Tumor and Peritoneum-Associated Macrophage Gene Signature as a Novel Molecular Biomarker in Gastric Cancer.

A spectrum of immune states resulting from tumor resident macrophages and T-lymphocytes in the solid tumor microenvironment correlates with patient outcomes. We hypothesized that in gastric cancer (GC), macrophages in a polarized immunosuppressive transcriptional state would be prognostic of poor survival. We derived transcriptomic signatures for M2 (M2TS, MRC1; MS4A4A; CD36; CCL13; CCL18; CCL23; SLC38A6; FGL2; FN1; MAF) and M1 (M1TS, CCR7; IL2RA; CXCL11; CCL19; CXCL10; PLA1A; PTX3) macrophages, and cytolytic T-lymphocytes (CTLTS, GZMA; GZMB; GZMH; GZMM; PRF1). Primary GC in a TCGA stomach cancer dataset was evaluated for signature expressions, and a log-rank test determined overall survival (OS) and the disease-free interval (DFI). In 341 TCGA GC entries, high M2TS expression was associated with histological types and later stages. Low M2TS expression was associated with significantly better 5-year OS and DFI. We validated M2TS in prospectively collected peritoneal fluid of a GC patient cohort (n = 28). Single-cell RNA sequencing was used for signature expression in CD68+CD163+ cells and the log-rank test compared OS. GC patients with high M2TS in CD68+CD163+ cells in their peritoneal fluid had significantly worse OS than those with low expression. Multivariate analyses confirmed M2TS was significantly and independently associated with survival. As an independent predictor of poor survival, M2TS may be prognostic in primary tumors and peritoneal fluid of GC patients.

Blockade of interleukin 10 potentiates antitumour immune function in human colorectal cancer liver metastases.

OBJECTIVE: Programmed cell death protein 1 (PD-1) checkpoint inhibition and adoptive cellular therapy have had limited success in patients with microsatellite stable colorectal cancer liver metastases (CRLM). We sought to evaluate the effect of interleukin 10 (IL-10) blockade on endogenous T cell and chimeric antigen receptor T (CAR-T) cell antitumour function in CRLM slice cultures. DESIGN: We created organotypic slice cultures from human CRLM (n=38 patients' tumours) and tested the antitumour effects of a neutralising antibody against IL-10 (αIL-10) both alone as treatment and in combination with exogenously administered carcinoembryonic antigen (CEA)-specific CAR-T cells. We evaluated slice cultures with single and multiplex immunohistochemistry, in situ hybridisation, single-cell RNA sequencing, reverse-phase protein arrays and time-lapse fluorescent microscopy. RESULTS: αIL-10 generated a 1.8-fold increase in T cell-mediated carcinoma cell death in human CRLM slice cultures. αIL-10 significantly increased proportions of CD8+ T cells without exhaustion transcription changes, and increased human leukocyte antigen - DR isotype (HLA-DR) expression of macrophages. The antitumour effects of αIL-10 were reversed by major histocompatibility complex class I or II (MHC-I or MHC-II) blockade, confirming the essential role of antigen presenting cells. Interrupting IL-10 signalling also rescued murine CAR-T cell proliferation and cytotoxicity from myeloid cell-mediated immunosuppression. In human CRLM slices, αIL-10 increased CEA-specific CAR-T cell activation and CAR-T cell-mediated cytotoxicity, with nearly 70% carcinoma cell apoptosis across multiple human tumours. Pretreatment with an IL-10 receptor blocking antibody also potentiated CAR-T function. CONCLUSION: Neutralising the effects of IL-10 in human CRLM has therapeutic potential as a stand-alone treatment and to augment the function of adoptively transferred CAR-T cells.

Safety and Efficacy of Oxaliplatin Pressurized Intraperitoneal Aerosolized Chemotherapy (PIPAC) in Colorectal and Appendiceal Cancer with Peritoneal Metastases: Results of a Multicenter Phase I Trial in the USA.

