUND: The purpose of this study was to analyze the oncolytic and immunomodulatory functions of an M protein mutant of vesicular stomatitis virus (M51R VSV) in a murine model of peritoneal surface dissemination from colon cancer (PSD from CRC). METHODS: Luciferase-expressing CT26 peritoneal tumors were established in Balb/c mice to evaluate the impact of M51R VSV treatment on intraperitoneal tumor growth and overall survival. The mice were treated with either intraperitoneal phosphate buffered saline (n = 10) or 5 × 106 PFU M51R VSV (n = 10) at 5 d after tumor implantation. Tumor bioluminescence was measured every 3 d during the 60-day study period. The immunomodulatory effect of M51R VSV treatment was evaluated in mice treated with either intraperitoneal phosphate buffered saline (n = 21) or M51R VSV (n = 21). Peritoneal lavages were collected at days 1, 3, and 7 after M51R VSV treatment for flow cytometry and multiplex cytokine bead analysis. RESULTS: A single, intraperitoneal treatment with M51R VSV inhibited the growth of PSD from CRC as evidenced by decreased bioluminescence and improved survival. This treatment approach also resulted in significantly higher frequencies of peritoneal CD4+ T (10.95 ± 1.17 versus 6.19 ± 0.44, P = 0.004) and B1b cells (5.01 ± 0.97 versus 2.20 ± 0.2, P = 0.024). On the other hand, treatment with M51R VSV resulted in fewer myeloid-derived suppressor cells relative to controls (10.66 ± 1.48 versus 14.47 ± 1.06, P = 0.035). M51R-treated peritoneal cavities also contained lower concentrations of immunosuppressive monocyte chemoattractant protein-1 and interleukin 6 cytokines relative to controls. CONCLUSIONS: Our findings suggest that M51R VSV alters the innate and adaptive immune responses in PSD from CRC. Future studies will delineate specific components of antitumor immunity that result in its therapeutic effect.

Efficacy of Talimogene Laherparepvec (T-VEC) Therapy in Patients with In-Transit Melanoma Metastasis Decreases with Increasing Lesion Size.

BACKGROUND: Talimogene laherparepvec (T-VEC) is the first injectable oncolytic viral therapy approved for in-transit melanoma metastasis, with a reported overall response rate (ORR) of 25% and complete response rate (CRR) of 10%. To ascertain the role of patient selection on outcomes in routine practice, we evaluated the impact of patient, lesion, and treatment factors on clinical response. METHODS: Medical records were extracted for patients with recurrent stage IIIB-IV melanoma completing T-VEC at Duke University Medical Center between 1 January 2016 and 1 September 2018. Kaplan-Meier analysis assessed time to response and survival, while logistic regression measured associations of clinicopathologic status, lesion burden, T-VEC dosing, and use of prior and concurrent therapy with ORR and CRR. RESULTS: Of 27 patients, an objective response was observed in 11 (40.7%), including one patient with partial response (3.7%) and 10 with complete response (37.0%). Time to complete response and overall response was a median 22 weeks (95% confidence interval [CI] 2.0-41.9 weeks and 15.8-28.2 weeks, respectively), and median progression-free survival was 17 weeks (95% CI 0-36 weeks). Logistic regression demonstrated each millimeter increase in maximum lesion diameter predicted decreased ORR (odds ratio [OR] 0.866, 95% CI 0.753-0.995; p = 0.04). Stage IV disease (OR 0.04, 95% CI 0.00-0.74; p = 0.031) and programmed death-1 inhibitor treatment (OR 0.06, 95% CI 0.01-0.74; p = 0.028) also predicted reduced clinical response. CONCLUSIONS: This study corroborates recent data suggesting response rates to T-VEC may be higher than reported in clinical trials, arising in part from patient selection. T-VEC lesion diameter was persistently associated with clinical response and is a readily assessed predictor of successful T-VEC therapy.

Routine Admission to Intensive Care Unit After Cytoreductive Surgery and Heated Intraperitoneal Chemotherapy: Not Always a Requirement.

