Transcriptomic Profiling of Tumor-Infiltrating CD4+TIM-3+ T Cells Reveals Their Suppressive, Exhausted, and Metastatic Characteristics in Colorectal Cancer Patients.

T cell immunoglobulin mucin-3 (TIM-3) is an immune checkpoint identified as one of the key players in regulating T-cell responses. Studies have shown that TIM-3 is upregulated in the tumor microenvironment (TME). However, the precise role of TIM-3 in colorectal cancer (CRC) TME is yet to be elucidated. We performed phenotypic and molecular characterization of TIM-3+ T cells in the TME and circulation of CRC patients by analyzing tumor tissues (TT, TILs), normal tissues (NT, NILs), and peripheral blood mononuclear cells (PBMC). TIM-3 was upregulated on both CD4+ and CD3+CD4- (CD8+) TILs. CD4+TIM-3+ TILs expressed higher levels of T regulatory cell (Tregs)-signature genes, including FoxP3 and Helios, compared with their TIM-3- counterparts. Transcriptomic and ingenuity pathway analyses showed that TIM-3 potentially activates inflammatory and tumor metastatic pathways. Moreover, NF-κB-mediated transcription factors were upregulated in CD4+TIM-3+ TILs, which could favor proliferation/invasion and induce inflammatory and T-cell exhaustion pathways. In addition, we found that CD4+TIM-3+ TILs potentially support tumor invasion and metastasis, compared with conventional CD4+CD25+ Tregs in the CRC TME. However, functional studies are warranted to support these findings. In conclusion, this study discloses some of the functional pathways of TIM-3+ TILs, which could improve their targeting in more specific therapeutic approaches in CRC patients.

Repeat liver resection for pure large cell neuroendocrine carcinoma of the gallbladder: a favorable outcome.

BACKGROUND: The pure large cell type is a rare variant of primary neuroendocrine carcinoma of the gallbladder. Few reports have mentioned extended survival. Although a multimodal treatment has been described in the treatment of such rare disease, redo liver resection has not yet been mentioned. CASE REPORT: A 67-year-old lady was found to have poorly differentiated, high grade, pure large cell neuroendocrine tumor of the gallbladder after cholecystectomy for gallstones. After the diagnosis, staging workup showed a lesion in segment IVB/V of the liver, and chromogranin was elevated (982 mcg/L). The patient underwent central inferior hepatectomy and wedge excision of a lesion in segment III (discovered intra-operatively), with hilar lymphadenectomy. Three months after the first liver resection, she developed a new liver lesion II/III and underwent left lateral liver resection. The patient remained disease-free for 4 months following the second liver resection but then developed recurrent liver disease and was started on chemotherapy. Further progression led to multi-organ failure and death at 26 months from initial diagnosis. CONCLUSION: This is the first reported repeat liver resection in such a rare disease that has led to extended overall survival. We suggest that a group of selected patients with this rare malignancy, and liver-limited disease, may benefit from repeated liver resection.

Noninvasive serum models to predict significant liver related events in chronic hepatitis C.

AIM: We aim to compare 20 noninvasive fibrosis scores (NIFS), derived from routine blood tests, for predicting significant liver-related adverse events (SLRE) in patients with chronic hepatitis C (CHC) after anti-viral treatment (AVT) with the goal to identify independent predictors for these outcomes. METHODS: From 1605 patients who received AVT (pegylated interferon and ribavirin) from January 2002 to June 2014, 20 NIFS were calculated from routine blood tests prior to AVT. Areas under the receiver-operating characteristic curve (AUROC) were calculated for each of these NIFS for predicting non-response to AVT and development of SLRE on follow-up. RESULTS: Mean age was 41.9 ± 9.7 years, and patients were predominantly genotype 4 (65%). After AVT, there were 1089 (67.8%) responders, 482 (30%) non-responders and 34 (2.1%) relapsers. After median follow-up of 6580.5 patient-years, 60 (3.8%) had SLRE, 52 (3.2%) had decompensation, and 11 (0.7%) had hepatocellular carcinoma (HCC). The predictive accuracy of NIFS and liver biopsy (LB) for non-response to AVT was low. FIB-4, FibroQ and King score showed high accuracy for predicting adverse events. For predicting decompensation, HCC and SLRE, FibroQ (0.881), King score (0.905) and FibroQ (0.877) had the highest AUROC, respectively. On multivariate analysis, independent predictors for treatment non-response (age, ALT, GGT, platelet count), HCC (albumin, GGT) and SLRE (albumin, GGT, platelet count) were identified. CONCLUSIONS: Some simple pretreatment blood parameters and NIFS showed high accuracy for predicting development of SLRE post treatment. Application of these simple scores can improve assessment of long-term liver prognosis for CHC.

