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Background: Lymph node (LN) harvesting is associated with outcomes in colonic cancer. We sought to interrogate whether a distinctive immune milieu of the primary tumour is associated with LN yield. Methods: A total of 926 treatment-naive patients with colorectal adenocarcinoma with more than 12 LNs (LN-high) were compared with patients with 12 or fewer LNs (LN-low). We performed immunohistochemistry and quantification on tissue microarrays for HLA class I/II proteins, beta-2-microglobulin (B2MG), CD8, CD163, LAG3, PD-L1, FoxP3, and BRAF V600E. Results: The LN-high group was comprised of younger patients, longer resections, larger tumours, right-sided location, and tumours with deficient mismatch repair (dMMR). The tumour microenvironment showed higher CD8+ cells infiltration and B2MG expression on tumour cells in the LN-high group compared to the LN-low group. The estimated mean disease-specific survival was higher in the LN-high group than LN-low group. On multivariate analysis for prognosis, LN yield, CD8+ cells, extramural venous invasion, perineural invasion, and AJCC stage were independent prognostic factors. Conclusion: Our findings corroborate that higher LN yield is associated with a survival benefit. LN yield is associated with an immune high microenvironment, suggesting that tumour immune milieu influences the LN yield. [ABSTRACT FROM AUTHOR]

Aims: Immunoglobulin 4‐related disease (IgG4‐RD) is a multisystem disease, characterised by tumefactive lesions and a swift response to immunosuppressive therapy. Although elevated serum and tissue IgG4 are characteristic, T cells appear to be the primary driver of this immunologically mediated disease. The overarching goal was to examine the role of immunomodulatory cells in IgG4‐RD. Methods and results: Biopsies from patients with IgG4‐RD (n = 39) and mimics of this disease (n = 78) were evaluated for IgG4, IgG, CD8, programmed cell death ligand 1 (PD‐L1) and a subset (n = 18) evaluated for CD4, purine rich box 1 (PU.1), forkhead box protein 3 (FoxP3), PD‐L1, programmed cell death 1 (PD‐1), indoleamine 2,3‐dioxygenase 1 (IDO1) and lymphocyte‐activation gene 3 (LAG3). Data pertaining to demographics and laboratory findings at baseline evaluation was extracted from electronic medical records. When compared to mimics, IgG4‐RD showed increased numbers of PD‐L1‐ (P = 0.0001), PD‐1‐ (P = 0.001), IDO1‐ (P = 0.03), LAG3‐ (P = 0.04) and FoxP3‐ (P = 0.04)‐positive immune cells. The PD‐L1‐positive cells were enriched within aggregates of CD4 and CD8‐positive T cells. Thirty‐one of 39 (80%) IgG4‐RD cases showed greater than five PD‐L1‐positive cells per high‐power field (HPF), while four of 78 (5%) mimics of this disease exceeded this cut‐point. In IgG4‐RD, PD‐L1‐positive macrophages correlated with PD‐1‐ (P = 0.002), LAG3‐ (P = 0.001) and IDO1‐positive cells (P = 0.001); a‐positive correlation was also noted between IgG4/IgG ratio and PD‐L1‐, PD‐1‐ and IDO1‐positive cells. Conclusions: IgG4‐RD shows expansion of mechanisms that maintain peripheral tolerance. The spatial and temporal relationship between T cells and the PD‐L1–PD‐1 axis and the up‐regulation of multiple immunomodulatory proteins suggests that these immunoregulatory mechanisms play a significant role in IgG4‐RD. [ABSTRACT FROM AUTHOR]

Indeed, a recent case report implicated enrichment of CD16+ NK cells in one patient with advanced HCC that spontaneously regressed.[6] Our patient's tumor exhibited a high TMB (Table 1). Hepatocellular carcinoma (HCC) is the sixth leading cause of cancer-related death in the United States[1] and the fourth worldwide.[2] Treatment of advanced HCC has been revolutionized in the past few years by combinations of therapies that stimulate the immune system to recognize and attack the cancer.[3],[4] The empirical success of this paradigm implies an immune-responsive nature of the HCC tumor microenvironment that can be pharmacologically manipulated. This case scores in the 95th percentile across all cancer types (out of 4,800 solid tumor specimens profiled) and in the 86th percentile in the subset of HCC (15 HCC specimens profiled) on our targeted panel assay. [Extracted from the article]

Hepatocellular carcinoma (HCC) is the sixth leading cause of cancer-related death in the United States[1] and the fourth worldwide.[2] Treatment of advanced HCC has been revolutionized in the past few years by combinations of therapies that stimulate the immune system to recognize and attack the cancer.[3],[4] The empirical success of this paradigm implies an immune-responsive nature of the HCC tumor microenvironment that can be pharmacologically manipulated. This case scores in the 95th percentile across all cancer types (out of 4,800 solid tumor specimens profiled) and in the 86th percentile in the subset of HCC (15 HCC specimens profiled) on our targeted panel assay. Indeed, a recent case report implicated enrichment of CD16+ NK cells in one patient with advanced HCC that spontaneously regressed.[6] Our patient's tumor exhibited a high TMB (Table 1). [Extracted from the article]

