Junya Fujita

Anti-interleukin-6 receptor antibody prevents muscle atrophy in colon-26 adenocarcinoma-bearing mice with modulation of lysosomal and ATP-ubiquitin-dependent proteolytic pathways

Progression of skeletal muscle atrophy is one of the characteristic features in cancer patients. Interleukin‐6 (IL‐6) has been reported to be responsible for the loss of lean body mass during cancer cachexia in colon‐26 adenocarcinoma (C‐26)‐bearing mice. This study was carried out to elucidate the intracellular proteolytic pathways operating in skeletal muscle in C‐26‐bearing mice, and to examine the effect of anti IL‐6 receptor antibody on muscle atrophy. On day 17 after tumor inoculation, the gastrocnemius muscle weight of C‐26‐bearing mice had significantly decreased to 69% of that of the pair‐fed control mice. This weight loss occurred in association with increases in the mRNA levels of cathepsins B and L, poly‐ubiquitin (Ub) and the subunits of proteasomes in the muscles. Furthermore, enzymatic activity of cathepsin B+L in the muscles also increased to 119% of the control. The administration of antimurine IL‐6 receptor antibody to C‐26‐bearing mice reduced the weight loss of the gastrocnemius muscles to 84% of that of the control mice, whose enzymatic activity of cathepsin B+L and mRNA levels of cathepsin L and poly‐Ub were significantly suppressed compared with those of the C‐26‐bearing mice. Our data indicate that both the lysosomal cathepsin pathway and the ATP‐dependent proteolytic pathway might be involved in the muscle atrophy of C‐26‐bearing mice. The results also suggest that anti IL‐6 receptor antibody could be a potential therapeutic agent against muscle atrophy in cancer cachexia by inhibiting these proteolytic systems.

CYP1A1 CYP2E1 and GSTM1 polymorphisms are not associated with susceptibility to squamous-cell carcinoma of the esophagus

We investigated the genetic polymorphisms of CYPIAI, CYP2EI and GSTMI in Japanese esophageal cancer patients (n = 53) with a histological diagnosis of squamous‐cell carcinoma, to determine whether susceptibility to esophageal cancer is associated with these polymorphisms. There were no significant differences in the frequency distribution of any one of the 3 polymorphisms between esophageal cancer patients and 132 healthy Japanese controls. The genotype distributions in tobacco smokers or alcohol drinkers were also quite similar for male patients and male controls. The age at onset of esophageal cancer was also similar for patients with any genotype of the 3 polymorphisms. We conclude that the 3 polymorphisms are unlikely to be associated with esophageal cancer susceptibility. Int. J. Cancer 71:192–195, 1997.

Prospective randomized trial of preoperative enteral immunonutrition followed by elective total gastrectomy for gastric cancer.

Perioperative enteral immunonutrition is thought to reduce postoperative morbidity in patients undergoing major gastrointestinal surgery. This study assessed the clinical effects of preoperative enteral immunonutrition in well nourished patients with gastric cancer undergoing total gastrectomy.

NY-ESO-1 antibody as a novel tumour marker of gastric cancer.

Background:NY-ESO-1 antibodies are specifically observed in patients with NY-ESO-1-expressing tumours. We analysed whether the NY-ESO-1 humoral immune response is a useful tumour marker of gastric cancer.Methods:Sera from 363 gastric cancer patients were screened by enzyme-linked immunosorbent assay (ELISA) to detect NY-ESO-1 antibodies. Serial serum samples were obtained from 25 NY-ESO-1 antibody-positive patients, including 16 patients with curative resection and 9 patients who received chemotherapy alone.Results:NY-ESO-1 antibodies were detected in 3.4% of stage I, 4.4% of stage II, 25.3% of stage III, and 20.0% of stage IV patients. The frequency of antibody positivity increased with disease progression. When the NY-ESO-1 antibody was used in combination with carcinoembryonic antigen and CA19-9 to detect gastric cancer, information gains of 11.2% in stages III and IV, and 5.8% in all patients were observed. The NY-ESO-1 immune response levels of the patients without recurrence fell below the cutoff level after surgery. Two of the patients with recurrence displayed incomplete decreases. The nine patients who received chemotherapy alone continued to display NY-ESO-1 immune responses.Conclusion:When combined with conventional tumour markers, the NY-ESO-1 humoral immune response could be a useful tumour marker for detecting advanced gastric cancer and inferring the post-treatment tumour load in seropositive patients.