Primary apocrine carcinoma of the axilla in a male patient: a case report.

Primary apocrine sweat gland carcinoma is a rare neoplasm. It is usually slow growing and is often suspected to be a benign disease at initial assessment. A thorough clinical and histological workup is required for diagnosis. Treatment of choice is wide local excision with clear margins.

Mean Platelet Volume, Red Cell Distribution Width to Platelet Count Ratio, Globulin Platelet Index, and 16 Other Indirect Noninvasive Fibrosis Scores: How Much Do Routine Blood Tests Tell About Liver Fibrosis in Chronic Hepatitis C?

BACKGROUND AND AIM: Many indirect noninvasive scores to predict liver fibrosis are calculated from routine blood investigations. Only limited studies have compared their efficacy head to head. We aimed to compare these scores with liver biopsy fibrosis stages in patients with chronic hepatitis C. MATERIALS AND METHODS: From blood investigations of 1602 patients with chronic hepatitis C who underwent a liver biopsy before initiation of antiviral treatment, 19 simple noninvasive scores were calculated. The area under the receiver operating characteristic curves and diagnostic accuracy of each of these scores were calculated (with reference to the Scheuer staging) and compared. RESULTS: The mean age of the patients was 41.8±9.6 years (1365 men). The most common genotype was genotype 4 (65.6%). Significant fibrosis, advanced fibrosis, and cirrhosis were seen in 65.1%, 25.6, and 6.6% of patients, respectively. All the scores except the aspartate transaminase (AST) alanine transaminase ratio, Pohl score, mean platelet volume, fibro-alpha, and red cell distribution width to platelet count ratio index showed high predictive accuracy for the stages of fibrosis. King's score (cutoff, 17.5) showed the highest predictive accuracy for significant and advanced fibrosis. King's score, Göteborg university cirrhosis index, APRI (the AST/platelet count ratio index), and Fibrosis-4 (FIB-4) had the highest predictive accuracy for cirrhosis, with the APRI (cutoff, 2) and FIB-4 (cutoff, 3.25) showing the highest diagnostic accuracy.We derived the study score 8.5 - 0.2(albumin, g/dL) +0.01(AST, IU/L) -0.02(platelet count, 10(9)/L), which at a cutoff of >4.7 had a predictive accuracy of 0.868 (95% confidence interval, 0.833-0.904) for cirrhosis. CONCLUSIONS: King's score for significant and advanced fibrosis and the APRI or FIB-4 score for cirrhosis could be the best simple indirect noninvasive scores.

Liver biopsy for parenchymal liver disease - is routine real time image guidance unnecessary?

Liver biopsy even today remains the standard of care for grading and staging chronic hepatitis despite advances in noninvasive markers of liver fibrosis. Literature suggests an expanding role for real-time image guided liver biopsy and declining trend for blind liver biopsies. In our center, where we perform around 400 liver biopsies per year, we performed a prospective clinical audit of our practice of blind outpatient percutaneous liver biopsies. Patients requiring histological grading and staging of chronic hepatitis routinely undergo blind outpatient percutaneous liver biopsies in our endoscopy unit unless there is a definite indication for real-time image guidance. All procedures were assessed for safety, and all specimens were evaluated by a specimen quality grading score for adequacy for grading and staging of chronic hepatitis. Of the 446 patients referred for histological grading and staging of chronic hepatitis C by liver biopsy, only 42 patients (9.5 %) required real-time ultrasound for liver biopsy. The remaining 404 patients underwent blind outpatient percutaneous liver biopsies which were found to be extremely safe with no major complications, yielding adequate liver tissue with high specimen quality score allowing optimal grading and staging of chronic hepatitis.