[A Case of Fatal Interstitial Pneumonia during FOLFIRI plus Cetuximab Therapy for Liver Metastasis of Colon Cancer].

The patient was a 76-year-old woman who underwent sigmoidectomy in April 2011 for sigmoid colon cancer with multiple concurrent liver metastases. She was treated postoperatively with mFOLFOX6 plus cetuximab but was diagnosed with the progressive disease at the end of course 14. The patient started receiving FOLFIRI plus cetuximab therapy in May 2012. Later in August 2012, she was examined for respiratory distress on the scheduled date of receiving course 7 and was diagnosed with drug-induced interstitial pneumonia resulting from systemic chemotherapy. The patient was administered oxygen, and her symptoms improved temporarily with steroid half-pulse and endotoxin adsorption therapy, but on inpatient day 10, her respiratory condition deteriorated. She was treated with steroid pulse therapy, but died of respiratory failure on inpatient day 17. The main adverse events associated with FOLFIRI plus cetuximab therapy are gastrointestinal symptoms, hematotoxicity, peripheral nerve damage, and dermatological symptoms. However, reports of respiratory conditions such as interstitial pneumonia are rare. Although the incidence is low, interstitial pneumonia can be severe and fatal and therefore requires close attention.

ARID2 modulates DNA damage response in human hepatocellular carcinoma cells.

BACKGROUND & AIMS: Recent genomic studies have identified frequent mutations of AT-rich interactive domain 2 (ARID2) in hepatocellular carcinoma (HCC), but it is not still understood how ARID2 exhibits tumor suppressor activities. METHODS: We established the ARID2 knockout human HCC cell lines by using CRISPR/Cas9 system, and investigated the gene expression profiles and biological functions. RESULTS: Bioinformatic analysis indicated that UV-response genes were negatively regulated in the ARID2 knockout cells, and they were sensitized to UV irradiation. ARID2 depletion attenuated nucleotide excision repair (NER) of DNA damage sites introduced by exposure to UV as well as chemical compounds known as carcinogens for HCC, benzo[a]pyrene and FeCl3, since xeroderma pigmentosum complementation group G (XPG) could not accumulate without ARID2. By using large-scale public data sets, we validated that ARID2 knockout could lead to similar molecular changes between in vitro and in vivo settings. A higher number of somatic mutations in the ARID2-mutated subtypes than that in the ARID2 wild-type across various types of cancers including HCC was observed. CONCLUSIONS: We provide evidence that ARID2 knockout could contribute to disruption of NER process through inhibiting the recruitment of XPG, resulting in susceptibility to carcinogens and potential hypermutation. These findings have implications for therapeutic targets in cancers harboring ARID2 mutations. LAY SUMMARY: Recent genomic studies have identified frequent mutations of ARID2, a component of the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex, in hepatocellular carcinoma, but it is not still understood how ARID2 exhibits tumor suppressor activities. In current study, we provided evidence that ARID2 knockout could contribute to disruption of DNA repair process, resulting in susceptibility to carcinogens and potential hypermutation. These findings have far-reaching implications for therapeutic targets in cancers harboring ARID2 mutations.

Dominant Expression of DCLK1 in Human Pancreatic Cancer Stem Cells Accelerates Tumor Invasion and Metastasis.

Patients with pancreatic cancer typically develop tumor invasion and metastasis in the early stage. These malignant behaviors might be originated from cancer stem cells (CSCs), but the responsible target is less known about invisible CSCs especially for invasion and metastasis. We previously examined the proteasome activity of CSCs and constructed a real-time visualization system for human pancreatic CSCs. In the present study, we found that CSCs were highly metastatic and dominantly localized at the invading tumor margins in a liver metastasis model. Microarray and siRNA screening assays showed that doublecortin-like kinase 1 (DCLK1) was predominantly expressed with histone modification in pancreatic CSCs with invasive and metastatic potential. Overexpression of DCLK1 led to amoeboid morphology, which promotes the migration of pancreatic cancer cells. Knockdown of DCLK1 profoundly suppressed in vivo liver metastasis of pancreatic CSCs. Clinically, DCLK1 was overexpressed in the metastatic tumors in patients with pancreatic cancer. Our studies revealed that DCLK1 is essential for the invasive and metastatic properties of CSCs and may be a promising epigenetic and therapeutic target in human pancreatic cancer.

The difficulty of laparoscopic liver resection.

Grading of difficulty is needed for laparoscopic liver resection (LLR). Indications for LLR are expanding worldwide from minor to major resections, particularly in institutions having surgeons with advanced skills. If the degrees of surgical difficulty were defined, it would serve as a useful guide when introducing LLR and stepping up to the more advanced LLR. As no previous study has addressed the degrees of difficulty of various LLR procedures, we devised a practical scoring system for this purpose. We extracted the following five factors from preoperative information to score difficulty levels: (1) tumor location, (2) extent of liver resection, (3) tumor size, (4) proximity to major vessels, and (5) liver function. This difficulty index is comprised of the cumulative score for the five individual factors. There has not yet been a standard definition of difficulty. Our proposed scoring system might be a practical means of assessing the difficulty of LLR procedures. However, this system must be prospectively validated.

