Impact of Second-line Chemotherapy on Prognosis: Response of Advanced Gastric Cancer to Taxanes Plus Ramucirumab.

BACKGROUND/AIM: The impact of clinical response to taxanes plus ramucirumab (RAM) on overall survival (OS) has not been clarified for advanced gastric cancer (AGC), although this type of therapy is already in use as second-line chemotherapy (CTx). This study aimed to investigate the prognostic impact of the clinical response to taxanes plus ramucirumab (RAM) for AGC patients. PATIENTS AND METHODS: This study included AGC patients treated with paclitaxel (PTX) or nab-paclitaxel (nab-PTX) and RAM. A retrospective analysis of response and survival rates in consecutive medical records of patients was performed. RESULTS: Forty-two patients were enrolled. Median progression-free survival and OS were 5.4 months [95% confidence interval (CI)=4.440-6.361] and 11.8 months (95% CI=8.648-15.019), respectively. In Cox-hazard multivariate analysis, peritoneal metastasis [hazard ratio (HR)=2.830; 95% CI=1.320-6.067; p=0.008], and disease control rate (HR=0.310; 95% CI=0.129-0.741; p=0.008) were independent factors. CONCLUSION: The response to taxanes plus RAM CTx had an impact on the survival of patients with AGC.

An advanced case of gastric histiocytic sarcoma treated with chemotherapy and gastrectomy: a case report and review of literature.

Histiocytic sarcoma is a relatively new disease category and the gastrointestinal origin is sporadic. We report a case of a 74-year-old woman who underwent chemotherapy and proximal gastrectomy for extremely rare, advanced gastric histiocytic sarcoma. The resected specimen was subjected to numerous immunostainings to meet the diagnostic criteria of histiocytic sarcoma and was positive for the histiocyte markers' cluster of differentiation 68 and lysozyme. The markers of Langerhans cells, follicular dendritic cells, and myelocyte were all negative. Six reports of surgical resection of histiocytic sarcoma originating in the stomach exist, including our case. We reviewed the clinical course and the histological and immunohistochemical diagnostic features of surgically resected gastric histiocytic sarcoma.

A case of vascular Ehlers-Danlos syndrome with a ruptured hepatic artery after surgical treatment of peritonitis caused by the perforation of the colon.

BACKGROUND: Ehlers-Danlos syndrome (EDS) is an inherited disorder that causes connective tissue fragility. The vascular type of EDS (vEDS) caused by defective collagen type III production accounts for 5%-10% of all EDS cases. Patients can develop gastrointestinal or arterial ruptures, which cause poor prognosis. We report a case of a patient who experienced colonic rupture, which was immediately followed by arterial rupture. CASE PRESENTATION: A 40-year-old man who had been genetically diagnosed with vEDS 6 years previously was admitted to our hospital with ischemic colitis. After 3 days of conservative treatment, his abdominal pain worsened, and computed tomography (CT) revealed free air in the abdominal cavity. Pan-peritonitis due to perforation of the sigmoid colon was diagnosed. Intraperitoneal lavage and drainage and Hartmann's operation were urgently performed. Because the patient had confirmed vEDS, we performed the surgery in a protective manner. The postoperative course was initially good, and he was transferred to the general ward 3 days after surgery. However, 5 days after surgery, massive intra-abdominal hemorrhage suddenly occurred, and contrast-enhanced CT showed an aneurysm in the common hepatic artery that had ruptured; this aneurysm was not present before surgery and was far from the surgical field. Although we considered an emergency operation, the patient suddenly experienced cardiac arrest and was unresponsive to resuscitation. CONCLUSIONS: In cases of vEDS, vascular rupture can occur immediately after surgery for intestinal rupture. We recommend paying special attention to vascular complications in patients in their forties, as such complications are the most common causes of death.

Treatment of Gastric Cancer in Japan.

Although the incidence of gastric cancer has decreased because of the lower rate of Helicobacter pylori infection, it still accounts for a large number of deaths in Japan. Gastric cancer is mainly treated by resection, and the rate of radical resection is high in Japan because approximately 50% of cases are diagnosed at an early stage. Treatment advances have increased the number of endoscopic submucosal dissections, and development of laparoscopic surgery and robot-assisted surgery as minimally invasive approaches has yielded results similar to those of conventional surgeries, at least in the short term. Cases for which resection is contraindicated are treated with chemotherapy if performance status can be maintained. Although anticancer drugs are continuously under development, treatment outcomes remain unsatisfactory. As Japan becomes a super-aging society, the number of refractory cases is projected to increase. Therefore, evidence of any benefit for minimally invasive surgery and function-preserving surgery needs to be reported quickly. In this paper, we discuss gastric cancer treatment modalities recommended in the fifth edition of the gastric cancer treatment guidelines and describe recent research findings.

Methylation status and long-fragment cell-free DNA are prognostic biomarkers for gastric cancer.

