Masataka Shimotsuma

Treatment strategy of limited surgery in the treatment guidelines for gastric cancer in Japan

Surgical practice for gastric cancer in Japan is based on the Gastric Cancer Treatment Guidelines issued in 2001 by the Japanese Gastric Cancer Association. These recommendations list options for treatment of each stage of cancer, with clear distinctions between interventions recommended for routine use and those that should be confined to trial settings until further evidence for their curative potential becomes available. In this review, we discuss standard surgery, local resection, segmental resection, and pylorus-preserving gastrectomy (PPG) as examples of limited resection and describe in detail the indications for limited lymph-node dissection in cases of early-stage gastric cancer. At present, evidence does not support the conclusion that limited surgery is effective for local resection or for improving quality of life. Thus, use of limited surgery should be considered an experimental approach both in Japan and the West. We conclude that surgeons who are familiar with the criteria for selecting surgical procedures should decide on a case-by-case basis which technique is most appropriate. Choices should be made with consideration of the stage of the cancer, invasiveness of the surgical procedure, and the patients history. For all procedures, the patient must give informed consent and the surgeons must accurately assess the success of the operation after surgery.

Cellular subsets of the milky spots in the human greater omentum

SummaryThe cellular composition of the human milky spots was investigated on surgically removed specimens of the greater omentum of three 8-month-old infants operated on for neuroblastoma. Monoclonal antibodies and immunohistochemical methods for recognition of macrophages, B-lymphocytes and T-lymphocytes and toluidine-blue staining for mast cells were used. The mean number of cells in one milky spot amounted to 570±33. This cell population was composed of 47.5% macrophages, 29.1% B-lymphocytes, 11.7% T-lymphocytes and 6.1% mast cells. Since inflammation was absent in the material investigated, the numerical data found in the present paper could be regarded as representative cell levels of normal milky spots.

Phase I/II Study of a Combination of S-1 and Weekly Paclitaxel in Patients with Advanced or Recurrent Gastric Cancer

Objective: A phase I study of weekly intravenous paclitaxel combined with a fixed dose of S-1, a dihydropyrimidine-dehydrogenase-inhibitory oral fluoropyrimidine, was conducted for patients with advanced or recurrent gastric cancer (ARGC). Endpoints of this study were to examine the toxicity profile of this regimen and to determine the recommended dose (RD) of paclitaxel. Methods: S-1 was fixed at a dose of 80 mg/m2 per day and was administered for 2 weeks (days 1–14) followed by a 2-week rest. Two dose levels of paclitaxel (level 1: 60 mg/m2, level 0: 50 mg/m2) were studied. Paclitaxel was infused over 1 h on days 1, 8, and 15. Plasma sampling was performed to characterize the pharmacokinetics and pharmacodynamics of paclitaxel in some patients. Fifteen patients were enrolled (6 patients in level 1, and 9 patients in level 0). Dose-limiting toxicities were defined as grade 4 hematological (including grade 3 febrile neutropenia) and grade 3 non-hematological (except anorexia, nausea, vomiting and depilation) toxicities. Results: Three of 6 patients in level 1 developed grade 4 neutropenia or grade 3 febrile neutropenia, and 1 of them also showed grade 3 diarrhea, which settled the maximum-tolerated dose at this level. At level 0, 2 of 9 patients developed grade 4 neutropenia or grade 3 febrile neutropenia, and the RD of paclitaxel for this protocol was set at this level. Pharmacologic studies demonstrated the persistence of significant serum paclitaxel levels over 24 h after drug administration at both levels. Objective responses according to Response Evaluation Criteria in Solid Tumors were observed in 3 of 6 patients who had measurable disease. Conclusion: A combination of S-1 and weekly paclitaxel was feasible and well tolerated, and is suggested to produce a worthwhile response in ARGC. These results warrant further investigation, and a phase II study has already been started.

