Impact of Indocyanine Green Fluorescence Imaging on Lymphadenectomy Quality During Laparoscopic Distal Gastrectomy for Gastric Cancer (Greeneye): An Adaptative, Phase 2, Clinical Trial.

BACKGROUND: Indocyanine green (ICG)-guided lymphadenectomy using near-infrared visualization (NIR) may increase nodal yield during gastrectomy. The purpose of this study was to evaluate the clinical benefit of NIR visualization on the quality of D2 lymphadenectomy during laparoscopic distal gastrectomy. METHODS: This single-arm, open-label, Simon's two-stage, adaptive, phase 2 trial included patients who underwent laparoscopic distal gastrectomy for gastric adenocarcinoma. Endoscopic peritumoral injection of ICG was performed 24 ± 6 h before surgery. Intraoperatively, after standard D2 lymphadenectomy and specimen extraction, NIR was used for eventual completion lymphadenectomy. The primary endpoint was clinical benefit of NIR (i.e., at least one additional harvested station containing lymph nodes, with negative points for every harvested station with no lymph nodes at final pathology). RESULTS: We enrolled 18 patients (61% female, median age 69 years). With NIR, an extra 23 stations were harvested: 9 contained no lymph nodes, 12 contained nonmetastatic lymph nodes, and 2 contained metastatic lymph nodes. The most commonly visualized station with NIR were station 6 (8 patients) and 1 (4 patients). The total number of harvested nodes per patient was 32 (interquartile range [IQR] 26-41), with a median of 1 (IQR 0-1) additional lymph node after NIR. Overall, seven (39%) patients had a clinical benefit from NIR, of which two (11%) had one metastatic lymph node harvested with NIR. CONCLUSIONS: NIR visualization improves the quality of D2 lymphadenectomy in distal gastrectomy for gastric cancer. Considering the limited improve in the number of harvested lymph nodes, its real oncological benefit is still questionable.

Pro (With Caution): Extended oncologic indications in liver transplantation.

The success of liver transplantation (LT) in curing cancer (particularly hepatocellular carcinoma and hepatic metastases from neuroendocrine tumors) is based on the augmented oncologic potentials of the total hepatectomy and on restrictive criteria applied to patient selection. Consensus on the grade of expansion of conventional limits and implementation of alternative indications to LT (cholangiocarcinoma and metastases from colorectal cancer) has not been reached. On top of regional/local conditions for wait-list dynamics and organ availability, expanded cancer indications for LT should be explored with caution. Prospective investigations should rely on staging protocols predicting the exclusive hepatic location of cancer; restrictions on clinical conditions, tumor biology, and molecular profile, including the response to neoadjuvant therapies; confirmed tumor nonresectability with curative intent; sufficient life span of the transplant candidates to assess survival and transplant benefit; and use of marginal and extended criteria donors. In conclusion, the arguments supporting moderately loosened criteria for cancer seem more valid today than in the past. Transplant oncology is likely to represent a leading field in the near future, also because comorbidities and transplant-related causes of death are better managed and often eliminated. Liver Transplantation 24 98-103 2018 AASLD.

Preoperative Capecitabine, Oxaliplatin, and Irinotecan in Resectable Gastric or Gastroesophageal Junction Cancer: Pathological Response as Primary Endpoint and FDG-PET Predictions.

OBJECTIVES: This phase II trial was aimed at assessing the safety and activity of capecitabine, oxaliplatin, and irinotecan (COI regimen) as a preoperative treatment for resectable gastric cancer (GC) or gastroesophageal junction (GEJ) cancer. METHODS: Patients affected by T3-T4/N0-N+/M0 GC/GEJ cancer were treated with the COI regimen for 4 cycles followed by restaging and gastroresection with D2 lymphadenectomy. Four postoperative cycles were scheduled. The primary endpoint was pathological response rate according to Becker et al. [Cancer 2003;98:1521-1530]. The potential role of fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) as a predictive biomarker of pathological tumor response was assessed in a subgroup of 19 evaluable patients. RESULTS: Between January 2011 and October 2015, a total of 40 patients were enrolled. After the preoperative phase, 36 out of 40 patients (90%) were considered eligible for surgery: 12 patients (30%) achieved a pathological response. The most frequent grade 3/4 adverse events were diarrhea (27%), nausea (25%), and fatigue (17%). Grade 3 neutropenia occurred in 7.5% of patients. A lower standard uptake value at baseline FDG-PET/CT was associated with pathological response. CONCLUSION: COI combination is active with a manageable toxicity profile in patients with resectable GC or GEJ cancer. FDG-PET/CT imaging as a surrogate biomarker of pathological response in this setting appears fascinating but should be further investigated.

