Masato Kataoka

Aberrant Elevation of Tyrosine‐specific Phosphorylation in Human Gastric Cancer Cells

Phosphotyrosine‐containing proteins in various human cancer cell lines were studied by immunoblotting with anti‐phosphotyrosine antibody. Of 29 cell lines derived from oral epidermoid cancer, esophageal cancer, gastric cancer, colon cancer, pancreatic cancer, hepatocellular carcinoma and malignant melanoma, 3 of the 6 gastric cancer cells showed aberrant elevation of tyrosine‐speciflc phosphorylation. On the other hand, both esophageal cancer cells and colon cancer cells, which were reported to have amplified epidermal growth factor receptor and activated p60v‐src kinase, respectively, showed no apparent elevation of tyrosine‐specific phosphorylation, and their profiles of phosphorylation were similar to that of normal human fibroblasts. Two gastric cancer cells, NUGC‐4 and MKN‐45, showed similar profiles of phosphorylation but their responses to growth factors differed from each other. Tyrosine phosphorylation in NUGC‐4 was strongly activated by treatment with epidermal growth factor and quickly reduced by the acid treatment which is effective in removing growth factors from cellular surface receptors. On the contrary, phosphorylation in MKN‐45 did not respond to either growth factor or acid treatment. These results suggest that NUGC‐4 and MKN‐45 have tyrosine kinases which are activated by different mechanisms but share similar substrates.

Pulmonary capillary hemangiomatosis incidentally detected in a lobectomy specimen for a metastatic colon cancer

Pulmonary capillary hemangiomatosis is a rare vascular proliferative disease of unknown etiology. The common clinical features are slowly progressive and finally fatal pulmonary hypertension. The clinical diagnosis is usually difficult. Because most reported cases are of autopsy, little is known about its incipient lesion and natural history. Presented herein is a case of pulmonary capillary hemangiomatosis incidentally detected in a surgically resected lung for a metastatic colon cancer. The patient was a 60‐year‐old Japanese woman with a history of sigmoid colon cancer 3 years previously. The patient had undergone a right lower lobectomy for a metastatic tumor in the hilar region and a thoracoscopic tumorectomy of the peripheral area of the left upper lobe. Except for an episode of hemoptysis 2 weeks prior to the lung surgery, there were no other clinical symptoms characteristic of pulmonary capillary hemangiomatosis. The non‐tumor area of right lower lobe showed multiple foci of capillary proliferation affecting alveolar walls, interlobular septa and pleura associated with patchy hemorrhage. There was a minor degree of vascular and bronchial involvement by capillary proliferation. It is suggested this particular case is an incidentally detected clinically incipient stage of pulmonary capillary hemangiomatosis. Passive congestion secondary to metastatic colon cancer in the hilar region may have contributed to the pathogenesis of this lesion.

Lipoma of the esophagus—Report of a case and review of the literature

We report herein, a rare case of esophageal lipoma and review the Japanese literature on this subject. Lipoma of the alimentary tract is relatively uncommon but that of the esophagus is extremely rate with only 17 cases having been reported in Japan. The majority of these cases occurred in the cervical esophagus with the most serious symptom being regurgitation of the pedunculated tumor which lead to asphyxia and death in one case. Only 2 cases occurred in the thoracic esophagus and these tumors were small in size and resected endoscopically. This is the first reported case of an esophageal lipoma being located in the thoracic esophagus which was resected through a thorocotomy. The clinical features of esophageal lipoma are also described herein.

Polyoxyethylene‐modified Superoxide Dismutase Reduces Side Effects of Adriamycin and Mitomycin C

Polyoxyethylene‐modified superoxide dismutase (SOD‐POE) is a newly developed long‐acting superoxide dismutase. Adriamycin (ADR) and mitomycin C (MMC) generate superoxide, which contributes to their cytocidal effects or side effects. We examined whether SOD‐POE could prevent the side effects induced by superoxide generated by antitumor agents, and the following results were obtained. SOD‐POE did not influence the antitumor effects of ADR and MMC either in vitro or in vivo, but prevented the toxic death of BALB/c, nu/nu male mice caused by overdoses of ADR or MMC. As for its effective sites, SOD‐POE prevented a decrease in the specific activity of rotenone‐sensitive NADH‐ubiquinone oxidoreductase (complex I) in heart muscle mitochondrial respiratory chain function in BALB/c male mice administered 10 mg/kg ADR, and prevented damage to the sarcoplasmic reticulum and mitochondria of mouse heart muscle by ADR as observed by electron microscopy. Furthermore, SOD‐POE prevented bone marrow suppression induced by MMC in Donryu rats. The above results suggest that combination chemotherapy with SOD‐POE would make it possible to increase the maximum permissible doses of antitumor agents, improving the efficacy of these agents.