BACKGROUND: Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a laparoscopic locoregional treatment for peritoneal metastases (PM) from colorectal cancer (CRC) or appendiceal cancer (AC) in patients who cannot undergo cytoreductive surgery (CRS). While PIPAC has been studied in Europe and Asia, it has not been investigated in the USA. PATIENTS AND METHODS: We evaluated PIPAC with 90 mg/m2 oxaliplatin alone (cycle 1) and preceded by systemic chemotherapy with fluorouracil (5-FU) and leucovorin (LV) (cycle 2-3) as a multicenter prospective phase I clinical trial (NCT04329494). The primary endpoint was treatment-related adverse events (AEs). Secondary endpoints included survival and laparoscopic, histologic, and radiographic response. RESULTS: 12 patients were included: 8 with CRC and 4 with AC. Median prior chemotherapy cycles was 2 (interquartile range (IQR) 2-3). All patients were refractory to systemic oxaliplatin-based chemotherapy. Median peritoneal carcinomatosis index (PCI) was 28 (IQR 19-32). Six (50%) of twelve patients completed three PIPAC cycles. No surgical complications or dose-limiting toxicities were observed. Two patients developed grade 3 treatment-related toxicities (one abdominal pain and one anemia). Median overall survival (OS) was 12.0 months, and median progression-free survival (PFS) was 2.9 months. OS was correlated with stable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria but not with laparoscopic response by PCI or histologic response by peritoneal regression grading system (PRGS). CONCLUSIONS: This phase I trial in the USA demonstrated safety, feasibility, and early efficacy signal of PIPAC with oxaliplatin and chemotherapy in patients with PM from AC or CRC who are refractory to standard lines of systemic chemotherapy.

IWATE criteria are associated with perioperative outcomes in robotic hepatectomy: a retrospective review of 225 resections.

BACKGROUND: Robotic hepatectomy (RH) is increasingly utilized for minor and major liver resections. The IWATE criteria were developed to classify minimally invasive liver resections by difficulty. The objective of this study was to apply the IWATE criteria in RH and to describe perioperative and oncologic outcomes of RH over the last decade at our institution. METHODS: Perioperative and oncologic outcomes of patients who underwent RH between 2011 and 2019 were retrospectively collected. The difficulty level of each operation was assessed using the IWATE criteria, and outcomes were compared at each level. Univariate linear regression was performed to characterize the relationship between IWATE criteria and perioperative outcomes (OR time, EBL, and LOS), and a multivariable model was also developed to address potential confounding by patient characteristics (age, sex, BMI, prior abdominal surgery, ASA class, and simultaneous non-hepatectomy operation). RESULTS: Two hundred and twenty-five RH were performed. Median IWATE criteria for RH were 6 (IQR 5-9), with low, intermediate, advanced, and expert resections accounting for 23% (n = 51), 34% (n = 77), 32% (n = 72), and 11% (n = 25) of resections, respectively. The majority of resections were parenchymal-sparing approaches, including anatomic segmentectomies and non-anatomic partial resections. 30-day complication rate was 14%, conversion to open surgery occurred in 9 patients (4%), and there were no deaths within 30 days postoperatively. In the univariate linear regression analysis, IWATE criteria were positively associated with OR time, EBL, and LOS. In the multivariable model, IWATE criteria were independently associated with greater OR time, EBL, and LOS. Two-year overall survival for hepatocellular carcinoma and intrahepatic cholangiocarcinoma was 94% and 50%, respectively. CONCLUSION: In conclusion, the IWATE criteria are associated with surgical outcomes after RH. This series highlights the utility of RH for difficult hepatic resections, particularly parenchymal-sparing resections in the posterosuperior sector, extending the indication of minimally invasive hepatectomy in experienced hands and potentially offering select patients an alternative to open hepatectomy or other less definitive liver-directed treatment options.

Engaging Frontline Providers Prevents Hypothermia and Improves Communication in the Postoperative Neonate.