Role of Interleukin-6 in Skeletal Muscle Protein Breakdown and Cathepsin Activity in vivo

In order to elucidate the acute and chronic effects of interleukin-6 (IL-6) on muscle protein degradation, the weight of skeletal muscles and the activities of lysosomal cathepsins (B and L) in the muscles were examined in two animal models. Two intraperitoneal injections of recombinant human IL-6 into rats did neither significantly affect the cathepsin activities in the soleus and the extensor digitorum longus muscles nor the weight of these muscles. On the other hand, the gastrocnemius muscles of the IL-6 transgenic mice underwent severe atrophy accompanied by a marked increase in cathepsin activities. We conclude that IL-6 mediates muscle protein degradation with enhancing lysosomal cathepsin activity, and that these muscle reactions are mandated by chronic exposure to a high level of IL-6.

Comparison of Perioperative and Long-term Outcomes of Total and Proximal Gastrectomy for Early Gastric Cancer: A Multi-institutional Retrospective Study

BackgroundVarious surgical procedures are used to treat early gastric cancers in the upper third of the stomach (U-EGCs). However, there is no general agreement regarding the optimal surgical procedure.MethodsThe medical records of 203 patients with U-EGC were collected from 13 institutions. Surgical procedures were classified as Roux-en-Y esophagojejunostomy after total gastrectomy (TG-RY), esophagogastrostomy after proximal gastrectomy (PG-EG), or jejunal interposition after PG (PG-JI). Patient clinical characteristics and perioperative and long-term outcomes were compared among these three groups.ResultsTG-RY, PG-EG, and PG-JI were performed in 122, 49, and 32 patients, respectively. Tumors were larger in TG-RY patients than in PG-EG and PG-JI patients, and undifferentiated-type gastric adenocarcinoma tended to be more frequent in TG-RY than in PG-EG. The operative time was shorter for PG-EG than for PG-JI and TG-RY. Hospital stay and early postoperative complications were not different for the three procedures. With respect to gastrectomy-associated symptoms, a “stuck feeling” and heartburn tended to be more frequent in PG-EG patients, while dumping syndrome and diarrhea were more frequent in TG-RY patients. Post-surgical weight loss was not different among the three groups, however, serum albumin and hemoglobin levels tended to be lower in TG-RY patients.ConclusionThree surgical procedures for U-EGC did not result in differences in weight loss, but PG-EG and PG-JI were better than TG-RY according to some nutritional markers. In U-EGC, where patients are expected to have long survival times, PG-EG and PG-JI should be used rather than TG-RY.

Subcuticular sutures versus staples for skin closure after open gastrointestinal surgery: a phase 3, multicentre, open-label, randomised controlled trial