BACKGROUND: Routine postoperative intensive care unit (ICU) observation of patients undergoing cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) is driven by historically reported morbidity and mortality data. The validity of this practice and the criteria for ICU admission have not been elucidated. METHODS: A prospectively maintained database of 1146 CRS/HIPEC procedures performed from December 1991 to 2014 was retrospectively analyzed. Patients with routine postoperative ICU admission were compared with patients sent directly to the surgical floor. To test the safety of non-ICU care practice, patients with less than 48 h ICU admission were compared with patients directly admitted to the floor. Demographics, primary tumor site, comorbidities, estimated blood loss (EBL), extent of CRS, Eastern Cooperative Oncology Group (ECOG) status, and overall survival were analyzed. RESULTS: Complete data were available for 1064 CRS/HIPEC procedures, of which 244 cases (22.93 %) did not require ICU admission. Multivariate logistic regression identified age [odds ratio (OR) 1.024; p = 0.02], EBL (OR 1.002; p < 0.0001), number of resected organs (OR 1.308; p = 0.01) and ECOG > 2 (OR 6.387; p = 0.003) as predictive variables of postoperative ICU admission. The cohort directly admitted to the floor demonstrated less minor grade I/II morbidity (29 vs. 47 %; p < 0.0001) and similar grade III/IV major morbidity (16.5 vs. 13.4 %; p = 0.3) than the patients admitted to the ICU for less than 48 h. CONCLUSIONS: ICU observation is not routinely required for all patients treated with CRS/HIPEC. Selective ICU admission based on ECOG status, nutritional status, age, EBL, and CRS extent is safe, with potential implications for hospitalization cost for these complex cases.

Conditional Survival After Cytoreductive Surgery with Heated Intraperitoneal Chemotherapy for Low- and High-Grade Appendiceal Primaries.

INTRODUCTION: Survival of patients after cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy for appendiceal neoplasms is projected by conventional overall survival (OS) curves that do not address the survival time a patient has already accrued. We sought to study the conditional survival (CS) after CRS, contingent on patients surviving a fixed duration of time after surgery. METHODS: A retrospective analysis of 493 appendiceal cancer patients from a prospective database was performed. OS was calculated for patients who achieved a complete CRS. CS was estimated based on Kaplan-Meier curves to determine what the patient's long-term survival (3-, 5-, 7-, or 10-year) would be if they were alive at 1, 2, or 3 years from surgery. RESULTS: OS at 5 and 10 years for 137 low-grade patients with complete resections was 83.3 and 74.2 %, respectively. For low-grade patients still alive at 3 years, 5- and 10-year CS was 93.4 and 83.2 %, respectively. For the 35 high-grade patients with complete CRS who survived to 3 years, CS at 10 years was 41.7 %, while their 10-year conventional OS was 24.6 %. CONCLUSIONS: Conventional analysis underestimates OS due to unpredictable variations in tumor biology. When adjusted for time already elapsed since surgery, improvements in survival estimates are more pronounced with high-grade tumors. CS outcomes can be used in determining the optimal frequency of long-term follow-up of these patients.

Stoma Creation and Reversal After Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy.