Role of milky spots as selective implantation sites for malignant cells in peritoneal dissemination in mice

We investigated the significance of milky spots for malignant cells in peritoneal dissemination using three mouse carcinomatous peritonitis models. P388 leukemia and Colon 26 cancer cells were labeled with bromodeoxyuridine (BrdU) and mice were inoculated intraperitoneally. After 24 h the greater omentum and the mesenterium were removed and stained immunohistochemically with anti-BrdU antibody. The labeled cells were found to have preferentially infiltrated into the milky spots in these specimens. Next, using B16 PC melanoma cells, which can be easily distinguished from the other cells by the intrinsic black melanin, the distribution of the melanoma cells was observed macro- and microscopically following intraperitoneal inoculation. The melanoma cells were similarly found to have selectively infiltrated into the milky spots in the omentum and mesenterium after 1 day. Moreover, the melanoma cells were growing and forming distinct metastic lesions within the milky spots 1 week later.

How safe are the xenogeneic hemostats?--Report of a case of severe systemic allergic reaction.

We report herein the unusual case of a 55-year-old woman who developed a severe systemic allergy to Avitene (microfibrillar collagen hydrochloride), a xenogeneic agent sometimes used for topical hemostasis in laparoscopic cholecystectomy. The patient developed fever, general fatigue, mild liver dysfuction, and prominent eosinophilia postoperatively. A skin allergy test confirmed that these abnormal findings were attributable to an allergic reaction to Avitene.

Multicenter phase II study of weekly paclitaxel plus S-1 combination chemotherapy in patients with advanced gastric cancer.

BackgroundA multicenter phase II study was conducted to evaluate the efficacy and safety of a combination regimen of weekly paclitaxel plus S-1 in patients with advanced gastric cancer.MethodsPatients with previously untreated metastatic or recurrent gastric cancer received intravenous paclitaxel 50 mg/m2 on days 1, 8, and 15, plus oral S-1 40 mg/m2 b.i.d. on days 1 to 14 followed by 2 weeks off, in a 28-day cycle.ResultsA total of 54 patients were registered. All of them had measurable disease and were determined to be eligible for the present study. Two complete responses and 23 partial responses were confirmed, giving an overall response rate of 46.3%. At a final follow up of 3 years, the median progressionfree survival and median overall survival were 6.0 and 14.3 months, respectively. Grade 3 neutropenia occurred in 14 patients, and grade 4 in 1 patient (total, 27.8%). The most serious nonhematological toxicity was diarrhea, where grade 3 occurred in 5 patients (9.3%). There were no treatmentrelated deaths.ConclusionA combination of weekly paclitaxel plus S-1 was found to be well tolerated and effective in patients with advanced gastric cancer. Further investigation with comparative trials is needed for confirmation.

Therapeutic effects of the angiogenesis inhibitor TNP-470 against carcinomatous peritonitis in mice.

The therapeutic effects of the new anti-angiogenesis factor TNP-470 were examined against carcinomatous peritonitis in mice. In the first experiment using carcinomatous peritonitis caused by i.p. inoculation of 10(6) M5076 tumor cells, TNP-470 solution was injected i.p. in a bolus of 50 mg/kg body weight into two groups of 10 mice either 1 or 8 days after the i.p. inoculation. The administration of TNP-470 on day 1 extended the survival time of the mice compared with 10 control mice receiving no treatment, whereas TNP-470 given on day 8 did not affect the survival time. In the next experiment on the M5076 tumor, TNP-470 solutions at 100 or 300 mg/kg were injected i.p. in a bolus into two groups of 20 mice 1 day after the inoculation 10(6) tumor cells, respectively. The administration of TNP-470 at 100 mg/kg also had an inhibitory effect. However, TNP-470 at 300 mg/kg caused toxic death in half of the mice. Next, we examined the effects of TNP-470 on another type of carcinomatous peritonitis model, which was caused by i.p. inoculation of 10(6) B16 melanoma cells. In this experiment, TNP-470 solutions in a bolus of 150 mg/kg were injected i.p. into six groups of 10 mice each on day 1 only (group 1), on days 1 and 4 (group 2), on days 1, 4 and 7 (group 3), on day 8 only (group 4), on days 8 and 11 (group 5), or on days 8, 11 and 14 (group 6), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of omentum-associated lymphoid tissue in the progression of peritoneal carcinomatosis

