Masanori Toyoda

Primary Levofloxacin Resistance and gyrA/B Mutations Among Helicobacter pylori in Japan

Background:  Recent years have witnessed a decrease in the rate of Helicobacter pylori eradication due to antimicrobial resistance, clarithromycin or metronidazole resistance in particular. As one of the alternatives to the standard regimens, levofloxacin‐containing therapy has been considered a promising regimen. Nevertheless, there is a little information concerning the prevalence of levofloxacin resistance and this resistance mechanism.

Malignant endocrine tumor of the pancreas associated with von Recklinghausen's disease.

We describe a case of malignant endocrine tumor of the pancreas associated with von Recklinghausens disease. A 66-year-old woman with familial von Recklinghausens disease was admitted to our hospital with weight loss and lower abdominal pain. Endoscopy revealed a submucosal tumor in the second part of the duodenum. Contrast-enhanced computed tomography showed a heterogeneous low-density tumor, measuring 20 x 15 mm, in the head of the pancreas, and metastatic lymphadenopathy. Angiography showed faint tumor staining without encasement or apparent increase in vascularity. Pancreatoduodenectomy was performed. Macroscopically, there was a solid tumor, measuring 20 x 18 mm, in the head of the pancreas. Histologically, a malignant endocrine tumor was shown, with direct invasion to the duodenum, and lymph node metastases. This is the thirteenth case of pancreatic malignant tumor and the fourth case of pancreatic endocrine tumor associated with von Recklinghausens disease reported in the world literature.

Excessive MET signaling causes acquired resistance and addiction to MET inhibitors in the MKN45 gastric cancer cell line

SummaryThe clinical efficacy of MET tyrosine kinase inhibitors (MET-TKIs) is hindered by the emergence of acquired resistance, presenting an obstacle to drug discovery. To clarify the mechanisms underlying acquired resistance to MET-TKIs, we established resistance models by continuous exposure of the MET-amplified gastric cancer cell line MKN45 to MET-TKIs, PHA665752 (MKN45-PR) and GSK1363089 (MKN45-GR). Baseline expression and phosphorylation of MET were elevated in MKN45-PR and MKN45-GR compared to MKN45 cells, and higher concentrations of MET-TKIs were required to inhibit MET phosphorylation compared to parental cells. Alterations in MET previously associated with resistance to MET-TKIs were observed in resistant cells, including elevated MET copy number, observed in both resistant lines compared to MKN45 cells, and the Y1230H mutation, detected in MKN45-PR cells. Notably, the growth of resistant lines was lower in the absence of MET-TKIs, suggesting “addiction” to inhibitors. While MKN45-PR cells exhibited a higher S-phase fraction in the absence of PHA665752, bromodeoxyuridine (BrdU) uptake was identical. Baseline phosphorylation of ATR, Chk1 and p53 and p21waf1/Cip1 expression was higher in MKN45-PR compared to MKN45 cells, and levels were reduced to those observed in untreated MKN45 cells following PHA665752 treatment. Furthermore, targeted knockdown of MET enhanced the growth of MKN45-PR cells. These findings suggest that alterations in MET leading to acquired MET-TKI resistance, may cause excessive MET signaling, subsequent replication stress and DNA damage response, and intra-S-phase arrest in the absence of MET-TKIs. Thus, partial MET inhibition is necessary for resistant cells to proliferate, a phenomenon we refer to as MET-TKI “addiction”.

Metabolomics evaluation of serum markers for cachexia and their intra-day variation in patients with advanced pancreatic cancer.

Purpose Cancer cachexia is a multifactorial syndrome characterized by progressive loss of weight and muscle atrophy. Using metabolomics, we investigated serum markers and their intra-day variation in advanced pancreatic cancer patients with cachexia. Methods Patients were enrolled in two groups: those with or without cachexia. Blood samples collected at 6:30 AM, 11:30 AM, 4:30 PM, and 9:30 PM were analyzed using metabolomics, and serum levels of IL-6, TNF-α, and leptin were measured and compared between the two groups. Intra-day variation was then evaluated. Results Twenty-one patients were enrolled in total. In the cachexia group (n = 9), median body weight loss rate over 6 months was greater, performance status was poorer, and anorexia was more severe than in the non-cachexia group (n = 12). Each metabolites level showed substantial intra-day variation, and some of them displayed significant differences between the two groups. Levels of paraxanthine remained markedly lower in the cohort with cachexia at all measurement points. Besides, median IL-6 and TNF-α levels appeared higher and leptin concentration appeared lower in the cachexia group, albeit without statistical significance. Conclusion Some metabolites and some serological marker levels were affected by cancer cachexia. Although paraxanthine levels were consistently lower in patients with cachexia, we identified that many metabolites indicated large intra- and inter-day variation and that it might be necessary to pay attention to intra-day variation in metabolomics research.

