Adrenocortical carcinoma in patients with MEN1: a kindred report and review of the literature

Objective: Up to 40% of multiple endocrine neoplasia type 1 (MEN1) patients may have adrenal cortical tumors. However, adrenocortical carcinoma (ACC) is rare. The clinical manifestations, prevalence, inheritance and prognosis of ACC associated with MEN1 remain unclear. Here we report the clinical manifestations and prevalence of ACC in patients with MEN1. Design and methods: A retrospective analysis of ACC associated with MEN1 patients at a single tertiary care center from December 2001 to June 2017. Genetic analysis of MEN1 and other ACC associated genes, loss of heterozygosity (LOH) of MEN1 locus, immunohistochemistry staining of menin, P53 and β-catenin in ACC tissue were performed. Results: Two related patients had ACC associated with MEN1. The father had ENSAT stage IV tumor with excessive production of cortisol; the daughter had nonfunctional ENSAT stage I tumor. Both patients carried novel germline heterozygous mutation (c.400_401insC) of MEN1. The wild-type MEN1 allele was lost in the resected ACC tissue from the daughter with no menin staining. The ACC tissue had nuclear β-catenin staining, with heterozygous CTNNB1 mutation of 357del24 and P53 staining in only 20% cells. Conclusions: ACC associated with MEN1 is rare and may occur in familial aggregates

Survey of Tyrosine Kinase Signaling Reveals ROS Kinase Fusions in Human Cholangiocarcinoma

Cholangiocarcinoma, also known as bile duct cancer, is the second most common primary hepatic carcinoma with a median survival of less than 2 years. The molecular mechanisms underlying the development of this disease are not clear. To survey activated tyrosine kinases signaling in cholangiocarcinoma, we employed immunoaffinity profiling coupled to mass spectrometry and identified DDR1, EPHA2, EGFR, and ROS tyrosine kinases, along with over 1,000 tyrosine phosphorylation sites from about 750 different proteins in primary cholangiocarcinoma patients. Furthermore, we confirmed the presence of ROS kinase fusions in 8.7% (2 out of 23) of cholangiocarcinoma patients. Expression of the ROS fusions in 3T3 cells confers transforming ability both in vitro and in vivo, and is responsive to its kinase inhibitor. Our data demonstrate that ROS kinase is a promising candidate for a therapeutic target and for a diagnostic molecular marker in cholangiocarcinoma. The identification of ROS tyrosine kinase fusions in cholangiocarcinoma, along with the presence of other ROS kinase fusions in lung cancer and glioblastoma, suggests that a more broadly based screen for activated ROS kinase in cancer is warranted

The association between Toll-like receptor 2 single-nucleotide polymorphisms and hepatocellular carcinoma susceptibility

<p>Abstract</p> <p>Background</p> <p>Toll-like receptors (TLR) are key innate immunity receptors participating in an immune response. Growing evidence suggests that mutations of TLR2/TLR9 gene are associated with the progress of cancers. The present study aimed to investigate the temporal relationship of single nucleotide polymorphisms (SNP) of TLR2/TLR9 and the risk of hepatocellular carcinoma (HCC).</p> <p>Methods</p> <p>In this single center-based case-control study, SNaPshot method was used to genotype sequence variants of TLR2 and TLR9 in 211 patients with HCC and 232 subjects as controls.</p> <p>Results</p> <p>Two synonymous SNPs in the exon of TLR2 were closely associated with risk of HCC. Compared with those carrying wild-type homozygous genotypes (T/T), risk of HCC decreased significantly in individuals carrying the heterozygous genotypes (C/T) of the rs3804099 (adjusted odds ratio (OR), 0.493, 95% CI 0.331 - 0.736, <it>P </it>< 0.01) and rs3804100 (adjusted OR, 0.509, 95% CI 0.342 - 0.759, <it>P </it>< 0.01). There was no significant association found in two TLR9 SNPs concerning the risk of HCC. The haplotype TT for TLR2 was associated significantly with the decreased risk of HCC (OR 0.524, 95% CI 0.394 - 0.697, <it>P </it>= 0.000). Inversely, the risk of HCC increased significantly in patients with the haplotype CC (OR 2.743, 95% CI 1.915 - 3.930, <it>P </it>= 0.000).</p> <p>Conclusions</p> <p>These results suggested that TLR2 rs3804099 C/T and rs3804100 C/T polymorphisms were closely associated with HCC. In addition, the haplotypes composed of these two TLR2 synonymous SNPs have stronger effects on the susceptibility of HCC.</p