Background: While many pancreatic neuroendocrine tumours (PanNET) show indolent behaviour, predicting the biological behaviour of small nonfunctional PanNETs remains a challenge. Nonfunctional PanNETs with an epigenome and transcriptome that resemble islet alpha cells (ARX‐positive) are more aggressive than neoplasms that resemble islet beta cells (PDX1‐positive). In this study, we explore the ability of immunohistochemistry for ARX and PDX1 and telomere‐specific fluorescence in situ hybridisation (FISH) for alternative lengthening of telomeres (ALT) to predict recurrence. Methods: Two hundred fifty‐six patients with PanNETs were identified, and immunohistochemistry for ARX and PDX1 was performed. Positive staining was defined as strong nuclear staining in >5% of tumour cells. FISH for ALT was performed in a subset of cases. Results: ARX reactivity correlated with worse disease‐free survival (DFS) (P = 0.011), while there was no correlation between PDX1 reactivity and DFS (P = 0.52). ALT‐positive tumours (n = 63, 31.8%) showed a significantly lower DFS (P < 0.0001) than ALT‐negative tumours (n = 135, 68.2%). ARX reactivity correlated with ALT positivity (P < 0.0001). Among nonfunctional tumours, recurrence was noted in 18.5% (30/162) of ARX‐positive tumours and 7.5% (5/67) of ARX‐negative tumours. Among WHO grade 1 and 2 PanNETs with ≤2 cm tumour size, 14% (6/43) of ARX‐positive tumours recurred compared to 0 of 33 ARX‐negative tumours and 33.3% (3/9) ALT‐positive tumours showed recurrence versus 4.4% (2/45) ALT‐negative tumours. Conclusion: Immunohistochemistry for ARX and ALT FISH status may aid in distinguishing biologically indolent cases from aggressive small low‐grade PanNETs, and help to identify patients who may preferentially benefit from surgical intervention. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Infiltrating tumor border configuration (ITBC) portends a poor prognosis compared with pushing tumor border configuration (PTBC) in colorectal cancer. The tumor and its surrounding immune microenvironment of tumor border configuration is not well-characterized. We aim to elucidate the differences in expression of molecular markers between the 2 groups using tissue microarray (TMA). STUDY DESIGN: Immunohistochemistry was performed on TMAs of surgical pathology specimens obtained from colorectal cancer patients consecutively operated at our institution from 2004 to 2015. TMAs were stained for immune cells (CD8, FOXP3, LAG3, PU1, CD163, and PDL1); HLA II, beta 2 microglobulin, and HC10 on tumor cells; BRAFV600E mutation; and DNA mismatch repair proteins (MMR) status. Patients who received neoadjuvant therapy were excluded. RESULTS: There were 646 tumors with ITBC and 310 tumors with PTBC. There was a significantly lower expression (p < 0.05) of immune components, namely CD8, FOXP3, LAG3, PU1, PDL1 immune cells, and Beta-2 Microglobulin on tumor cells in the tumors with ITBC compared with PTBC, except CD163 immune cells, and HC10 and HLAII on tumor cells. Tumors with ITBC were less likely to be associated with BRAFV600E mutations and deficient MMR proteins (p < 0.001). On analyzing MMR-proficient tumors separately, we could not find any difference in the expression of any molecular marker (including BRAF), except a lower expression of PDL1 immune cells in tumors with ITBC (p < 0.001). CONCLUSIONS: Colorectal tumors with ITBC are associated with a generalized low immune microenvironment and low rates of BRAFV600E mutation compared with tumors with PTBC. However, the molecular expression of tumor border configuration seems confounded by the MMR molecular signature. MMR-proficient colorectal tumors with ITBC are associated with a lower expression of only PDL1 immune cells among all immune markers examined. [ABSTRACT FROM AUTHOR]

Background: Serrated adenocarcinoma (SAC), a recognised WHO variant of colonic adenocarcinoma, is the purported end‐product of serrated neoplasia. However, the diagnosis of SAC is infrequently rendered, and little is known about its prognosis, immune microenvironment and molecular alterations. Materials and methods: We assessed 903 consecutive colon carcinomas and recognised tumours with ≥ 5% (n = 77) serrated and ≥ 50% serrated patterns (n = 13). We assessed precursor polyps and synchronous polyps. We recorded demographic/clinical parameters, histological features and mismatch repair (MMR) status. We performed immunohistochemistry and quantification on tissue microarray for HLA class I/II proteins, B2MG, CD8, CD163, LAG3, FoxP3, PD‐L1 and BRAF V600E. Results: We identified ≥ 5% epithelial serration prevalence in 8.5% of cases and ≥ 50% epithelial serration prevalence in 1.4% of cases. Precursor lesions were present in 21.4% of cases; these were mostly tubular adenomas with two traditional serrated adenomas identified. SAC with ≥ 5% serrations exhibited lower numbers of CD8‐positive lymphocytes (P = 0.002) and lower B2MG expression (P = 0.048), although neither value was significant at ≥ 50% serration threshold. There was no difference in HLA class I/II, or PD‐L1 expression on tumour cells and no difference in PD‐L1, LAG3, FoxP3 and CD163 expression on immune cells. There was no association with MMR status, or BRAFV600E relative to conventional adenocarcinoma. There was improved disease‐specific survival on univariate (but not multivariate) analysis between carcinomas with serrated pattern and non‐mucinous conventional colonic carcinomas at ≥ 5% epithelial serrations (P = 0.04). Conclusion: SAC category shows a limited impact on survival, and this phenotype may harbour a unique immunological milieu. [ABSTRACT FROM AUTHOR]