Prediction of Glomerular Filtration Rate in Cancer Patients by an Equation for Japanese Estimated Glomerular Filtration Rate

BACKGROUND Assessment of renal function is important for safe cancer chemotherapy, and eligibility criteria for clinical trials often include creatinine clearance. However, creatinine clearance overestimates glomerular filtration rate, and various new formulae have been proposed to estimate glomerular filtration rate. Because these were developed mostly in patients with chronic kidney disease, we evaluated their validity in cancer patients without kidney disease. METHODS Glomerular filtration rate was measured by inulin clearance in 45 Japanese cancer patients, and compared with creatinine clearance measured by 24-h urine collection as well as that estimated by the Cockcroft-Gault formula, Japanese estimated glomerular filtration rate developed in chronic kidney disease patients, the Modification of Diet in Renal Disease study equation and the Chronic Kidney Disease Epidemiology Collaboration equation. The Modification of Diet in Renal Disease study and Chronic Kidney Disease Epidemiology Collaboration equations were adjusted for the Japanese population by multiplying by 0.808 and 0.813, respectively. RESULTS The mean inulin clearance was 79.2 ± 18.7 ml/min/1.73 m(2). Bias values to estimate glomerular filtration rate for Japanese estimated glomerular filtration rate, the Cockcroft-Gault formula, creatinine clearance measured by 24-h urine collection, the 0.808 × Modification of Diet in Renal Disease study equation and the 0.813 × Chronic Kidney Disease Epidemiology Collaboration equation were 0.94, 9.75, 29.67, 5.26 and -0.92 ml/min/1.73 m(2), respectively. Precision (root-mean square error) was 14.7, 22.4, 39.8, 16.0 and 14.1 ml/min, respectively. Of the scatter plots of inulin clearance versus each estimation formula, the Japanese estimated glomerular filtration rate correlated most accurately with actual measured inulin clearance. CONCLUSION The Japanese estimated glomerular filtration rate and the 0.813 × Chronic Kidney Disease Epidemiology Collaboration equation estimated glomerular filtration rate with lower bias and higher precision than the other formulae. We therefore propose Japanese estimated glomerular filtration rate for the estimation of glomerular filtration rate in Japanese cancer patients.

Role of metallothionein in Helicobacter pylori-positive gastric mucosa with or without early gastric cancer and the effect on its expression after eradication therapy

Background and Aim:  Metallothionein (MT) has a proven relationship with various kinds of cancer and reduces tissue damage. Helicobacter pylori (H. pylori) infection is associated with the alteration of gastric epithelial cell cycle events, a condition implicated in the initiation and development of gastric cancer. This study investigates the role of MT in H. pylori‐induced gastritis with or without early gastric cancer (ECG) and evaluates the effect on MT expression after eradication therapy.

Randomized trial of standard pain control with or without gabapentin for pain related to radiation-induced mucositis in head and neck cancer

OBJECTIVE Radiation-induced mucositis (RIM) in chemoradiotherapy (CRT) for head and neck cancer (HNC) causes severe pain and worsens CRT compliance, QOL and outcome. Following retrospective reports, we conducted a randomized trial of the safety and efficacy of gabapentin for RIM-associated pain during CRT. METHODS HNC patients (pts) receiving CRT were randomized to standard pain control (SPC) with acetaminophen and opioids, or SPC plus gabapentin (SPC+G). Gabapentin was maintained at 900mg/day for 4 weeks after CRT. Primary endpoint was maximum visual analogue scale (VAS) score during CRT, and secondary endpoints were total opioid dose, changes in QOL (EORTC QLQ-C30 and QLQ-HN 35) from baseline to 4 weeks after CRT, and adverse events. RESULTS Twenty-two eligible Stage III or IV pts were randomly assigned to SPC or SPC+G (n=11 each). Twelve were treated in a locally advanced setting and 10 in a postoperative setting. Median maximum VAS scores, median total dose of opioids at maximum VAS and total dose of opioids at 4 weeks after CRT tended to be higher in the SPC+G arm (47 in SPC vs. 74 in SPC+G, p=0.517; 215mg vs. 745.3mg, p=0.880; and 1260mg vs. 1537.5mg, p=0.9438, respectively), without significance. QOL analysis showed significantly worse scores in the SPC+G arm for weight gain (p=0.005). Adverse events related to gabapentin were manageable. CONCLUSIONS This pilot study is the first prospective randomized trial of gabapentin for RIM-related pain. Gabapentin had no apparent beneficial effect. Further research into agents for RIM-related pain is warranted.