Single Nucleotide Polymorphisms of Toll-Like Receptor 4 Decrease the Risk of Development of Hepatocellular Carcinoma

BACKGROUND: Toll-like receptor 4 (TLR4) is a key innate immunity receptor that initiates an inflammatory response. Growing evidence suggests that mutation of TLR4 gene may play a role in the development of cancers. This study aimed to investigate the temporal relationship of single nucleotide polymorphisms of TLR4 and the risk of hepatocellular carcinoma, a single center-based case-control study was conducted. METHODS: A systematic genetic analysis of sequence variants of TLR4 by evaluating ten single-nucleotide polymorphisms was performed from 216 hepatocellular carcinoma cases and 228 controls. RESULTS: Six single nucleotide polymorphisms of the TLR4 in the 5'-untranslated region and intron were associated with risk of hepatocellular carcinoma. Individuals carrying the heterozygous genotypes for the rs10759930, rs2737190, rs10116253, rs1927914, rs12377632 and rs1927911 had significantly decreased risk of hepatocellular carcinoma (adjusted odds ratio [OR], from 0.527 to 0.578, P<0.01) comparing with those carrying wild-type homozygous genotypes. In haplotype analysis, one haplotype (GCCCTTAG) of TLR4 was associated significantly with decrease of the occurrence of hepatocellular carcinoma (OR, 0.556, 95% confidence interval [CI], 0.407-0.758, P = 0.000). CONCLUSIONS: Collectively, these results suggested that the risk of hepatocellular carcinoma was associated with TLR4 sequence variation. TLR4 single nucleotide polymorphisms may play an important protective role in the development of hepatocellular carcinoma

Real‐world implications of nonbiological factors with staging, clinical management, and prognostic prediction in pancreatic ductal adenocarcinoma

Abstract Background The American Joint Committee on Cancer (AJCC) tumor‐node‐metastasis (TNM) staging system focuses on traditional biological factors (BFs). The present study incorporates nonbiological factors (NBFs) into the AJCC‐TNM staging system in terms of the advanced clinical management and prognostic‐prediction accuracy of pancreatic ductal adenocarcinoma (PDAC). Methods Eight thousand three hundred and thirty eligible patients with PDAC were obtained from Surveillance, Epidemiology, and End Results database between January 1, 2011, and December 31, 2015. Multivariate Cox proportional hazards regression analysis and Kaplan–Meier curves were used to testify the feasibility of cancer‐specific survival (CSS) prediction based on TNM‐NBF stages. Results The large population‐based study demonstrated that NBFs (insurance status, marital status, county‐level median household income, and unemployment) were significant prognostic indicators (p < 0.005), and multivariate Cox regression analysis demonstrated that the NBF1 stage carried a 29.4% increased risk of cancer‐specific mortality than NBF0 stage (p < 0.001). The concordance index of TNM‐NBF stage was 0.755 (95% confidence interval: 0.740–0.769). Conclusions The novel NBF stage was independently associated with CSS of PDAC. In addition, combining TNM with the NBF stage could provide better clinical management and prognostic‐prediction accuracy

Pancreatic index: A prognostic factor of upfront surgery for body or tail pancreatic ductal adenocarcinoma with vascular involvement—A retrospective study