BACKGROUND Staples have been widely used for skin closure after open gastrointestinal surgery. The potential advantages of subcuticular sutures compared with staples have not been assessed. We assessed the differences in the frequency of wound complications, including superficial incisional surgical site infection and hypertrophic scar formation, depending on whether subcuticular sutures or staples are used. METHODS We did a multicentre, open-label, randomised controlled trial at 24 institutions between June 1, 2009, and Feb 28, 2012. Eligible patients aged 20 years or older, with adequate organ function and undergoing elective open upper or lower gastrointestinal surgery, were randomly assigned preoperatively to either staples or subcuticular sutures for skin closure. Randomisation was done via a computer-generated permuted-block sequence, and was stratified by institution, sex, and type of surgery (ie, upper or lower gastrointestinal surgery). Our primary endpoint was the incidence of wound complications within 30 days of surgery. Analysis was done by intention to treat. This study is registered with UMINCTR, UMIN000002480. FINDINGS 1080 patients were enrolled and randomly assigned in a one to one ratio: 562 to subcuticular sutures and 518 to staples. 1072 were eligible for the primary endpoint and 1058 for the secondary endpoint. Of the 558 patients who received subcuticular sutures, 382 underwent upper gastrointestinal surgery and 176 underwent lower gastrointestinal surgery. Wound complications occurred in 47 of 558 patients (8·4%, 95% CI 6·3-11·0). Of the 514 who received staples, 413 underwent upper gastrointestinal surgery and 101 underwent lower gastrointestinal surgery. Wound complications occurred in 59 of 514 (11·5%, 95% CI 8·9-14·6). Overall, the rate of wound complications did not differ significantly between the subcuticular sutures and staples groups (odds ratio 0·709, 95% CI 0·474-1·062; p=0·12). INTERPRETATION The efficacy of subcuticular sutures was not validated as an improvement over a standard procedure for skin closure to reduce the incidence of wound complications after open gastrointestinal surgery. FUNDING Johnson & Johnson.

Increased Urinary Excretion of Bilirubin Metabolites in Association with Hyperbilirubinemia After Esophagectomy

This study was conducted to investigate the rationale for postoperative hyperbilirubinemia after major surgery. The serum bilirubin values and urinary excretion of bilirubin metabolites (BM) were monitored in 11 patients who underwent esophagectomy via right thoracotomy for esophageal cancer. Both the serum bilirubin values and the urinary excretion of BM increased postoperatively in all patients. The maximum serum bilirubin level in four patients with septic complications, two of whom developed pneumonia and two, anastomotic leakage (group A), was significantly higher at 5.25+/-4.16 mg/dl than in the remaining patients without septic complications (group B), at 2.11+/-0.07 mg/dl. The peak value of urinary BM was 99.5+/-88.2 micromol/day in group A and 23.5 +/-26.7 micromol/day in group B. The correlation between the level of serum bilirubin and urinary BM excretion was found to be significant. Thus, the metabolism of bilirubin was increased by extensive surgical stress and septic insult.

Long-term outcomes after prophylactic bursectomy in patients with resectable gastric cancer: Final analysis of a multicenter randomized controlled trial

BACKGROUND Bursectomy, a traditional operative procedure to remove the peritoneal lining covering the pancreas and the anterior plane of the transverse mesocolon, has been performed for serosa-positive gastric cancer in Japan and Eastern Asia. We conducted a multicenter, randomized, controlled trial to demonstrate the noninferiority of the omission of bursectomy. METHODS Between July 2002 and January 2007, 210 patients with cT2-3 gastric adenocarcinoma were randomized intraoperatively to D2 gastrectomy with or without bursectomy. The primary endpoint was overall survival (OS). We provide the results of the final analysis of the complete 5-year follow-up data. RESULTS After the median follow-up of 80 months, 5-year OS was 77.5% for the bursectomy group and 71.3% for the nonbursectomy group (2-sided P = .16 for superiority; 1-sided P = .99 for noninferiority). The hazard ratio for death in the nonbursectomy group was 1.40 (95% CI, 0.87-2.25). The 5-year recurrence-free survivals were 73.7% and 66.6% in the bursectomy and nonbursectomy groups, respectively (2-sided P = .33 for superiority; 1-sided P = .99 for noninferiority). Cox multivariate analysis revealed that bursectomy was an independent prognostic factor of good OS (P = .033). Subgroup analysis showed a trend toward improved survival after bursectomy for tumors in the middle or lower third of the stomach and for pathologically serosa-positive tumors. CONCLUSION The final analysis could not demonstrate the noninferiority of the omission of bursectomy. Bursectomy should not be abandoned as a futile procedure.

Prognostic information derived from RT-PCR analysis of peritoneal fluid in gastric cancer patients: results from a prospective multicenter clinical trial.

The purpose of this study is to define the clinical significance of the molecular analysis of peritoneal lavage fluid in patients with gastric cancer in a multicenter prospective trial.