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The initiation and progression of cancer are intricately linked to the tumor microenvironment (TME). Understanding the function of specific cancer-TME interactions poses a major challenge due in part to the complexity of the in vivo microenvironment. Here we predict cancer-TME interactions from single cell transcriptomic maps of both human colorectal cancers (CRCs) and mouse CRC models, ask how these interactions are altered in human tumor organoid (tumoroid) cultures, and functionally recapitulate human myeloid-carcinoma interactions in vitro. Tumoroid cultures suppress gene expression programs involved in inflammation and immune cell migration, providing a reductive platform for re-establishing carcinoma-immune cell interactions in vitro. Introduction of human monocyte-derived macrophages into tumoroid cultures instructs macrophages to acquire immunosuppressive and pro-tumorigenic gene expression programs similar to those observed in vivo. This includes hallmark induction of SPP1 , encoding Osteopontin, an extracellular CD44 ligand with established oncogenic effects. Taken together, these findings offer a framework for understanding CRC-TME interactions and provide a reductionist tool for modeling specific aspects of these interactions. Tumour-microenvironment interactions, pivotal in cancer progression, are challenging to replicate in vitro. Here, the authors use single-cell RNA-seq to analyse these interactions in colorectal cancer within organoid models, and aim to emulate and understand these crucial interactions by introducing specific microenvironmental components.

BackgroundType I gastric neuroendocrine tumors (GNETs) are typically managed either expectantly or endoscopically. In contrast, locoregional surgery has been recommended for patients with type III GNETs because of the risk of metastasis. This study aimed to identify predictors of outcome independent of type in a contemporary cohort of GNET patients.MethodsA single-institution retrospective cohort study of 121 patients with a pathologic diagnosis of primary GNET between January 2009 and June 2019 was performed. GNETs were designated as type 1 (n = 74) if atrophic gastritis was present, or as type III (n = 47) in the absence of atrophic gastritis. Demographic, clinical, and histopathologic factors were examined using Kaplan–Meier and multivariable Cox regression to assess the impact of various factors on recurrence and overall survival.ResultsMedian follow-up for the entire cohort was 62.7 months. While there was no difference in OS in patients with different GNET types (p = 0.10), higher tumor grade (p = 0.02) and presence of nodal or distant metastases (p = 0.02) predicted worse survival on multivariable analysis. Among type III GNET patients, those with small (< 0.5 cm), grade 1 lesions (“low-risk”) were less likely to develop metastases (0% versus 33%, p < 0.01) and more likely to survive (100% versus 67%, p < 0.01) at 5 years.ConclusionsSize and tumor grade predict recurrence and survival in patients with GNETs irrespective of type. Small, low-grade type III GNETs are associated with minimal risk of progression and may be managed accordingly.

The last decade has witnessed significant progress in the field of cancer immunotherapy. This has, in part, been driven by a growing recognition that elements of the innate immune response can be harnessed to induce robust immunity against tumor-associated targets. Nonetheless, as clinically effective immunotherapy for the majority of cancers remains a distant goal, attention has shifted toward multimodality approaches to cancer therapy, sometimes combining novel immunotherapeutics and conventional therapeutics. The traditional view of radiation therapy as immunosuppressive has been challenged, prompting a re-evaluation of its potential as an adjunct to, or even a component of immunotherapy. Radiation therapy may enhance expression of tumor-associated antigens, induce targeting of tumor stroma, diminish regulatory T-cell activity and activate effectors of innate immunity such as dendritic cells through Toll-like receptor (TLR)-dependent mechanisms. Here, we review recent progress in the field of dendritic cell-based immunotherapy, evidence for radiation-induced antitumor immunity and TLR signaling and the results of efforts to rationally integrate radiation into dendritic cell-based immunotherapy strategies.