Abstract Background The pancreatic index (PI) is a useful preoperative imaging predictor for pancreatic ductal adenocarcinoma (PDAC). In this retrospective study, we determined the predictive effect of PI to distinguish patients of pancreatic body/tail cancer (PBTC) with vascular involvement who can benefit from upfront surgery. Method All patients who received distal pancreatectomy for PDAC from 2016 to 2020 at the Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine were considered for the study. A total of 429 patients with PBTC were assessed in relation to the value of PI. Fifty‐five patients were eventually included and divided into low PI group and 29 patients in the normal PI group. Results The median overall survival (mOS) was significantly shorter in the low PI group (13.1 vs. 30.0 months, p = 0.002) in this study, and PI ≥ 0.78 (OR = 0.552, 95% CI: 0.301–0.904, p = 0.020) was an independent influencing factor confirmed by multivariate analysis. Subgroup analysis showed that PI was an independent prognostic factor for LA‐PBTC (OR = 0.272, 95% CI: 0.077–0.969, p = 0.045). As for BR PBTC, PI (OR = 0.519, 95% CI: 0.285–0.947, p = 0.033) combined with carbohydrate antigen 125 (CA125) (OR = 2.806, 95% CI: 1.206–6.526, p = 0.017) and chemotherapy (OR = 0.327, 95% CI: 0.140–0.763, p = 0.010) were independent factors. Conclusion This study suggests that the PI can be used as a predictive factor to optimize the surgical indication for PBTC with vascular involvement. Preoperative patients with normal PI and CA125 can achieve a long‐term prognosis comparable to that of resectable PBTC patients

The impact of Omicron pandemic and COVID‐19 vaccination on the pancreatic adenocarcinoma patients

Abstract Background The coronavirus disease 2019 (COVID‐19) pandemic resulted in enormous medical and economic burden worldwide during the past 3 years. The vaccination was deemed the effective option to prevent the severe symptoms, and especially recommended among cancer patients. Shanghai experienced the first lockdown during the recent Omicron pandemic since 2019. How patients with pancreatic adenocarcinoma (PAC) suffered from the pandemic and how vaccination influenced their oncological outcomes were unexplored yet. Method The retrospective study was carried out in a high‐volume referral center including 1157 consecutively enrolled patients with PAC experiencing the COVID‐19 pandemic. The primary outcome was the overall survival (OS). Results Limited postoperative patients (9.21%) received the vaccination. The lockdown in Shanghai (April to May, 2022) was not observed impacting the survival prognoses of patients with PAC. Though vaccination was not significantly associated with OS itself (adjusted hazard ratio (aHR): 2.032 [0.940–4.391], p = 0.071), it was discovered to synergistically improve the chemotherapy effect in the multivariate analyses (interaction p = 0.023). Conclusion The vaccination itself did not influence the survival prognoses of patients with PAC. A potential positive interaction was observed between chemotherapy and vaccination despite the limited follow‐up time. The postoperative patients should consider the vaccination more. The patients with PAC did not suffer worse prognostic outcomes from the strict sanitary policy during the wave of COVID‐19 pandemic in Shanghai

The proposed modification of TNM staging and therapeutic strategy for skip metastasis in papillary thyroid carcinoma: A multicenter retrospective cohort study

Abstract Background Skip metastasis is a special type of lateral lymph node metastasis, which is not classified definitely by the eighth edition of the AJCC TNM staging system. The aim of the research was to study the prognosis of skip metastasis in PTC patients, and carry out a more appropriate N staging for skip metastasis. Methods Study subjects were 3167 patients with papillary thyroid carcinoma (PTC), who underwent thyroidectomy at three clinical centers from 2016 to 2019. We identified two well‐balanced cohorts matched on the basis of propensity score. Results During a median follow‐up of 42 months, recurrence occurred in 68 (4.3%) patients with lymph node metastasis. 34 cases recurred in 1120 patients with central lymph node metastasis (N1a), and 34 recurred in 461 patients with lateral lymph node metastasis (N1b), among which 73 patients were diagnosis with skip metastasis. The RFS of N1a was significantly lower than that of N1b (p < 0.001). After propensity‐score matching, recurrence rate was significantly lower in the skip metastasis group than in the LLNM group (p = 0.039), whereas the rate was similar in the skip metastasis groups and the CLNM group (p = 0.29). Conclusions In conclusion, our study indicated that, among patients with LLNM, those with positive skip metastasis showed significantly lower recurrence, exhibiting a similar rucurrence tendency as patients with CLNM. Thus, skip metastasis could be categorized into N1a stage rather than N1b stage based on the AJCC TNM staging system. The downstaging of skip metastasis may reveal more conservative treatment strategy