Validity of new methods to evaluate renal function in cancer patients treated with cisplatin

PurposeCreatinine clearance (Ccr) is used as a marker of renal function in cancer chemotherapy, but it is not correlated with glomerular filtration rate (GFR) after high-dose cisplatin treatment. In addition to Ccr, measured using 24-h urine collection (24-h Ccr) or Cockcroft–Gault formula (CGF), the Chronic Kidney Disease Epidemiology Collaboration (CKD–EPI) equation and the Japanese GFR estimation equation (the Japanese equation) have been recently developed to estimate GFR for predicting renal function. However, these equations remain to be evaluated, particularly in cancer patients treated with cisplatin. Therefore, we investigated the validity of these equations for predicting the GFR in cancer patients treated with cisplatin.MethodsGFR was measured by inulin clearance (Cin) in 50 cancer patients and compared with GFR estimated by the CKD–EPI equation, the Japanese equation, and Ccr estimated by CGF or measured by 24-h Ccr before the first and third cisplatin-containing chemotherapy cycles (considered pretreatment and posttreatment, respectively).ResultsBefore treatment, the CKD–EPI and the Japanese equations estimated GFR with higher accuracy than Ccr. Posttreatment bias values for GFR estimation using the CKD–EPI and the Japanese equations were lower than those for Ccr. The CKD–EPI and the Japanese equations were also more precise than Ccr. However, for patients with low renal function, these equations still overestimated Cin.ConclusionThe CKD–EPI and the Japanese equations estimated GFR with lower bias and higher precision than Ccr pre- and postcisplatin treatment. This study is registered at UMIN: 000002167.

Pharmacokinetic Study of Adjuvant Gemcitabine Therapy for Biliary Tract Cancer following Major Hepatectomy (KHBO1101).

Background Biliary tract cancer (BTC) patients who have undergone surgical resection with major hepatectomy cannot tolerate the standard gemcitabine regimen (1,000 mg/m2 on days 1, 8, and 15 every 4 weeks) due to severe toxicities such as myelosuppression. Our dose-finding study of adjuvant gemcitabine therapy for biliary tract cancer following major hepatectomy determined that the recommended dose is 1,000 mg/m2 on days 1 and 15 every 4 weeks. Here, we evaluate the pharmacokinetics and pharmacodynamics of gemcitabine in these subjects. Methods We evaluated BTC patients scheduled to undergo surgical resection with major hepatectomy followed by gemcitabine therapy. A pharmacokinetic evaluation of gemcitabine and its main metabolite, 2′,2′-difluorodeoxyuridine (dFdU), was conducted at the initial administration of gemcitabine, which was given by intravenous infusion over 30 min at a dose of 800–1,000 mg/m2. Physical examination and adverse events were monitored for 12 weeks. Results Thirteen patients were enrolled from August 2011 to January 2013, with 12 ultimately completing the pharmacokinetic study. Eight patients had hilar cholangiocarcinoma, three had intrahepatic cholangiocarcinoma, and one had superficial spreading type cholangiocarcinoma. The median interval from surgery to first administration of gemcitabine was 65.5 days (range, 43–83 days). We observed the following toxicities: neutropenia (n = 11, 91.7%), leukopenia (n = 10, 83.3%), thrombocytopenia (n = 6, 50.0%), and infection (n = 5, 41.7%). Grade 3 or 4 neutropenia was observed in 25% (n = 3) of patients. There were differences in clearance of gemcitabine and dFdU between our subjects and the subjects who had not undergone hepatectomy. Conclusion Major hepatectomy did not affect the pharmacokinetics of gemcitabine or dFdU. Trial Registration UMIN-CTR in (JPRN) UMIN000005109

Impact of Helicobacter pylori Eradication Therapy on Histologic Change in the Distal Esophagus

Background:  Although cases of reflux esophagitis (RE) developing after treatment to eradicate Helicobacter pylori have been discussed in some detail, no reports are available concerning the histologic examination of RE both before and after eradication therapy.