BACKGROUND: Neonates undergoing surgery are at high risk for perioperative hypothermia. Hypothermia has been associated with increased adverse events. Transfer of care from the operating room (OR) to the neonatal intensive care unit (NICU) adds another layer of risk for this population introducing the potential for miscommunication leading to preventable adverse events. PURPOSE: The aim of this quality improvement initiative is to decrease mean postoperative hypothermia rate and achieve compliance with use of a standardized postoperative hand-off in neonates transferred to the NICU from the OR. METHODS: An interdisciplinary team identified opportunities for heat loss during the perioperative period. The lack of standardized perioperative communication between the NICU and the OR and postoperative communication between neonatology, anesthesiology, surgery, and nursing were noted. Guidelines for maintaining euthermia in the perioperative period and a standardized interdisciplinary postoperative hand-off communication tool were created. FINDINGS/RESULTS: Mean rate for participation in the hand-off process increased from 78.8% to 98.4% during the study period. The mean hypothermia rate improved from 28.6% to 6.3% (P < .0001) and was sustained. IMPLICATIONS FOR PRACTICE: Creating a hypothermia guideline and standardizing temperature monitoring can significantly decrease the rate of postoperative hypothermia in neonates. Standardization of transfer of care from OR to NICU increases consistent communication between the services. IMPLICATIONS FOR RESEARCH: Future research and improvement efforts are needed to optimize the management of surgical neonates through their transfers of care.

Center, Gestational Age, and Race Impact End-of-Life Care Practices at Regional Neonatal Intensive Care Units.

OBJECTIVE: To assess the impact of intercenter variation and patient factors on end-of-life care practices for infants who die in regional neonatal intensive care units (NICUs). STUDY DESIGN: We conducted a retrospective cohort analysis using the Children's Hospital Neonatal Database during 2010-2016. A total of 6299 nonsurviving infants cared for in 32 participating regional NICUs were included to examine intercenter variation and the effects of gestational age, race, and cause of death on 3 end-of-life care practices: do not attempt resuscitation orders (DNR), cardiopulmonary resuscitation within 6 hours of death (CPR), and withdrawal of life-sustaining therapies (WLST). Factors associated with these practices were used to develop a multivariable equation. RESULTS: Dying infants in the cohort underwent DNR (55%), CPR (21%), and WLST (73%). Gestational age, cause of death, and race were significantly and differently associated with each practice: younger gestational age (<28 weeks) was associated with CPR (OR 1.7, 95% CI 1.5-2.1) but not with DNR or WLST, and central nervous system injury was associated with DNR (1.6, 1.3-1.9) and WLST (4.8, 3.7-6.2). Black race was associated with decreased odds of WLST (0.7, 0.6-0.8). Between centers, practices varied widely at different gestational ages, race, and causes of death. CONCLUSIONS: From the available data on end-of-life care practices for regional NICU patients, variability appears to be either individualized or without consistency.

Immune checkpoint inhibitors in lung cancer: past, present and future.

Inhibitory ligands on tumor cells and their corresponding receptors on T cells are collectively called immune checkpoint molecules and have emerged as druggable targets that harness endogenous immunity to fight cancer. Immune checkpoint inhibitors targeting CTLA-4, PD-1 and PD-L1 have been developed for the treatment of patients with non-small-cell lung cancer and other malignancies, with impressive clinical activity, durable responses and a favorable toxicity profile. This article reviews the development, current status and future directions for some of these agents. The efficacy and safety data for drugs such as ipilimumab, nivolumab, pembrolizumab, atezolizumab and durvalumab are reviewed, along with combination strategies and response evaluation criteria. The toxicity profiles and predictive biomarkers of response are also discussed.

Obese women less likely to have low serum ferritin, Nicaragua.

OBJECTIVE: To examine the association between overweight and obesity and serum ferritin among women of reproductive age (15-49 years) in Nicaragua, considering the effect of α1-acid glycoprotein (AGP), a marker of inflammation. DESIGN: We analysed data from the 2004-05 Nicaraguan Integrated Surveillance System for Nutrition Interventions. Three logistic regression models were analysed with low serum ferritin (<15 µg/l) as the dependent variable: (i) overweight or obese status and covariates; (ii) model 1 plus AGP; and (iii) model 1 restricted to only women with normal AGP levels (≤1.0 g/l). SETTING: Nicaragua. SUBJECTS: Included in this analysis were 832 non-pregnant mother/caregivers (15-49 years) surveyed in 2004-2005. RESULTS: In the sample, prevalence of overweight and obesity was 31.8 % and 19.2 %, respectively, and 27.6 % had low serum ferritin. In model 1, the adjusted OR of low serum ferritin was 0.74 (95 % CI 0.52, 1.05) for overweight women and 0.42 (95 % CI 0.26, 0.65) for obese women. In model 2, AGP was significantly independently associated with low serum ferritin (adjusted OR=0.56, 95 % CI 0.34, 0.92) while the adjusted OR for overweight and obesity were largely unchanged. Excluding women with elevated AGP did not appreciably affect the relationship between overweight or obesity and low serum ferritin (model 3). CONCLUSIONS: Overall, in this population of reproductive-age women, obese women were less likely to have low serum ferritin levels, and this was independent of inflammation as measured by AGP.

