[A Case of Intestinal Fistula Associated with Small Intestinal Metastasis from Small Cell Lung Carcinoma].

A 53-year-old man who complained of dyspnea and prolonged cough visited to our hospital. Computed tomography (CT)revealed massive tumors of right lung and small intestine. CT-guided fine-needle aspiration(FNA)on lung lesion was performed and the lung tumor was diagnosed as small cell carcinoma. We subsequently performed surgical resection for the tumor of small intestine, but part of tumor lesion remained due to pelvic wall invasion. The resected tumor was diagnosed as metastasis from lung carcinoma by histopathological examination. After surgery the patient was treated with atezolizumab and carboplatin-etoposide chemotherapy, but the remnant metastasis caused intestinal fistula. Treatment was continued carefully with fistula management using pouches. Although the fistula was closed during chemotherapy response, it recurred after discontinuation of treatment due to severe adverse events. The patient died 325 days after the surgery.

[A Case of Severe Hyperammonemic Encephalopathy in a Dialysis Patient Following mFOLFOX6 Therapy].

A 69-year-old man on hemodialysis for chronic renal failure was diagnosed with ascending colon cancer, and received surgical resection. Multiple liver metastases were detected after surgery. He was administered modified FOLFOX6 therapy (reducing the dose to 50%), and showed severe disturbance of consciousness due to hyperammonemia on treatment day 6. After treatment with daily hemodialysis, branched-chain amino acid solutions, lactulose and rifaximin, his conscious level improved on day 9. Intensive chemotherapy in dialysis patients should be carefully performed considering the serious adverse events including hyperammonemia.

Comprehensive molecular and immunological characterization of hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a heterogeneous disease with various etiological factors, and ranks as the second leading cause of cancer-related mortality worldwide due to multi-focal recurrence. We herein identified three major subtypes of HCC by performing integrative analysis of two omics data sets, and clarified that this classification was closely correlated with clinicopathological factors, immune profiles and recurrence patterns. METHODS: In the test study, 183 tumor specimens surgically resected from HCC patients were collected for unsupervised clustering analysis of gene expression signatures and comparative analysis of gene mutations. These results were validated by using genome, methylome and transcriptome data of 373 HCC patients provided from the Cancer Genome Atlas Network. In addition, omics data were obtained from pairs of primary and recurrent HCC. FINDINGS: Comprehensive molecular evaluation of HCC by multi-platform analysis defined three major subtypes: (1) mitogenic and stem cell-like tumors with chromosomal instability; (2) CTNNB1-mutated tumors displaying immune suppression; and (3) metabolic disease-associated tumors, which included an immunogenic subgroup characterized by macrophage infiltration and favorable prognosis. Although genomic and epigenomic analysis explicitly distinguished between HCC with intrahepatic metastasis (IM) and multi-centric HCC (MC), the phenotypic similarity between the primary and recurrent tumors was not correlated to the IM/MC origin, but to the classification. INTERPRETATION: Identification of these HCC subtypes provides further insights into patient stratification as well as presents opportunities for therapeutic development. FUND: Ministry of Education, Culture, Sports, Science and Technology of Japan (16H02670 and 18K19575), Japan Agency for Medical Research and Development (JP15cm0106064, JP17cm0106518, JP18cm0106540 and JP18fk0210040).

Preoperative direct bilirubin to prothrombin time ratio index to prevent liver failure after minor hepatectomy.

BACKGROUND: The most reliable index to predict the safety of hepatectomy for patients with poor liver function remains unknown. We aimed to construct a novel preoperative index to predict early liver failure (ELF) and mortality due to recurrence-free liver failure (MLF) after hepatectomy. METHODS: Between 2000 and 2012, 385 consecutive patients with hepatocellular carcinoma undergoing curative minor hepatectomy were divided into two sequential cohorts: training set (n = 143) and validation set (n = 242), and observed until 2015. RESULTS: Prothrombin time and direct bilirubin were independent predictors of both ELF and MLF in the training set. Thus we devised a novel index, the direct bilirubin to prothrombin time ratio index (DBPTRI). The areas under ROC curves of DBPTRI for predicting ELF and MLF were 0.78 and 0.93, respectively, in the validation set. Using a preoperative DBPTRI cut off of 4.2, we accurately predicted ELF and MLF in 86.8% and 88.4% of patients, respectively. DBPTRI was the best predictor of ELF and MLF when compared with conventional indices such as ICG-R15 and Child-Pugh score. Moreover, the 5-year overall survival rates of the patients with low and high DBPTRI were 59% and 36%, respectively (P < 0.0001). CONCLUSIONS: DBPTRI may serve as a simple, non-invasive index for estimating liver failure after hepatectomy.