A novel difficulty scoring system for laparoscopic liver resection.

Early on, laparoscopic liver resection (LLR) was limited to partial resection, but major LLR is no longer rare. A difficulty scoring system is required to guide surgeons in advancing from simple to highly technical laparoscopic resections. Subjects were 90 patients who had undergone pure LLR at three medical institutions (30 patients/institution) from January 2011 to April 2014. Surgical difficulty was assessed by the operator using an index of 1-10 with the following divisions: 1-3 low difficulty, 4-6 intermediate difficulty, and 7-10 high difficulty. Weighted kappa statistic was used to calculate the concordance between the operators' and reviewers' (expert surgeon) difficulty index. Inter-rater agreement (weighted kappa statistic) between the operators' and reviewers' assessments was 0.89 with the three-level difficulty index and 0.80 with the 10-level difficulty index. A 10-level difficulty index by linear modeling based on clinical information revealed a weighted kappa statistic of 0.72 and that scored by the extent of liver resection, tumor location, tumor size, liver function, and tumor proximity to major vessels revealed a weighted kappa statistic of 0.68. We proposed a new scoring system to predict difficulty of various LLRs preoperatively. The calculated score well reflected difficulty.

Mixed adenoneuroendocrine carcinoma of the colon progressed rapidly after hepatic rupture: report of a case.

The rupture of a metastatic mixed adenoneuroendocrine carcinoma (MANEC) has not been previously reported, although the neuroendocrine cell carcinoma is often associated with a high incidence of hepatic metastases. The patient was a 39-year-old male who presented with upper abdominal pain over 3 months. Computed tomography showed multiple tumors in both hepatic lobes, while lower gastrointestinal endoscopy revealed a tumor in the transverse colon. Histopathologic examination of the tumor revealed it to be a neuroendocrine cell carcinoma. After the resection of the primary tumor, hepatic metastases rapidly increased, and one of them in the left lateral segment was ruptured with significant hemorrhage. The rupture led us to undertake the emergency operation to stop the bleeding. Histology showed a high-grade large-cell neuroendocrine carcinoma associated with moderately differentiated tubular adenocarcinoma. The Ki-67 labeling index was 80% (G3). The diagnosis was mixed adenoneuroendocrine carcinoma according to the 2010 World Health Organization guidelines. Hepatic arterial infusion chemotherapy, systemic chemotherapy, and transcatheter arterial chemoembolization did not decrease the tumor progress, and the patient died on postoperative day 110. Reporting this highly malignant case, I hope all doctors can be interested in MANEC.

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.

Patient with esophageal cancer showing remission of nephrotic syndrome after esophagectomy: report of a case.

A 73-year-old male patient was admitted to our hospital due to bilateral leg edema and proteinuria in April 2009. After admission, nephrotic syndrome (membranous nephropathy) was diagnosed. At that point, a cancer screening test was performed; however, no abnormalities were noted. Medical treatment with prednisolone and cyclosporine was started, which resulted in the temporary improvement of markers of laboratory data. The patient was re-examined in November of the same year, and esophageal cancer (squamous cell carcinoma, T2N0M0 Stage IIA according to the UICC TNM classification) was detected in the lower thoracic esophagus. Subtotal esophagectomy was performed via right thoracolaparotomy with two-field lymph node dissection. Although the patient's course was complicated by respiratory failure, he was discharged after 38 days. After performing esophagectomy, prompt amelioration of the nephrotic syndrome occurred, allowing the withdrawal of prednisolone and cyclosporine. There has been no recurrence of esophageal cancer or relapse of nephrotic syndrome during a period of 18 months after esophagectomy.

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.

Curative resection of a huge malignant pancreatic endocrine tumor by pancreatoduodenectomy with portal and superior mesenteric vein resection and reconstruction using the right ovarian vein: report of a case.

Nonfunctioning pancreatic endocrine tumors (PETs) are rare and generally asymptomatic. A 68-year-old woman who had refused treatment for a pancreatic mass, revealed by ultrasonography to be 55 mm in diameter, was referred to us again 29 months later with jaundice. Investigations showed an 82-mm tumor in the head of pancreas, exposed from the papilla of Vater to the duodenal lumen. After biliary decompression and drainage, we performed pancreatoduodenectomy with resection of the portal vein and superior mesenteric vein, followed by reconstruction using a cylindrically customized autologous graft harvested from the right ovarian vein. The tumor was resected curatively. Microscopically, it consisted of trabecular and ribbon-like arrangement of neoplastic cells. Immunohistochemical staining was positive for chromogranin A and synaptophysin and negative for insulin, gastrin, glucagons, somatostatin, and pancreatic peptide. Although metastasis was detected in a lymph node along the superior mesenteric vein with perineural invasion, the portal and superior mesenteric veins had not been invaded. The diagnosis was well-differentiated nonfunctioning PET. The patient had an uneventful postoperative course, and there has been no evidence of recurrence in 12 months.