Neutrophil-to-lymphocyte ratio as a predictor of outcomes for patients with hepatocellular carcinoma: a Western perspective.

BACKGROUND AND OBJECTIVES: Neutrophil-to-lymphocyte ratio (NLR) is simple, inexpensive, and has been proposed to be predictive in hepatocellular carcinoma (HCC) in Europe and Asia. We aimed to evaluate whether NLR at presentation in a Western center provides any prognostic value compared to other common prognostic scores. METHODS: NLR was calculated for 75 consecutive patients at presentation with HCC and regression models were used to analyze its value for predicting treatment strategy and short-term survival with Child-Pugh and Model for End Stage Liver Disease (MELD). RESULTS: NLR was not predictive of future treatment regimens with hepatectomy, liver transplant, or transarterial chemoembolization (TACE; odds ratio [OR]: 0.85, 95% confidence interval [CI]: 0.71-1.02, P = 0.079) as compared the predictive value of MELD (OR: 0.81, CI: 0.72-0.93, P = 0.002) or Child-Pugh (OR: 0.48, CI: 0.34-0.69, P < 0.001). Adding additional adjustment for treatment, NLR did not correlate with short-term overall survival (hazard ratio [HR]: 1.09, CI: 0.95-1.24, P = 0.227). MELD also did not correlate with overall survival (HR: 1.04, CI: 0.96-1.13, P = 0.357) whereas Child-Pugh (HR: 1.56, CI: 1.10-2.19, P = 0.011) was predictive. CONCLUSIONS: This study does not support the prognostic value of NLR to guide therapy for HCC in a Western center, whereas MELD and Child-Pugh score were more predictive.

Emerging therapeutic approaches for peritoneal metastases from gastrointestinal cancers.

Peritoneal metastases from gastrointestinal malignancies present difficult management decisions, with options consisting primarily of systemic chemotherapy or major surgery with or without hyperthermic intraperitoneal chemotherapy. Current research is investigating expanding therapeutic modalities, and the aim of this review is to provide an overview of the existing and emerging therapies for the peritoneal metastases from gastrointestinal cancers, primarily through the recent literature (2015 and newer). These include the current data with systemic therapy and cytoreduction with hyperthermic intraperitoneal or pressurized intraperitoneal aerosol chemotherapy, as well as novel promising modalities under investigation, including dominating oncolytic viral therapy and adoptive cellular, biologic, and bacteria therapy, or nanotechnology. The novel diverse strategies, although preliminary and preclinical in murine models, individually and collectively contribute to the treatment of peritoneal metastases, offering hope for improved outcomes and quality of life. We foresee that these evolving treatment approaches will facilitate the transfer of knowledge and data among studies and advance discovery of new drugs and optimized treatments for patients with peritoneal metastases.

Diffuse-Type Histology Is Prognostic for All Siewert Types of Gastroesophageal Adenocarcinoma.

PURPOSE: The optimal treatment for gastroesophageal junction adenocarcinoma (GEJA) remains controversial. We evaluated the treatment patterns and outcomes of patients with locally advanced GEJA according to the histological type. MATERIALS AND METHODS: We conducted a single-institution retrospective cohort study of patients with locally advanced GEJA who underwent curative-intent surgical resection between 2010 and 2020. Perioperative therapies as well as clinicopathologic, surgical, and survival data were collected. The results of endoscopy and histopathological examinations were assessed for Siewert and Lauren classifications. RESULTS: Among the 58 patients included in this study, 44 (76%) were clinical stage III, and all received neoadjuvant therapy (72% chemoradiation, 41% chemotherapy, 14% both chemoradiation and chemotherapy). Tumor locations were evenly distributed by Siewert Classification (33% Siewert-I, 40% Siewert-II, and 28% Siewert-III). Esophagogastrectomy (EG) was performed for 47 (81%) patients and total gastrectomy (TG) for 11 (19%) patients. All TG patients received D2 lymphadenectomy compared to 10 (21%) EG patients. Histopathological examination showed the presence of 64% intestinal-type and 36% diffuse-type histology. The frequencies of diffuse-type histology were similar among Siewert groups (37% Siewert-I, 36% Siewert-II, and 33% Siewert-III). Regardless of Siewert type and compared to intestinal-type, diffuse histology was associated with increased intraabdominal recurrence rates (P=0.03) and decreased overall survival (hazard ratio, 2.33; P=0.02). With a median follow-up of 31.2 months, 29 (50%) patients had a recurrence, and the median overall survival was 50.5 months. CONCLUSIONS: Present in equal proportions among Siewert types of esophageal and gastric cancer, a diffuse-type histology was associated with high intraabdominal recurrence rates and poor survival. Histopathological evaluation should be considered in addition to anatomic location in the determination of multimodal GEJA treatment strategies.