Proteasome activity is required for the initiation of precancerous pancreatic lesions.

Proteasome activity is significantly increased in advanced cancers, but its role in cancer initiation is not clear, due to difficulties in monitoring this process in vivo. We established a line of transgenic mice that carried the ZsGreen-degron(ODC) (Gdeg) proteasome reporter to monitor the proteasome activity. In combination with Pdx-1-Cre;LSL-Kras(G12D) model, proteasome activity was investigated in the initiation of precancerous pancreatic lesions (PanINs). Normal pancreatic acini in Gdeg mice had low proteasome activity. By contrast, proteasome activity was increased in the PanIN lesions that developed in Gdeg;Pdx-1-Cre;LSL-Kras(G12D) mice. Caerulein administration to Gdeg;Pdx-1-Cre;LSL-Kras(G12D) mice induced constitutive elevation of proteasome activity in pancreatic tissues and accelerated PanIN formation. The proteasome inhibitor markedly reduced PanIN formation in Gdeg;Pdx-1-Cre;LSL-Kras(G12D) mice (P = 0.001), whereas it had no effect on PanIN lesions that had already formed. These observations indicated the significance of proteasome activity in the initiation of PanIN but not the maintenance per se. In addition, the expressions of pERK and its downstream factors including cyclin D1, NF-κB, and Cox2 were decreased after proteasome inhibition in PanINs. Our studies showed activation of proteasome is required specifically for the initiation of PanIN. The roles of proteasome in the early stages of pancreatic carcinogenesis warrant further investigation.

Favorable response after gemcitabine-radiotherapy for invasive pancreatic intraductal papillary mucinous neoplasm: a case report.

The efficacy of chemoradiotherapy for invasive pancreatic ductal carcinoma derived from an intraductal papillary mucinous neoplasm (IPMN) has not been established. The subject of the present report was a 53-year-old man admitted for the treatment of IPMN. The tumor, located in the pancreatic body, was of the mixed type of IPMN, and it involved the branch duct, where it was 38 mm in diameter, and the main duct, where it was 6 mm in diameter. Distal pancreatectomy was performed and the postoperative course was uneventful; however, histopathologic diagnosis revealed invasive ductal carcinoma with a positive surgical margin in the pancreatic duct. Although total pancreatectomy was recommended, chemoradiotherapy (50.4-Gy irradiation and gemcitabine) was preferred by the patient. At 9-month follow up, computed tomography and magnetic resonance imaging showed a cystic mass at the surgical margin of the pancreas. Endoscopic ultrasonography showed a 44-mm cystic lesion with nodules in the remnant pancreas, on the basis of which he underwent total pancreatectomy. Pathologic examination of the resected specimen revealed absence of the epithelium at the surgical margin of the main pancreatic duct, and malignant cells were not detected.

Successful combination therapy of radical liver resection with 5-fluorouracil/leucovorin, oxaliplatin, plus bevacizumab for ascending colon cancer with pulmonary and 43 liver metastases: report of a case.

At the time of diagnosis, 20% to 25% of patients with colorectal cancer already have liver metastases, the presence of which is a most important prognostic factor. A 64-year-old man was admitted to our hospital for investigation of anemia and multiple liver tumors. Examinations revealed ascending colon carcinoma with more than 40 liver metastases and 2 lung metastases. We performed right hemicolectomy with lymph node dissection, which was followed by 5-fluorouracil/leucovorin, oxaliplatin, plus bevacizumab (FOLFOX-BV). After 4 courses of chemotherapy, the lung metastases were in complete remission and the liver metastases had shrunk. We suggested the option of radical liver resection, but the patient declined initially as he had not suffered any severe side effects of FOLFOX-BV. After 23 courses of the chemotherapy, he agreed to undergo hepatectomy. We performed extended right lobectomy with partial left and caudal lobe resection. All of the macroscopic metastatic lesions were resected. Histopathologically, viable cancer cells were recognized in 7 of the 43 liver metastatic lesions. Postoperatively, FOLFOX-BV was restarted and continued for 10 months. At the time of writing, 15 months after the hepatectomy, the patient was well without evidence of recurrence of the cancer.