BACKGROUND: Circulating tumor DNA (ctDNA) detected before surgery disappears after complete surgical resection of the cancer. Residual ctDNA indicates minimal residual disease (MRD), which is a cause of recurrence. The presence of long-fragment circulating cell-free DNA (cfDNA) or methylated cfDNA also implies the presence of cancer. In this study, we evaluated the prognostic value of cfDNA methylation and long-fragment cfDNA concentration in gastric cancer patients undergoing curative surgery METHODS: Ninety-nine gastric cancer patients were included. Peripheral blood samples were collected before and 1 month after surgery. In patients administered chemotherapy, samples were collected before starting chemotherapy. qPCR was performed to detect long- and short-fragment LINE-1. A plasma HELP (HpaII tiny fragment Enrichment by Ligation-mediated PCR) assay to determine the concentration of HpaII small fragments was performed using ligation-mediated PCR and HpaII was quantified as the HpaII:MspI ratio to detect methylation levels of cfDNA. RESULTS: Overall survival (OS) of patients with low methylation levels before starting treatment was significantly worse than that of patients with high methylation levels (P = 0.006). In the 90 patients who underwent curative surgery, recurrence-free survival (RFS) and OS of patients with low methylation levels before surgery were worse than those with high methylation levels (P=0.08 and P = 0.11, respectively). RFS and OS of patients with high concentrations of long-fragment LINE-1 after surgery were significantly worse than those with low concentrations of long-fragment LINE-1 (P = 0.009, P = 0.04). CONCLUSIONS: Pre-surgical low methylation levels of LINE-1 are a negative prognostic factor. Post-surgical high concentrations of long-fragment LINE-1 indicate MRD and a high risk of recurrence.

Preoperatively diagnosed gastric collision tumor with mixed adenocarcinoma and gastrointestinal stromal tumor: a case report and literature review.

Reports of gastric collision tumors, comprising adenocarcinoma and gastrointestinal stromal tumor, are extremely rare. Here, we report the case of a 68-year-old male who was diagnosed with a lower-body, moderately differentiated, tubular-type adenocarcinoma and submucosal tumor and underwent an elective D2 distal gastrectomy. The tumor cells of the gastrointestinal stromal tumor were positive for H-caldesmon and CD117, weakly positive for smooth muscle actin and DOG-1, and negative for desmin, S-100 protein, CD31, and AE1/AE3. The tumor had grown into a mixed form of adenocarcinoma and gastrointestinal stromal tumor. Thus, we report the first case of a preoperatively diagnosed collision tumor in the stomach consisting of adenocarcinoma and gastrointestinal stromal tumor.

Ligation and Fibrin Glue Spraying for Intractable Chylous Ascites after Radical Gastrectomy for Gastric Cancer: Case Report and Literature Review.

Chylous ascites associated with radical resection of gastric cancer is a serious clinical condition. Lymph node dissection is indispensable during gastrectomy for gastric cancer. However, postoperative chylous ascites prolongs the hospital stay and re-operation. There are few reports on this subject. Most cases of chylous ascites resolve without treatment, but the condition can result in substantial morbidity. The definition of chylous ascites is ambiguous and varies in the English literature. In this report, we discuss a case of chylous ascites in a 68-year-old man who underwent distal gastrectomy for early gastric cancer at our hospital. He was admitted 8 months after surgery with a main complaint of abdominal swelling. Abdominal puncture helped to diagnose chylous ascites with marked elevation of triglyceride level. The patient received a hypercaloric infusion through a central line, and octreotide acetate, but did not improve. After assessment of lymph outflow by lymph scintigraphy, surgical ligation of the lymph vessels was performed through laparotomy. The volume of milky-white ascites in the abdominal cavity was 3,000 mL. Macroscopically, the fluid was confirmed as flowing from behind the common hepatic artery. Thus, ligation was performed. Chylous ascites has not recurred at 12 months after the re-operation. In summary, a case of chylous ascites after radical gastrectomy for gastric cancer was successfully treated by surgery. We review and discuss the relevant literature.

Skeletal Muscle Mass Depletion After Gastrectomy Negatively Affects the Prognosis of Patients With Gastric Cancer.

BACKGROUND/AIM: Skeletal muscle mass (SMM) is often depleted in patients with gastric cancer undergoing gastrectomy. Using a novel method, we evaluated the effect of SMM depletion after gastrectomy on disease prognosis. PATIENTS AND METHODS: The maximum cross-sectional area of the psoas-muscle (MCA-PM) was measured before surgery and at 1 year after in 233 patients with gastric cancer who underwent radical gastrectomy to determine the ratio (MCA-PMR) as an indicator of SMM depletion. RESULTS: The MCA-PMR cutoff value was set at 90%, and patients were divided into the groups with <90% and ≥90%. MCA-PMR <90% was an independent prognostic factor for all patients. In 88 patients who received adjuvant chemotherapy including S-1, the 5-year cancer-specific survival rate was significantly better for those with MCA-PMR ≥90% than for those with MCA-PMR <90% (84.1% vs. 59.1%; p=0.010; hazard ratio=2.974; 95% confidence interval=1.241-7.124). CONCLUSION: SMM depletion after gastrectomy can be measured using the MCA-PMR. This novel measurement can be easily implemented in the clinical setting.