Initial surgery for spontaneous intestinal perforation in extremely low birth weight infants is not associated with mortality or in-hospital morbidities.

OBJECTIVE: Determine short-term outcomes following peritoneal drain (PD), laparotomy (LAP) after PD (PD-LAP), and LAP in extremely low birth weight (ELBW) infants with spontaneous intestinal perforation (SIP). STUDY DESIGN: ELBW infants with SIP were identified using the Children's Hospitals Neonatal Database. Mortality and length of stay (LOS) were compared among groups. RESULTS: Of 729 SIP infants from 6/2010-12/2016, 383(53%) received PD, 61(8%) PD-LAP, and 285(39%) LAP. PD infants had lower GA at birth, at SIP diagnosis and upon admission than PD-LAP or LAP; and higher sepsis rates than LAP. Bivariate analysis and Kaplan-Meier survival estimates suggested PD had increased mortality vs. PD-LAP and LAP (27%, 11.5%, and 15.8% respectively, p < 0.001). However, surgical approach was not significantly associated with mortality in multivariable analysis accounting for GA and illness severity. LOS did not differ by surgical approach. CONCLUSIONS: In ELBW infants with SIP, mortality, and LOS are independent of the initial surgical approach.

Intakes of dairy products and dietary supplements are positively associated with iodine status among U.S. children.

Although pregnant women and some groups of reproductive-age women in the US may be at risk of iodine deficiency, data also suggest that iodine intake among many U.S. children may be above requirements. Our objective was to describe the association of iodine sources with iodine status among children. We analyzed 2007-2010 NHANES data of urine iodine concentration (UIC) spot tests for children aged 6-12 y (n = 1553) and used WHO criteria for iodine status (median UIC: 100-199 µg/L = adequate; 200-299 µg/L = above requirements; ≥300 µg/L = excess). The overall median UIC was above requirements for children aged 6-12 y [211 µg/L (95% CI: 194, 228 µg/L)]. Median UIC increased by quartile of previous day dairy intake, ranging from adequate in the lowest quartile [157 µg/L (95% CI: 141, 170 µg/L)] to above requirements in the highest quartile [278 µg/L (95% CI: 252, 336 µg/L)]. Median UIC was 303 µg/L (95% CI: 238, 345 µg/L) among the 17% of children who had taken a dietary supplement containing iodine the previous day, compared with 198 µg/L (95% CI: 182, 214 µg/L) among those who had not. In adjusted regression analyses, recent dairy intake and recent supplement use were significantly positively associated with UIC levels, whereas recent grain intake was negatively associated. Adding salt to food at the table was not associated with UIC. Iodine-containing supplements are likely not needed by most schoolchildren in the US because dietary iodine intake is adequate in this age group.

Relationship between markers of inflammation and anaemia in children of Papua New Guinea.