Thymic carcinoid—A case report and review of the literature

We report herein a case of a patient with thymic carcinoid who was operated on twice and has been followed for 9 years. In 1979, the original tumor was removed through an emergency left thoracotomy incision done for a hemothorax caused by an anterior mediastinal biopsy. Tumor recurrence was found 6 years later and removal carried out through a median sternotomy. The patient has been working and enjoying life following radiation and chemotherapy for a total of 9 years after his first operation. Recurrent thymic carcinoid has been thought to carry a poor prognosis, but this successfully treated case has been followed up for a long time after the removal of his recurrent tumor. We present this case and discuss other such cases reported in the Japanese literature.

Malignant Lymphoma of the Gastric Stump Developing 25 Years After a Distal Gastrectomy for Benign Gastric Disease : Report of a Case

We report herein the case of a 57-year-old man in whom malignant lymphoma originating in the gastric remnant was confirmed 25 years after a subtotal gastrectomy with Billroth II reconstruction had been performed for gastric ptosis. Gastroscopy revealed an ulcerated tumor on the fornix, and histologic examination of the endoscopic biopsy specimens demonstrated malignant lymphoma. Thus, total gastrectomy with splenectomy, pancreatectomy, and resection of the previously anastomosed jejunal stoma were performed. Histologic examination of the stomach remnant comfirmed a diagnosis of B-cell lymphoma of the large-cell type. Although we were unable to study the surgical specimen from the initial operation, the possible relationship between pseudolymphoma and malignant lymphoma has been presented in the literature, which is reviewed following this case report.

Multicenter phase II study of infusional 5‑fluorouracil (5‑FU), leucovorin, and oxaliplatin, plus biweekly cetuximab as first‑line treatment in patients with metastatic colorectal cancer (CELINE trial)

The current phase II study investigated the efficacy and safety of biweekly cetuximab combined with standard oxaliplatin-based chemotherapy [infusional 5-fluorouracil (5-FU), leucovorin, and oxaliplatin (FOLFOX-6)] in the first-line treatment of KRAS wild-type metastatic colorectal cancer (mCRC). Sixty patients with a median age of 64 years (range, 38–82 syears) received a biweekly intravenous infusion of cetuximab (500 mg/m2 on day 1) followed by FOLFOX-6 (2-hour oxaliplatin 85 mg/m2 infusion on day 1 in tandem with a 2-h leucovorin 200 mg/m2 infusion on days 1 and 2, and 5-FU as a 400 mg/m2 bolus followed by a 46-hour 2,400 mg/m2 infusion on days 1–3). Patient response rate was 70%, with 95% disease control rates. The median progression-free survival was 13.8 months. Thirteen patients (21.7%) were able to undergo resection of previously unresectable metastases, with the aim of curing them. The median follow-up was 22.7 months, and median overall survival was 31.0 months. Cetuximab did not increase FOLFOX-6 toxicity and was generally well tolerated. The results of the current study demonstrate that the combination of biweekly cetuximab with FOLFOX-6 was well tolerated and had a manageable safety profile for the first-line treatment of KRAS wild-type metastatic colorectal cancer. Efficacy was comparable to other treatment regimens. The results support the administration of biweekly cetuximab in combination with FOLFOX-6, which may be more convenient and provide treatment flexibility in this setting for patients with metastatic colorectal cancers.