INTRODUCTION: Cytoreductive surgery with heated intraperitoneal chemotherapy (CRS/HIPEC) often includes stoma creation. We evaluated the indications, morbidity, and mortality associated with stoma creation and reversal after CRS/HIPEC. METHODS: Retrospective analysis of a prospective database of 1149 CRS-HIPEC procedures was performed. Patient demographics, type of malignancy, comorbidities, Clavien-graded morbidity, mortality, indications for stoma creation, and outcomes of subsequent reversal were abstracted. RESULTS: Sixteen percent (186/1149) of CRS/HIPEC procedures included stoma creation, whereas 1.1 % (11/963) of patients without initial stoma creation developed anastomotic leaks requiring stoma. Patients who required a stoma had worse preoperative performance status (ECOG 0/1: 77.2 vs. 86.1 %, p = 0.002), greater burden of disease (PCI 17.6 vs. 12.9, p < 0.0001), and were more likely to have R2 resections (74.5 vs. 48.8 %, p < 0.0001) than those without stoma creation. Stomas were intended to be permanent in 17.5 % (35/199). Of 164 patients with potentially reversible ostomies, only 26.2 % (43/164) underwent reversal. Disease progression (43/164, 26.2 %) and death (40/164, 24.3 %) most commonly precluded reversal. After reversal, 27.9 % (12/43) suffered a Clavien I/II morbidity, 27.9 % (12/43) suffered Clavien III/IV morbidity, and 30-day mortality was 4.7 % (2/43). Anastomotic leak occurred after 9 % (3/33) of ileostomy and 10 % (1/10) of colostomy reversals. CONCLUSIONS: Stomas are more common among CRS/HIPEC patients with a high burden of disease and poor functional status. Reversal is uncommon and is associated with significant major morbidity. Preoperative counseling for those with high disease burden and poor functional status should include the risk of permanent stoma.

Peritoneal surface disease (PSD) from appendiceal cancer treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC): overview of 481 cases.

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) used to treat peritoneal surface disease (PSD) from appendiceal cancer have shown variability in survival outcomes. The primary goal of this study was to determine predictors of surgical morbidity and overall survival. The secondary goal was to describe the impact of nodal status on survival after CRS/HIPEC for PSD from low-grade appendiceal (LGA) and high-grade appendiceal (HGA) primary lesions. METHODS: A retrospective analysis of 1,069 procedures from a prospective database was performed. Patient characteristics, tumor grade, nodal status, performance status, resection status, morbidity, mortality, and survival were reviewed. RESULTS: The study identified 481 CRS/HIPEC procedures: 317 (77.3 %) for LGA and 93 (22.7 %) for HGA lesions. The median follow-up period was 44.4 months, and the 30-day major morbidity and mortality rates were respectively 27.8 and 2.7 %. Major morbidity was jointly predicted by incomplete cytoreduction (p = 0.0037), involved nodes (p < 0.0001), and comorbidities (p = 0.003). Multivariate negative predictors of survival included positive nodal status (p = 0.003), incomplete cytoreduction (p < 0.0001), and preoperative chemotherapy (p = 0.04) in LGA patients and incomplete cytoreduction (p = 0.0003) and preoperative chemotherapy (p = 0.0064) in HGA patients. After complete cytoreduction, median survival was worse for patients with positive nodes than for those with negative nodes in LGA (85 months vs not reached [82 % alive at 90 months]; p = 0.002) and HGA (30 vs 153 months; p < 0.0001). CONCLUSIONS: Positive nodes are associated with decreased survival not only for HGA patients but also for LGA patients even after complete cytoreduction. Nodal status further stratifies histologic grade as a prognostic indicator of survival. Patients with node-negative HGA primary lesions who receive a complete cytoreduction may experience survival comparable with that for LGA patients.

Impact of distal pancreatectomy on outcomes of peritoneal surface disease treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

BACKGROUND: Left upper quadrant involvement by peritoneal surface disease (PSD) may require distal pancreatectomy (DP) to obtain complete cytoreduction. Herein, we study the impact of DP on outcomes of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). METHODS: Analysis of a prospective database of 1,019 procedures was performed. Malignancy type, performance status, resection status, comorbidities, Clavien-graded morbidity, mortality, and overall survival were reviewed. RESULTS: DP was a component of 63 CRS/HIPEC procedures, of which 63.3 % had an appendiceal primary. While 30-day mortality between patients with and without DP was no different (2.6 vs. 3.2 %; p = 0.790), 30-day major morbidity was worse in patients receiving a DP (30.2 vs. 18.8 %; p = 0.031). Pancreatic leak rate was 20.6 %. Intensive care unit days and length of stay were longer in DP versus non-DP patients (4.6 vs. 3.5 days, p = 0.007; and 22 vs. 14 days, p < 0.001, respectively). Thirty-day readmission was similar for patients with and without DP (29.2 vs. 21.1 %; p = 0.205). Median survival for low-grade appendiceal cancer (LGA) patients requiring DP was 106.9 months versus 84.3 months when DP was not required (p = 0.864). All seven LGA patients undergoing complete cytoreduction inclusive of DP were alive at the conclusion of the study (median follow-up 11.8 years). CONCLUSIONS: CRS/HIPEC including DP is associated with a significant increase in postoperative morbidity but not mortality. Survival was similar for patients with LGA whether or not DP was performed. Thus, the need for a DP should not be considered a contraindication for CRS/HIPEC procedures in LGA patients when complete cytoreduction can be achieved.