DNA methylation-based prognosis and epidrivers in hepatocellular carcinoma.

UNLABELLED: Epigenetic deregulation has emerged as a driver in human malignancies. There is no clear understanding of the epigenetic alterations in hepatocellular carcinoma (HCC) and of the potential role of DNA methylation markers as prognostic biomarkers. Analysis of tumor tissue from 304 patients with HCC treated with surgical resection allowed us to generate a methylation-based prognostic signature using a training-validation scheme. Methylome profiling was done with the Illumina HumanMethylation450 array (Illumina, Inc., San Diego, CA), which covers 96% of known cytosine-phosphate-guanine (CpG) islands and 485,000 CpG, and transcriptome profiling was performed with Affymetrix Human Genome U219 Plate (Affymetrix, Inc., Santa Clara, CA) and miRNA Chip 2.0. Random survival forests enabled us to generate a methylation signature based on 36 methylation probes. We computed a risk score of mortality for each individual that accurately discriminated patient survival both in the training (221 patients; 47% hepatitis C-related HCC) and validation sets (n = 83; 47% alcohol-related HCC). This signature correlated with known predictors of poor outcome and retained independent prognostic capacity of survival along with multinodularity and platelet count. The subset of patients identified by this signature was enriched in the molecular subclass of proliferation with progenitor cell features. The study confirmed a high prevalence of genes known to be deregulated by aberrant methylation in HCC (e.g., Ras association [RalGDS/AF-6] domain family member 1, insulin-like growth factor 2, and adenomatous polyposis coli) and other solid tumors (e.g., NOTCH3) and describes potential candidate epidrivers (e.g., septin 9 and ephrin B2). CONCLUSIONS: A validated signature of 36 DNA methylation markers accurately predicts poor survival in patients with HCC. Patients with this methylation profile harbor messenger RNA-based signatures indicating tumors with progenitor cell features.

miR-221 overexpression contributes to liver tumorigenesis.

MicroRNA (miRNAs) are negative regulators of gene expression and can function as tumor suppressors or oncogenes. Expression patterns of miRNAs and their role in the pathogenesis of hepatocellular carcinoma (HCC) are still poorly understood. We profiled miRNA expression in tissue samples (104 HCC, 90 adjacent cirrhotic livers, 21 normal livers) as well as in 35 HCC cell lines. A set of 12 miRNAs (including miR-21, miR-221/222, miR-34a, miR-519a, miR-93, miR-96, and let-7c) was linked to disease progression from normal liver through cirrhosis to full-blown HCC. miR-221/222, the most up-regulated miRNAs in tumor samples, are shown to target the CDK inhibitor p27 and to enhance cell growth in vitro. Conversely, these activities can be efficiently inhibited by an antagomiR specific for miR-221. In addition, we show, using a mouse model of liver cancer, that miR-221 overexpression stimulates growth of tumorigenic murine hepatic progenitor cells. Finally, we identified DNA damage-inducible transcript 4 (DDIT4), a modulator of mTOR pathway, as a bona fide target of miR-221. Taken together, these data reveal an important contribution for miR-221 in hepatocarcinogenesis and suggest a role for DDIT4 dysregulation in this process. Thus, the use of synthetic inhibitors of miR-221 may prove to be a promising approach to liver cancer treatment.

Combining clinical, pathology, and gene expression data to predict recurrence of hepatocellular carcinoma.

BACKGROUND & AIMS: In approximately 70% of patients with hepatocellular carcinoma (HCC) treated by resection or ablation, disease recurs within 5 years. Although gene expression signatures have been associated with outcome, there is no method to predict recurrence based on combined clinical, pathology, and genomic data (from tumor and cirrhotic tissue). We evaluated gene expression signatures associated with outcome in a large cohort of patients with early stage (Barcelona-Clinic Liver Cancer 0/A), single-nodule HCC and heterogeneity of signatures within tumor tissues. METHODS: We assessed 287 HCC patients undergoing resection and tested genome-wide expression platforms using tumor (n = 287) and adjacent nontumor, cirrhotic tissue (n = 226). We evaluated gene expression signatures with reported prognostic ability generated from tumor or cirrhotic tissue in 18 and 4 reports, respectively. In 15 additional patients, we profiled samples from the center and periphery of the tumor, to determine stability of signatures. Data analysis included Cox modeling and random survival forests to identify independent predictors of tumor recurrence. RESULTS: Gene expression signatures that were associated with aggressive HCC were clustered, as well as those associated with tumors of progenitor cell origin and those from nontumor, adjacent, cirrhotic tissues. On multivariate analysis, the tumor-associated signature G3-proliferation (hazard ratio [HR], 1.75; P = .003) and an adjacent poor-survival signature (HR, 1.74; P = .004) were independent predictors of HCC recurrence, along with satellites (HR, 1.66; P = .04). Samples from different sites in the same tumor nodule were reproducibly classified. CONCLUSIONS: We developed a composite prognostic model for HCC recurrence, based on gene expression patterns in tumor and adjacent tissues. These signatures predict early and overall recurrence in patients with HCC, and complement findings from clinical and pathology analyses.

