Modified FOLFIRINOX as a second-line therapy following gemcitabine plus nab-paclitaxel therapy in metastatic pancreatic cancer.

BACKGROUND: There is no established second-line treatment after failure of gemcitabine plus nab-paclitaxel (GnP) therapy for metastatic pancreatic cancer (MPC). The purpose of this study was to evaluate the efficacy and tolerability of the modified FOLFIRINOX (mFFX) as a second-line therapy for MPC and to investigate prognostic factors for survival. METHODS: From 2015 to 2019, we retrospectively reviewed the medical records of consecutive patients receiving mFFX for MPC after failure of GnP therapy. Patients were treated every 2 weeks with mFFX (intravenous oxaliplatin 85 mg/m2, intravenous irinotecan 150 mg/m2, and continuous infusion of 5-fluorouracil 2400 mg/m2 for 46 h without bolus infusion). RESULTS: In total, 104 patients received mFFX. The median overall survival (OS) was 7.0 months (95% confidence interval [CI]: 6.2-9.8) and the progression-free survival (PFS) 3.9 months (95% CI 2.8-5.0). The objective response rate was 10.6% and the disease control rate 56.7%. The median relative dose intensities of oxaliplatin, irinotecan, and infusional 5-FU were 80.0% (range 21.5-100%), 77.2% (range 38.1-100%), and 85.9% (range 36.9-100%), respectively. Grade 3-4 toxicities were reported in 57 patients (54.8%), including neutropenia, leukopenia, anemia, febrile neutropenia, and peripheral sensory neuropathy. Glasgow prognostic score and carcinoembryonic antigen level were independently associated with survival. Our prognostic model using these parameters could classify the patients into good (n = 38), intermediate (n = 47), and poor (n = 19) prognostic groups. The median OS and PFS time was 14.7 (95% CI 7.6-16.3) and 7.6 months (95% CI 4.1-10.5) for the good prognostic factors, 6.5 (95% CI 5.5-10.0) and 3.6 months (95% CI 2.7-4.8) for the intermediate prognostic factors and 5.0 (95% CI 2.9-6.6) and 1.7 months (95% CI 0.9-4.3) for the poor prognostic factors, respectively. CONCLUSIONS: The mFFX showed to be a tolerable second-line treatment for MPC after GnP failure. Our prognostic model might be useful for deciding whether mFFX is indicated in this setting.

Development of an external-to-internal convertible endoscopic biliary drainage device - a preliminary prospective feasibility study.

BACKGROUND AND STUDY AIMS: Endoscopic nasobiliary drainage (ENBD) for a malignant stricture in the bile duct has some advantages over endoscopic biliary stenting (EBS). However, ENBD may cause nasopharyngeal discomfort. We developed an external-to-internal convertible endoscopic biliary drainage (ETI-EBD) device that enables both internal and external drainage to occur during a single endoscopy. PATIENTS AND METHODS: This device consists of three parts, comprising a 5-Fr ENBD tube (250 cm) (ENBD-t), an 8.5-Fr EBS tube (7 cm) (EBS-t), and an 8-Fr pusher tube for EBS (230 cm) (P-t). The EBS-t is mounted over the ENBD-t at the distal end of the ENBD-t. The P-t is also placed over the ENBD-t. After an endoscopic sphincterotomy, the EBS-t of the device is inserted into the papilla, then the duodenal endoscope is withdrawn, leaving the device in place. After ENBD, only the ENBD-t was withdrawn from the P-t. At this point, the EBS-t was isolated and left without endoscopy or radiography. RESULTS: ETI-EBD was successfully placed in all consecutive 21 patients (100 %). The release of EBS-t from ENBD-t wit was successfully completed in 19 patients (90.5 %). There were 4 patients with kink of P-t when exchanging this device from the mouth to the nose. It was difficult for 2 patients to withdraw the ENBD-t because of poor lubrication performance. There were no significant complications associated with the use of the device. CONCLUSION: This device allows for both external and internal biliary drainage with a single endoscopy.

[A case of curatively resected AFP producing gastric cancer that responded remarkably to 1 course of TS-1 and showed complete loss of multiple liver metastatic tumors].

A 73-year-old woman was admitted to our hospital for evaluation of hypochondralgia, and a thorough examination revealed an AFP producing gastric cancer with multiple liver metastases. One course of TS-1 100 mg/day for 4 weeks and discontinuation for 2 weeks was started from February, 2003. After 3 months, the level of AFP reduced remarkably from 53,700 ng/ml to the normal limit. The metastatic tumors in the liver showed regression, and after 14 months, CT scanning showed that the tumors had disappeared. Since the size of the original tumor showed no change, distal gastrectomy was performed, and curability A was achieved. We consider this rare case has significant value in terms of treatment of AFP producing gastric cancer with multiple liver metastases. We think the combination of surgery and chemotherapy such as TS-1 will lead to a better prognosis in such cases.

Overexpression of plasma membrane-associated sialidase attenuates insulin signaling in transgenic mice.

Plasma membrane-associated sialidase is a key enzyme for ganglioside hydrolysis, thereby playing crucial roles in regulation of cell surface functions. Here we demonstrate that mice overexpressing the human ortholog (NEU3) develop diabetic phenotype by 18-22 weeks associated with hyperinsulinemia, islet hyperplasia, and increased beta-cell mass. As compared with the wild type, insulin-stimulated phosphorylation of the insulin receptor (IR) and insulin receptor substrate I was significantly reduced, and activities of phosphatidylinositol 3-kinase and glycogen synthase were low in transgenic muscle. IR phosphorylation was already attenuated in the younger mice before manifestation of hyperglycemia. Transient transfection of NEU3 into 3T3-L1 adipocytes and L6 myocytes caused a significant decrease in IR signaling. In response to insulin, NEU3 was found to undergo tyrosine phosphorylation and subsequent association with the Grb2 protein, thus being activated and causing negative regulation of insulin signaling. In fact, accumulation of GM1 and GM2, the possible sialidase products in transgenic tissues, caused inhibition of IR phosphorylation in vitro, and blocking of association with Grb2 resulted in reversion of impaired insulin signaling in L6 cells. The data indicate that NEU3 indeed participates in the control of insulin signaling, probably via modulation of gangliosides and interaction with Grb2, and that the mice can serve as a valuable model for human insulin-resistant diabetes.

Reduced sialidase expression in highly metastatic variants of mouse colon adenocarcinoma 26 and retardation of their metastatic ability by sialidase overexpression.

Sialidase expression levels are inversely correlated with the metastatic potential of mouse colon adenocarcinoma 26 sublines, as assessed by activity assays and RT-PCR, irrespective of total and cell surface sialic acid contents. Compared with low metastatic NL4 and NL44 cell lines, the highly metastatic NL17 and NL22 cells exhibit low expression of sialidases, accompanied with higher levels of sialylLe(x) and GM3. To investigate whether these properties of NL17 cells can be altered by sialidase overexpression, we transfected a cytosolic sialidase gene into NL17 cells. The result was markedly inhibited lung metastasis, invasion and cell motility with a concomitant decrease in sialylLe(x) and GM3 levels, in line with the case of spontaneously low metastatic sublines having relatively high endogenous sialidase levels, implying that sialidase level is a determining factor affecting metastatic ability. Treatment of the cells with antibodies against sialylLe(x) and GM3 affected cell adhesion and/or cell motility, providing evidence that desialylation of these molecules, as targets of sialidase, is involved in the suppression of metastasis.