The peritoneal cavity is vulnerable to the implantation of cancer cells that have escaped from a primary tumor into the peritoneal cavity. Although peritoneal metastases have been assumed classically to occur at random in every portion of the peritoneal membrane, they actually occur at anatomically or physiologically preferred sites, such as the greater omentum, diaphragm, and pelvic peritoneum [1]. An important function of the peritoneum is associated with the lymphatic system of the peritoneal cavity that helps to maintain its homeostasis [2]. In the greater omentum there are many omentum-associated lymphoid tissues (OALT), known as milky spots. The OALT acts a filter through which lymph and various substances are rapidly taken up, and it participates in the immune defense of the peritoneal cavity [3]. The OALT also plays an important role in the initial stages of peritoneal carcinomatosis.

Intraoperative cleansing of the impacted colon using an endotracheal tube

A simple technique for intraoperative cleansing of the impacted colon is described. Saline-irrigation through the torn balloon of the endotracheal tube (38 French) and massaging the impacted feces facilitated drainage of the obstructed colon. This technique was done in two emergent colon operations and immediate anastomosis could be performed safely. An endotracheal tube is always available in an operating room, so this technique is useful and effective in an emergent colon operation without special preparation.

Role of peritoneal lymphatics for peritoneal metastasis and chemotherapy with mitomycin C bound to activated carbon particles

SummaryBackgroundBased on the knowledge that omental milky spots take up cancer cells seeded in the peritoneal cavity as well as carbon particles, mitomycin C bound to activated carbon particles (MMC-CH) was examined in patients with advanced gastric cancer in a prospective randomized study.Methods104 patients who underwent gastrectomy for gastric cancer with definite serosal involvement were entered in this trial. Patients in the MMC-CH group were given 50 mg mitomycin C as MMC-CH dispersed throughout the peritoneal cavity just before surgical closure.Results3-year survival rates for all-over patients treated with MMC-CH was 48% and for patients without MMC-CH was 28%, the differences between these 2 groups being significant (p<0.05). In the patients with macroscopic peritoneal carcinomatosis, there was no difference in survival between these 2 groups. There were no operative deaths in this series but bowel fistula developed in 2 patients given MMC-CH.ConclusionsChemotherapy with MMC-CH improves the survival of patients with gastric cancer involving the serosa, but does not improve the survival of patients with evidence of macroscopic peritoneal carcinomatosis.ZusammenfassungGrundlagenDer Nachweis, daß an sogenannten «milky spots» des Peritoneums Kohlepartikel in gleicher Weise wie intraperitoneale Tumorzellen aufgenommen werden, führte zu einer prospektiven, randomisierten Studie über die Wirksamkeit von intraperitoneal verabreichtem, an Kohlepartikel gebundenem Mitomycin C bei Patienten mit lokal fortgeschrittenen Magenkarzinomen.Methodik104 Patienten mit Magenkarzinomen, entweder mit Serosainfiltration oder Carcinosis peritonei, wurden nach Gastrektomie in die Studie aufgenommen. Den der Therapiegruppe zugeordneten Patienten wurde vor Verschluß der Abdominalhöhle 50 mg an Kohlepartikel gebundenes Mitomycin C intraperitoneal instilliert.ErgebnisseDie 3-Jahres-Überlebensrate für Patienten der Therapiegruppe betrug 48%, für Patienten der unbehandelten Kontroll-gruppe 28% (statistisch signifikanter Unterschied, p<0,05). In der Subgruppe der Patienten mit makroskopisch bereits sichtbarer Carcinosis peritonei konnte kein Unterschied zwischen Therapie- und Kontrollgruppe hinsichtlich der Überlebenszeit gefunden werden. Operationsbedingte Todesfälle traten keine auf, in der Therapie-gruppe entwickelten sich bei 2 Patienten Darmfisteln.SchlußfolgerungenIntraperitoneale Chemotherapie mit an Kohlepartikel gebundenem Mitomycin C verbessert die Überlebensrate bei Patienten mit Magenkarzinomen mit Serosadurchbruch, beeinflußt jedoch nicht die Überlebensprognose bei bereits makroskopisch sichtbarer Carcinosis peritonei.