The clinical impact of Hangeshashinto (TJ-14) in the treatment of chemotherapy-induced oral mucositis in gastric cancer and colorectal cancer: Analyses of pooled data from two phase II randomized clinical trials (HANGESHA-G and HANGESHA-C)

Background: The current pooled analysis evaluated the efficacy of Hangeshashinto (TJ-14) in the prevention and/or treatment of chemotherapy-induced oral mucositis (COM) in gastric cancer and colorectal cancer using two prospective, multi-institutional, randomized, double-blind, placebo-controlled phase II trials. Patients and Methods: HANGESHA-G and HANGESHA-C randomly assigned patients with gastric cancer or colorectal cancer who developed moderate to severe COM (grade ≥1) during any cycle of chemotherapy to receive either TJ-14 or a placebo as a double-blind trial. The patients received a placebo or TJ-14 for four to six weeks, according to the chemotherapy regimen, from the start of their next course of chemotherapy. The primary endpoint was the incidence of grade ≥2 COM in the protocol treatment course, and the secondary endpoints were the time to disappearance of COM and the incidence of adverse events. Results: The pooled population included 181 patients. The incidence of grade ≥2 COM in the TJ-14 group was 55.7% (49 patients), while that in the placebo group was 53.8% (50 patients); there was no significant difference between the two groups (p=0.796). The median time to remission of grade ≥2 COM to grade <1 was 8 days in the TJ-14 group and 15 days in the placebo group (p= 0.072). The hazard ratio was 1.54 [1.02 to 2.31] in favor of TJ-14. Treatment with TJ-14 was associated with marginally significant reduction in the duration of severe grade ≥2 COM in comparison to patients receiving placebo indicating the effect of TJ-14 in reducing the severity of COM. Conclusion: The present-pooled analysis showed that TJ-14 had a treatment effect in gastric cancer and colorectal cancer patients with COM in comparison to a placebo. Further phase III studies with a larger sample size are needed to clarify the protective effects of TJ-14 against COM.

A prospective Phase II study to examine the relationship between quality of life and adverse events of first-line chemotherapy plus cetuximab in patients with KRAS wild-type unresectable metastatic colorectal cancer: QUACK trial

A prospective trial has not been performed to investigate associations between quality of life (QOL), adverse events (AEs), and overall survival (OS) in the first‐line treatment with cetuximab plus standard chemotherapy for advanced/metastatic colorectal cancer (mCRC). Associations between patient outcome and health‐related QOL (HRQOL) together with skin toxicity‐related QOL were prospectively evaluated using EORTC QLQ‐C30 and DLQI questionnaires. One hundred and forty mCRC patients were analyzed in this study, and 87.8% received pre‐emptive skin treatment. Skin toxicity had no clinical impact on HRQOL or skin‐related QOL during the first 8 weeks and throughout the study period. An early skin reaction with a grade ≥2 at 8 weeks was significantly associated with a favorable OS compared with a grade of ≤1 (HR, 0.50; 95% CI, 0.24‐0.95; P = .035) and was confirmed to be an independent predictor of OS (HR, 0.48; 95% CI, 0.21‐0.97; P = .040). Patients symptomatic at baseline who responded to treatment had improved HRQOL compared to nonresponding patients. Severe mucositis/stomatitis had a statistically significant and clinically meaningful negative impact on HRQOL (mean changes from baseline throughout the study period in global health status were −12.64 for a grade of ≥2 vs −0.35 for a grade of 0 or 1 (P = .005)). In conclusion, severe early skin reactions predict favorable OS for patients treated with cetuximab plus chemotherapy without impairing QOL. In addition, mucositis/stomatitis was the most substantial AE compromising both QOL and treatment compliance.

A CASE OF OBSTRUCTIVE ILEUS CAUSED BY ENDOMETORIOSIS IN THE ILEUM

A 45-year-old woman seen at the department because of a right lower quadrant abdominal pain at menstruation which started about 3 years before. Abdominal X-ray film revealed intestinal obstruction. Obstructive ileus following appendectomy was suspected and the patient was operated on. During surgery, adhesive ileus at the terminal ileum was detected. Ileocecal resection was performed. Pathological diagnosis was made with endometriosis in the ileum, Bowel endometriosis causing intestinal obstruction is rare. It presents difficulty in pre-and intra-operative diagnosis. In a review of the literature, 28 cases including this case have been reported in Japan. It was characteristic of this disease that seven cases (25%) had a previous history of endometriosis, and 14 cases (50%) developed symptoms at menstruations. Those symptoms included abdominal pain, consti-pation, melena, diarrhea, and vomitting. In this case, the patient also complained of abdominal pain and constipation at menstruations. Entertaining of these characteristics, careful attitude for history taking is very important to get the correct diagnosis.