BackgroundAdequate lymphadenectomy with at least 16 nodes retrieved at the time of gastrectomy is a quality measure recommended to ensure adequate staging. The minimum nodal retrieval recommended after receipt of neoadjuvant chemotherapy (NACT) is less defined.MethodsPatients with clinical stages 1 to 3 gastric adenocarcinoma who received NACT and surgical resection were identified from the 2004–2015 National Cancer Database. The optimal nodal harvest number was calculated with Cox spline regression modeling. Cohorts with a nodal harvest higher or lower than this number were 1:1 propensity score-matched. Overall survival (OS) was analyzed using Kaplan-Meier survival estimates.ResultsAmong 4337 patients receiving NACT, the optimal minimal nodal harvest at gastrectomy was 23 nodes. Compared with the patients who had fewer than 23 nodes retrieved, the patients with at least 23 nodes examined (n = 1073, 24.7%) were more likely to be female (26.1% vs 22%; p = 0.006) and non-white (29.3% vs 18.5%; p < 0.0001), to have a Charlson-Deyo score of 0 (71.5% vs 66.8%; p = 0.005), and to have undergone resection at an academic facility (67.9% vs 51.5%; p < 0.0001). The patients with at least 23 nodes examined had higher proportions of high-grade tumor (62% vs 57.4%; p = 0.030), pT3 or pT4 tumor (56.3% vs 48.7%; p < 0.0001), body tumor (21.3% vs 12.5%; p < 0.0001), or antrum/pylorus tumor (15.3% vs 11.4%; p < 0.0001). The patients with at least 23 nodes were more likely to have lymph node metastases identified (61% vs 51%; p < 0.0001). After matching, the patients with at least 23 nodes (n = 990) demonstrated an improved 5-year OS (57.9% vs 49%; p = 0.001).ConclusionsThe extent of lymphadenectomy during gastrectomy for gastric adenocarcinoma should not be reduced after NACT because adequate lymph node retrieval remains important for prognostication.

Background Cytoreduction with intraperitoneal chemotherapy (IPC) for treatment of peritoneal surface malignancies is increasingly utilized. However, the described morbidity and mortality rates are based predominantly on the experience at high-volume centers. We analyzed the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database for a nationwide perspective on morbidity and mortality associated with IPC. Methods The NSQIP database was queried for all patients undergoing IPC and cytoreduction from 2005 to 2011. Univariate and forward stepwise multivariate regression identified factors associated with 30-day death and morbidity. Results A total of 795 patients underwent IPC. Patients underwent a median of seven operative procedures (range 2–13). Median hospital stay was 9 days (range 2–79 days). A total of 521 complications occurred in 249 (31 %) patients, and there were 19 (2.3 %) mortalities. The most common complications were bleeding (15.1 %) and sepsis (14.6 %). Univariate analysis identified age ≥60 years, ascites, weight loss, recent prior operation, albumin <3 g/dl, bilirubin ≥2 mg/dl, hematocrit ≤30 %, colon, spleen, small bowel, liver, kidney, diaphragm, and gastric resections, wound classification, operative time, and intraoperative transfusion requirement as significantly associated with death and morbidity. By multivariate analysis, age ≥60 years, preoperative albumin <3 g/dl, gastrectomy, operative time, and intraoperative transfusion requirement remained significantly associated with death and morbidity. Particularly high death and morbidity rates were associated with preoperative albumin <3 g/dl (58 %), gastrectomy (62 %), and operative time of >500 min (46 %). Conclusions In this nationwide cohort, the death and morbidity rate associated with cytoreduction and IPC is consistent with other large series. Age ≥60 years, albumin <3 g/dl, gastrectomy, operative time, and intraoperative transfusion requirement were associated with 30-day death and morbidity. These factors may help guide patient selection, counseling, and preoperative optimization before IPC.