OBJECTIVE: To assess the association of the acute-phase protein biomarkers, C-reactive protein (CRP) and α1-acid glycoprotein (AGP), with anaemia in children aged 6-59·9 months in Papua New Guinea. DESIGN: A nationally representative household-based cross-sectional survey of children aged 6-59·9 months was used to assess the relationships between various combinations of elevated CRP (>5 mg/l) and AGP (>1·2 g/l) with anaemia. Logistic regression was used to determine if other factors, such as age, sex, measures of anthropometry, region, urban/rural residence and household size, modified or confounded the acute-phase protein-anaemia association. SETTING: Papua New Guinea. SUBJECTS: A total of 870 children aged 6-59·9 months from the 2005 Papua New Guinea National Micronutrient Survey were assessed. RESULTS: The following prevalence estimates were found: anaemia 48 %; elevated CRP 32 %; and elevated AGP 33 %. Children with elevated CRP had a prevalence of anaemia of 66 % compared with children with normal CRP who had a prevalence of 40 %. Corresponding estimates for AGP were 61 % and 42 %, respectively. Similar results were found with combinations of elevated CRP and AGP. The higher prevalence of anaemia in children with elevated CRP and/or AGP was still present after controlling for confounders. CONCLUSIONS: Elevated levels of CRP and AGP were significantly associated with a higher prevalence of anaemia in the children surveyed. There are no expert group recommendations on whether to or how to account for markers of inflammation in presenting results on anaemia prevalence. Additional research would be helpful to clarify this issue.

Medicare Advantage: A Disadvantage for Complex Cancer Surgery Patients.

PURPOSE: Nearly half of all Medicare beneficiaries are enrolled in privatized Medicare insurance plans (Medicare Advantage [MA]). Little comparative information is available about access, outcomes, and cost of inpatient cancer surgery between MA and Traditional Medicare (TM) beneficiaries. We set out to assess and compare access, postoperative outcomes, and estimated cost of inpatient cancer surgery among MA and TM beneficiaries. METHODS: Retrospective cohort analysis of MA or TM beneficiaries undergoing elective inpatient cancer surgery (for cancers located in lung, esophagus, stomach, pancreas, liver, colon, or rectum) was performed using the Office of Statewide Health Planning Inpatient Database linked to California Cancer Registry from 2000 to 2020. For each cancer site, risk-standardized access to high-volume hospitals, postoperative 30-day mortality, complications, failure to rescue, and surgery-specific estimated costs were compared between MA and TM beneficiaries. RESULTS: This analysis of 76,655 Medicare beneficiaries (median age 74 years, 51% female, 39% MA) included 31,913 colectomies, 10,358 proctectomies, 4,604 hepatectomies, 2,895 pancreatectomies, 3,639 gastrectomies, 1,555 esophagectomies, and 21,691 lung resections. Except for colon surgery, MA beneficiaries were less likely to receive care at a high-volume hospital. Mortality was significantly higher among MA beneficiaries (v TM) for gastrectomy (adjusted risk difference [ARD], 1.5%; 95% CI, 0.01 to 2.9; P = .036), pancreatectomy (ARD, 2.0%; CI, 0.80 to 3.3; P = .002), and hepatectomy (ARD, 1.4%; 95% CI, 0.1 to 2.9; P = .04). By contrast, compared with TM, MA beneficiaries incurred lower estimated hospital costs. CONCLUSION: Enrollment in MA plan is associated with lower estimated hospital costs. However, compared with TM, MA beneficiaries had lower access to high-volume hospitals and increased 30-day mortality for stomach, pancreas, or liver surgery.

Production of an interleukin-10 blocking antibody by genetically engineered macrophages increases cancer cell death in human gastrointestinal tumor slice cultures.

Although it can promote effector T-cell function, the summative effect of interleukin-10 (IL-10) in the tumor microenvironment (TME) appears to be suppressive; therefore, blocking this critical regulatory cytokine has therapeutic potential to enhance antitumor immune function. As macrophages efficiently localize to the TME, we hypothesized that they could be used as a delivery vehicle for drugs designed to block this pathway. To test our hypothesis, we created and evaluated genetically engineered macrophages (GEMs) that produce an IL-10-blocking antibody (αIL-10). Healthy donor human peripheral blood mononuclear cells were differentiated and transduced with a novel lentivirus (LV) encoding BT-063, a humanized αIL-10 antibody. The efficacy of αIL-10 GEMs was assessed in human gastrointestinal tumor slice culture models developed from resected specimens of pancreatic ductal adenocarcinoma primary tumors and colorectal cancer liver metastases. LV transduction led to sustained production of BT-063 by αIL-10 GEMs for at least 21 days. Transduction did not alter GEM phenotype as evaluated by flow cytometry, but αIL-10 GEMs produced measurable quantities of BT-063 in the TME that was associated with an ~5-fold higher rate of tumor cell apoptosis than control.