Aberrant expression of viral-like repeat elements is a common feature of epithelial cancers, and the substantial diversity of repeat species provides a distinct view of the cancer transcriptome. Repeatome profiling across ovarian, pancreatic, and colorectal cell lines identifies distinct clustering independent of tissue origin that is seen with coding gene analysis. Deeper analysis of ovarian cancer cell lines demonstrated that human satellite II (HSATII) satellite repeat expression was highly associated with epithelial-mesenchymal transition (EMT) and anticorrelated with IFN-response genes indicative of a more aggressive phenotype. SATII expression - and its correlation with EMT and anticorrelation with IFN-response genes - was also found in ovarian cancer RNA-Seq data and was associated with significantly shorter survival in a second independent cohort of patients with ovarian cancer. Repeat RNAs were enriched in tumor-derived extracellular vesicles capable of stimulating monocyte-derived macrophages, demonstrating a mechanism that alters the tumor microenvironment with these viral-like sequences. Targeting of HSATII with antisense locked nucleic acids stimulated IFN response and induced MHC I expression in ovarian cancer cell lines, highlighting a potential strategy of modulating the repeatome to reestablish antitumor cell immune surveillance. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the association between psychiatric comorbidities, substance use disorders and heroin overdose-related hospitalizations (HOD). Next, to understand the demographic trend of HOD hospitalizations and comorbidities. Methods: Using the Nationwide Inpatient Sample (NIS), we included 27,442,808 child and adolescent hospitalizations, and 1432 inpatients (0.005%) were managed primarily for HOD. The odds ratio (OR) of the association of variables in HOD inpatients were measured using a logistic regression model. Results: Adolescents had 56 times higher odds (95% CI 43.36–73.30) for HOD-related hospitalizations compared to 4.6% children under 11 years. About three-fifth of the HOD inpatients were male, and they had 1.5-fold higher odds (95% CI 1.30–1.64) compared to 43% females in the study population. Whites were considerably higher in proportion (81%) than other race/ethnicities. A greater portion of HOD inpatients (40%) were from high-income families. Most common comorbid psychiatric disorders were mood (43.8%) and anxiety (20.4%). The prevalent comorbid substance use disorders were opioid (62.4%), tobacco (36.8%) and cannabis (28.5%) use disorders. Conclusion: HOD-related hospitalizations were predominant in males, White and older adolescents (12–18 years). Prescription opioids are the bridge to heroin abuse, thereby increasing the vulnerability to other substance abuse. This requires more surveillance and should be explored to help reduce the heroin epidemic in children. [ABSTRACT FROM AUTHOR]

Objective: Our study aimed to compare the demographic characteristics of conduct disorder (CD) inpatients versus other psychiatric inpatients in children and adolescents, and assess the association between conduct disorder patients and the spectrum of substance use disorders (SUD). Methods: We included 800,614 psychiatric adolescent (12–18 years) inpatients, and this included 8885 inpatients (1.1%) primarily for conduct disorder in the Nationwide Inpatient Sample (2010–2014). ICD-9 codes were used to detect SUD, and a logistic regression model was used to evaluate the odds ratio (OR) for SUD in conduct disorder inpatients. Results: A higher proportion of conduct disorder inpatients were of 12–15 years of age (62.6%), male (64.4%), and White (45.7%). The lower median household income was correlated with a higher prevalence of conduct disorder (36.4%). Among SUD, cannabis use (23.7%) was most prevalent in conduct disorder inpatients followed by tobacco and alcohol use (10.1% each). Conduct disorder inpatients have 1.7-fold higher odds (95% confidence interval (CI) 1.52–1.82) for alcohol use and 1.4-fold higher odds (95% CI 1.31–1.49) for cannabis use compared to the non-conduct disorder inpatients. Cannabis use was seen significantly in adolescents (49.1%, 12–15 years), male (75.6%), and African Americans (45.6%). Conclusion: Conduct disorder inpatients have a higher risk of comorbid SUD compared to other psychiatric illnesses. The most common substance to be abused is cannabis followed by tobacco and alcohol. Varying pattern of substance use was seen by demographics and these predictors may help the clinicians for early diagnosis and treatment to improve overall health-related quality of life. [ABSTRACT FROM AUTHOR]