Five-year Survival After Surgical Removal and Gamma Knife Stereotactic Radiosurgery for a Cerebellar Metastasis from an Esophagogastric Junction Cancer: A Case Report and Literature Review.

Brain metastases originating from esophageal or gastric cancer are rare, accounting for 2.1-3.3% of all brain tumors registered in Japan. There are no established therapeutic measures for brain metastases, which accordingly have a poor prognosis. We present here a patient who survived for 5 years after surgery and gamma knife treatment of a cerebellar metastasis from esophagogastric adenocarcinoma. The primary gastric cancer was treated by laparotomy with total gastrectomy, splenectomy, and D2 lymphadenectomy. It was diagnosed as a esophagogastric junction Siewert type II tumor, type 3, tub1-2, pT3 (SS), pN1, and stage IIB on histopathological examination of the surgical specimen. Five months postoperatively, a solitary cerebellar metastasis was identified and surgically removed, followed by 20 Gy administered by gamma knife stereotactic radiosurgery; the patient received no subsequent treatment such as chemotherapy. Five years after the primary surgery, there have been no recurrences and the patient has a good quality of life. There are very few case reports of long-term survival after surgical treatment of cerebellar metastases from esophagogastric junction cancer. We report our experience and review published case reports of surgical treatment of brain metastases from gastric cancer.

In Vitro Chemosensitivity Test for Gastric Cancer Specimens Predicts Effectiveness of Oxaliplatin and 5-Fluorouracil.

AIM: Cisplatin plus 5-fluorouracil (5-FU) or S-1 is a standard therapy for gastric cancer (GC). However, cisplatin is emetic and potentially nephrotoxic. Oxaliplatin may be less toxic, but few basic data are available for this setting. Here, we evaluated oxaliplatin for GC, by testing surgical specimens. MATERIALS AND METHODS: We evaluated effects of oxaliplatin and 5-FU, alone and in combination, on surgical specimens from 11 patients with GC, using collagen gel droplet embedded culture drug tests. RESULTS: Oxaliplatin was less efficacious than 5-FU, and its synergistic effect was less in tumors highly sensitive to 5-FU than in those with low sensitivity. Tumor differentiation and drug sensitivity were not correlated. CONCLUSION: Although oxaliplatin monotherapy had little effect on GC, we saw a limited synergistic effect of oxaliplatin with 5-FU in 5-FU-sensitive patients. Collagen gel droplet embedded culture drug tests may predict this synergistic effect, and help select candidates for this or other regimens.

Initial Experience with Nab-Paclitaxel for Patients with Advanced Gastric Cancer: Safety and Efficacy.

BACKGROUND: Taxane-based chemotherapy is useful for peritoneal dissemination control in advanced/recurrent gastric cancer; however, insufficient relative dose intensity (RDI) may preclude disease control achievement. Nab-paclitaxel, with high tumour permeability, is a promising second- or later-line treatment. PATIENTS AND METHODS: We retrospectively evaluated the clinical safety and efficacy of nab-paclitaxel for advanced/recurrent gastric cancer patients treated between April 2013 and December 2015. The response rate, RDI and survival outcomes were assessed. RESULTS: Of 14 evaluated patients, 4 achieved partial response. Overall response and the disease control rates were 28.5% and 64.2%, respectively. Nine patients developed peritoneal metastasis; their overall response and disease control rate were 22.2% and 66.6%. Patients with high RDI (≥80%) showed longer progression-free and overall survival than those with low RDI (≤80%) (11.8 vs. 4.0 months, p=0.02; and 14.3 vs. 8.2 months, p=0.03, respectively). CONCLUSION: Nab-paclitaxel, at an RDI ≥80%, was safe and beneficial for these patients.

Redefining definitive endoderm subtypes by robust induction of human induced pluripotent stem cells.

Many reports have described methods that induce definitive endoderm (DE) cells from human pluripotent stem cells (hPSCs). However, it is unclear whether the differentiation propensity of these DE cells is uniform. This uncertainty is due to the different developmental stages that give rise to anterior and posterior DE from anterior primitive streak (APS). Therefore, these DE cell populations might be generated from the different stages of APS cells, which affect the DE cell differentiation potential. Here, we succeeded in selectively differentiating early and late APS cells from human induced pluripotent stem cells (hiPSCs) using different concentrations of CHIR99021, a small molecule Wnt/ß-catenin pathway activator. We also established novel differentiation systems from hiPSCs into three types of DE cells: anterior and posterior domains of anterior DE cells through early APS cells and posterior DE cells through late APS cells. These different DE cell populations could differentiate into distinct endodermal lineages in vitro, such as lung, liver or small intestine progenitors. These results indicate that different APS cells can produce distinct types of DE cells that have proper developmental potency and suggest a method to evaluate the quality of endodermal cell induction from hPSCs.