BackgroundSmall (< 2 cm) and diminutive (< 1 cm) rectal neuroendocrine tumors (RNETs) are often described as indolent lesions. A large single-center experience was reviewed to determine the incidence of metastasis and the risk factors for its occurrence.MethodsCases of RNET between 2010 and 2017 at a single institution were retrospectively reviewed. The rate of metastasis was determined, and outcomes were stratified by tumor size and grade. Uni- and multivariable predictors of metastasis were identified, and a classification and regression tree analysis was used to stratify the risk for distant metastasis.ResultsThe study identified 98 patients with RNET. The median follow-up period was 28 months. Of the 98 patients, 79 had primary tumors smaller than 1 cm, 8 had tumors 1 to 2 cm in size, and 11 had tumors 2 cm in size or larger. In terms of grade, 86 patients had grade 1 (G1) tumors, 8 patients had grade 2 (G2) tumors, and 4 patients had grade 3 (G3) tumors. Twelve patients developed metastatic disease. Both size and grade were associated with distant metastasis in the uni- and multivariable analyses, but when stratified by grade, size was predictive of metastasis only for G1 tumors (p < 0.001). Among the 12 patients with metastatic disease, 3 (25%) had diminutive primary tumors, and 9 (75%) had primary tumors 2 cm in size or larger. Diminutive tumors that metastasized were all G2.ConclusionsPatients with diminutive and small RNETs are at risk for metastatic disease. Tumor grade is a dominant predictor of dissemination. More rigorous staging, closer surveillance, or more aggressive initial management may be warranted for patients with G2 tumors, irrespective of size.

Abstract Context Pheochromocytomas and paragangliomas (PCC/PGL) are neuroendocrine tumors with discrete catecholamine profiles that cause incompletely understood metabolic and physiologic changes. Objective The objective was to evaluate relationships between plasma catecholamines, body weight, and hemoglobin A1c (HbA1c). We hypothesized that individual catecholamines would correlate negatively with weight and glucose control. Design A retrospective cohort study was performed (1999-2020). Wilcoxon rank-sum tests compared nonparametric, continuous variables; mixed-effect linear modeling (MEM) evaluated relationships between catecholamines and weight or HbA1c. The median study duration was 54.2 months [interquartile range (IQR) 19.0-95.1]. Setting Tertiary academic hospital. Patients 360 patients were identified prospectively by referral to our center for management or surveillance of PCC/PGL. The median age was 59 years (IQR 45-67) and 56.4% (n = 203) were female. Main outcome measures The primary and secondary outcomes were weight and HbA1c, respectively. Results On multivariable MEM, norepinephrine (P < 0.0005) negatively correlated with weight when all catecholamines and their derivatives were tried in the model, and normetanephrine (P < 0.0005) correlated when only metanephrines were included. In the surgical cohort (n = 272), normetanephrine decreased postoperatively and was inversely associated with weight (P < 0.0005). Elevated norepinephrine or normetanephrine at the study termination, indicative of metastatic and/or recurrent disease (MRD), correlated with weight loss. Norepinephrine and normetanephrine (P < 0.0005) directly correlated with HbA1c. Conclusion Plasma norepinephrine and its metabolite directly correlate with HbA1c and inversely correlate with weight in PCC/PGL. After resection, declining normetanephrine levels correlate with improving HbA1c despite an increase in patient body weight. Persistently elevated catecholamines and decreasing weight are observed in MRD.

This study assessed the relationship between surgeon volume, operative management, and resource utilization in adrenalectomy. Isolated adrenalectomies performed within our health system were identified (2016–2021). High-volume surgeons were defined as those performing ≥6 cases/year. Outcomes included indication for surgery, perioperative outcomes, and costs. Of 476 adrenalectomies, high-volume surgeons (n ​= ​3) performed 394, while low-volume surgeons (n ​= ​12) performed 82. High-volume surgeons more frequently operated for pheochromocytoma (19% vs. 16%, p ​< ​0.001) and less frequently for metastasis (6.4% vs. 23%, p ​< ​0.001), more frequently used laparoscopy (95% vs. 80%, p ​< ​0.001), and had lower operative supply costs ($1387 vs. $1,636, p ​= ​0.037). Additionally, laparoscopic adrenalectomy was associated with shorter length of stay (−3.43 days, p ​< ​0.001), lower hospitalization costs (-$72,417, p ​< ​0.001), and increased likelihood of discharge to home (OR 17.03, p ​= ​0.008). High-volume surgeons more often resect primary adrenal pathology and utilize laparoscopy. Laparoscopic adrenalectomy is, in turn, associated with decreased healthcare resource utilization. [Display omitted] •We assessed the relationship between surgeon volume and outcomes in adrenalectomy.•High-volume surgeons more frequently operated on primary adrenal pathology.•High-volume surgeons were more likely to use a laparoscopic approach.•Laparoscopy was associated with reduced resource utilization.