Peritoneal surface disease with synchronous hepatic involvement treated with Cytoreductive Surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC).

BACKGROUND: Patients with peritoneal surface disease (PSD) often present with synchronous hepatic involvement (HI). The impact of addressing the hepatic component during CRS/HIPEC on operative and survival outcomes is not clearly defined. METHODS: A prospective database of 1,067 procedures was reviewed based on primary tumor, performance status, resection status, type of liver involvement (superficial or parenchymal) and hepatic resection, morbidity, mortality, and overall survival. RESULTS: There were 108 (10 %) CRS/HIPEC procedures performed with synchronous liver debulking in 99 patients with PSD from 27 (33 %) appendiceal and 32 (39 %) colorectal primary lesions. Ninety percent of patients underwent subsegmental hepatic resection, whereas 22 % had disease with hepatic parenchymal involvement. Median intensive care unit (ICU) and hospital stay were 3.5 and 13.6 days, respectively. Clavien grade III/IV morbidity was similar for patients with or without resected HI (18.9 vs. 22.5 %; p = 0.39). The 30-day mortality rate was 6.5 and 2.8 % (p = 0.07) for patients with and without resected HI, respectively. The median survival for all patients with low-grade appendiceal cancer was 42.1 months with resected HI and 95.5 months without HI (p = 0.03). Median survival for colorectal cancer patients after complete cytoreduction was 21.2 months with HI versus 33.6 months without HI (p = 0.03). CONCLUSIONS: Synchronous resection of limited HI does not increase the morbidity or mortality of CRS/HIPEC procedures. The survival benefit, although still meaningful, was less for patients with HI. Resectable low volume HI in patients with PSD from colon and appendiceal primary lesions should not be considered a contraindication for CRS/HIPEC procedures.

Appendiceal goblet cell carcinomatosis treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

BACKGROUND: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is a treatment commonly applied to peritoneal surface disease from low-grade mucinous tumors of the appendix. Some centers have extended this therapy to carcinomatosis from more aggressive malignancies. Therefore, we reviewed our experience with CRS/HIPEC for patients with goblet cell carcinomatosis. METHODS: Patients with carcinomatosis from appendiceal primaries with goblet cell features were identified in a prospectively maintained database of 1198 CRS/HIPEC procedures performed between 1991 and 2014. Patient demographics, disease characteristics, morbidity, mortality, and survival were reviewed. RESULTS: A total of 31 patients with carcinomatosis originating from appendiceal goblet cell tumors underwent CRS/HIPEC during the study period. Patients were generally young (mean age, 53 y) and otherwise healthy (84% without comorbidities) with good performance status (94% Eastern Cooperative Oncology Group 0 or 1). The mean number of visceral resections was 3.5, and complete cytoreduction of macroscopic disease was accomplished in 36%. Major 90-d morbidity and mortality rates were 38.7% and 9.7%, respectively. Median overall survival (OS) for all patients was 18.4 mo. Patients with negative nodes had better survival than those with positive nodes (median OS, 29.2 versus 10.2 mo), respectively (P = 0.002). Although complete cytoreduction was associated with longer median OS after CRS/HIPEC (R0/R1 28.6 versus R2 17.2 mo, P = 0.47), the observed difference did not reach statistical significance. CONCLUSIONS: CRS/HIPEC may improve survival in patients with node negative goblet cell carcinomatosis when a complete cytoreduction is achieved. Patients with disease not amenable to complete cytoreduction should not be offered CRS/HIPEC.