Hepatocellular Carcinoma: Current Management and Future Development—Improved Outcomes with Surgical Resection

Currently, surgical resection is the treatment strategy offering the best long-term outcomes in patients with hepatocellular carcinoma (HCC). Especially for advanced HCC, surgical resection is the only strategy that is potentially curative, and the indications for surgical resection have expanded concomitantly with the technical advances in hepatectomy. A major problem is the high recurrence rate even after curative resection, especially in the remnant liver. Although repeat hepatectomy may prolong survival, the suitability may be limited due to multiple tumor recurrence or background liver cirrhosis. Multimodality approaches combining other local ablation or systemic therapy may help improve the prognosis. On the other hand, minimally invasive, or laparoscopic, hepatectomy has become popular over the last decade. Although the short-term safety and feasibility has been established, the long-term outcomes have not yet been adequately evaluated. Liver transplantation for HCC is also a possible option. Given the current situation of donor shortage, however, other local treatments should be considered as the first choice as long as liver function is maintained. Non-transplant treatment as a bridge to transplantation also helps in decreasing the risk of tumor progression or death during the waiting period. The optimal timing for transplantation after HCC recurrence remains to be investigated

Bilateral Approach for Thoracoscopic Esophagectomy in a Patient with Esophageal Cancer and Solitary Posterior Thoracic Para-aortic Lymph Node Metastasis

We report a successful dissection of metastatic posterior thoracic para-aortic lymph node (No. 112aoP) via bilateral thoracoscopic surgery. With the anesthetized patient (a 73-year-old Japanese woman) in the prone position, two working ports were inserted for the left-side approach, and artificial pneumothorax was created. Thoracoscopic examination revealed a swollen LN posterior to the descending aorta. Fat and metastatic LNs posterior to the aorta were dissected from the aortic arch level to the diaphragm while preserving intercostal arteries. For the right-side approach, two working ports were inserted and a routine thoracoscopic esophagec-tomy was performed. Gastric conduit reconstruction was achieved laparoscopically. Operation time for the left thoracic procedure: 54 min; estimated blood loss: almost none. No recurrence was detected 24 months post-operatively. There are several surgical options for approaching No. 112aoP, including transhiatal, left thora-cotomy, and thoracoscopy. Although a wide dissection of the posterior thoracic para-aortic area has not been reported, it may be feasible and safe if the artery of Adamkiewicz and intercostal arteries are preserved. A min-imally invasive bilateral thoracoscopic approach for a thoracoscopic esophagectomy is safe and useful for esophageal cancer patients with solitary No. 112aoP metastasis

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Bacterial Translocation in Gastrointestinal Cancers and Cancer Treatment

In recent years, there has been increasing evidence that gut microbiota is associated with the onset and exacerbation of various diseases, such as gastrointestinal cancer. For instance, it is well known that local inflammation of the intestinal tract in colorectal cancer that is caused by the increased number of Fusobacterium, due to changes in the intestinal bacterial flora, is involved in carcinogenesis. In contrast, gut bacteria or their products, pathogen-associated molecular patterns, not only cause intestinal inflammation but also invade the bloodstream through dysbiosis and gut barrier dysfunction, thereby leading to systemic inflammation, namely bacterial translocation. The involvement of bacterial translocation in the carcinogenesis of gastrointestinal cancers and their prognosis is increasingly being recognized. The Toll-like receptor signaling pathways plays an important role in the carcinogenesis of such cancers. In addition, bacterial translocation influences the treatment of cancers such as surgery and chemotherapy. In this review, we outline the concept of bacterial translocation, summarize the current knowledge on the relationship between gut bacteria and gastrointestinal cancer, and provide future perspectives of this field

Role of Microbial Infection-Induced Inflammation in the Development of Gastrointestinal Cancers

There has been increasing evidence that a local inflammatory response stimulates tumor cells to acquire metastatic potential, and the concept of inflammatory oncotaxis has been spreading in recent years. However, the interaction between microbial inflammation and the development of gastrointestinal cancer is still unclear. This review summarizes the present knowledge on the role of microbial inflammation in the development of gastrointestinal cancers from the perspective of molecular biological findings. Chronic inflammation caused by bacterial infection is known to induce cancers as exemplified by Helicobacter pylori, which is associated with the development of gastric cancer via the activation of the TLR4 pathway by bacterial lipopolysaccharide followed by cancer growth through CagA-MET signaling. In addition, the development of inflammatory bowel diseases has been known to become a risk factor for colorectal cancers, where inflammation caused by certain bacterial infections plays a key role. It is also known that the cancer microenvironment is associated with cancer growth. Moreover, infectious complication after surgery for gastrointestinal cancers may promote tumor progression via the stimulation of pathogen-associated molecular patterns and various inflammatory mediators secreted by immunocytes. Further research on the link between microbial inflammation and cancer progression is needed to drive a paradigm shift in cancer treatment