Massive APOBEC3 editing of hepatitis B viral DNA in cirrhosis.

DNA viruses, retroviruses and hepadnaviruses, such as hepatitis B virus (HBV), are vulnerable to genetic editing of single stranded DNA by host cell APOBEC3 (A3) cytidine deaminases. At least three A3 genes are up regulated by interferon-alpha in human hepatocytes while ectopic expression of activation induced deaminase (AICDA), an A3 paralog, has been noted in a variety of chronic inflammatory syndromes including hepatitis C virus infection. Yet virtually all studies of HBV editing have confined themselves to analyses of virions from culture supernatants or serum where the frequency of edited genomes is generally low (< or = 10(-2)). We decided to look at the nature and frequency of HBV editing in cirrhotic samples taken during removal of a primary hepatocellular carcinoma. Forty-one cirrhotic tissue samples (10 alcoholic, 10 HBV(+), 11 HBV(+)HCV(+) and 10 HCV(+)) as well as 4 normal livers were studied. Compared to normal liver, 5/7 APOBEC3 genes were significantly up regulated in the order: HCV+/-HBV>HBV>alcoholic cirrhosis. A3C and A3D were up regulated for all groups while the interferon inducible A3G was over expressed in virus associated cirrhosis, as was AICDA in approximately 50% of these HBV/HCV samples. While AICDA can indeed edit HBV DNA ex vivo, A3G is the dominant deaminase in vivo with up to 35% of HBV genomes being edited. Despite these highly deleterious mutant spectra, a small fraction of genomes survive and contribute to loss of HBeAg antigenemia and possibly HBsAg immune escape. In conclusion, the cytokine storm associated with chronic inflammatory responses to HBV and HCV clearly up regulates a number of A3 genes with A3G clearly being a major restriction factor for HBV. Although the mutant spectrum resulting from A3 editing is highly deleterious, a very small part, notably the lightly edited genomes, might help the virus evolve and even escape immune responses.

Therapeutic strategies for post-transplant recurrence of hepatocellular carcinoma.

Despite stringent selection criteria, hepatocellular carcinoma recurrence after liver transplantation (LT) still occurs in up to 20% of cases, mostly within the first 2-3 years. No adjuvant treatments to prevent such an occurrence have been developed so far. However, a balanced use of immunosuppression with minimal dose of calcineurin inhibitors and possible addition of mammalian target of rapamycin inhibitors is strongly advisable. Moreover, several pre- and post-transplant predictors of recurrence have been identified and may help determine the frequency and duration of post-transplant follow-up. When recurrence occurs, the outcomes are poor with a median survival of 12 mo according to most retrospective studies. The factor that most impacts survival after recurrence is timing (within 1-2 years from LT according to different authors). Several therapeutic options may be chosen in case of recurrence, according to timing and disease presentation. Surgical treatment seems to provide a survival benefit, especially in case of late recurrence, while the benefit of locoregional treatments has been suggested only in small retrospective studies. When systemic treatment is indicated, sorafenib has been proved safe and effective, while only few data are available for lenvatinib and regorafenib in second line. The use of immune checkpoint inhibitors is controversial in this setting, given the safety warnings for the risk of acute rejection.

Colorectal medullary carcinoma: heterogeneous presentations of a rare clinico-pathological entity. Report of two cases.

Colorectal medullary carcinoma (CMC) is a rare subset of minimally differentiated carcinomas. CMC tend to be right-sided and present at an advanced stage. Despite this, distant metastases are rare at presentation. The liver and the regional lymph nodes represent the most common sites of metastases. Most of the time, CMCs exhibit mismatch repair deficiency and a strong association with high-level microsatellite instability. There is no conspicuous data regarding treatment strategies and short-term outcomes. CMC is supposed to be related to better prognosis compared to poorly-differentiated and undifferentiated colonic adenocarcinomas, but reports are controversial.This lesion, with heterogeneous presentations and unclear prognostic significance, may be unfamiliar to histopathologists and can lead to diagnostic uncertainty and overtreatments.Our aim is to renew the attention to this rare histological subtype through the report of two cases.