Takafumi Kamei

Gastric carcinoma confined to the muscularis propria: how can we detect, evaluate, and cure intermediate-stage carcinoma of the stomach?

OBJECTIVE:The most important surgical strategy for advanced gastric cancer is its detection at the curative stage. The aim of this study was to characterize the curable intermediate-stage gastric carcinomas.METHODS:Of 1120 consecutive patients who underwent gastric resection for primary gastric cancer from 1979 through 1996, 94 patients were histologically diagnosed as having cancer confined to the muscularis propria (mp cancer), analyzed clinicopathologically, and compared with patients with early and serosal cancers.RESULTS:The operative incidence of mp cancer was around 8% among cases of gastrectomy, and the ratio of mp cancer to advanced cancer began to increase in 1991. Mp cancer was at a statistically intermediate stage, between early and serosal cancers in terms of symptoms, surgical curability (96%), size and histology of the tumor, and the rate of lymph node metastasis (46%). Preoperative assessments of tumor depth were unclear using radiology and endoscopy; however, 35% of 31 cases studied were diagnosed precisely by endoscopic ultrasonography (EUS). Accuracy of lymph node metastasis diagnosis was the same (65%) by preoperative EUS and by surgeon; however, sensitivity of the surgeons assessment was higher (69%vs 38%) and specificity of EUS was higher (83%vs 39%). The 5-yr survival rate was 85%, which was significantly better than that of serosal cancer and similar to that of early cancer. Patient outcome was not affected by lymph node metastasis or macroscopic type of tumor.CONCLUSIONS:Mp cancer should be considered an intermediate-stage cancer. Surgery with level 2 lymph node dissection should provide a cure rate similar to that for early cancer.

FK506 as the sole immunosuppressive agent for prolongation of islet allograft survival in the rat.

The purpose of the present study was to determine immunosuppressive effects of a new immunosuppressive agent, FK506, on rat islet allografts and also whether FK is toxic to the islet grafts since the diabetogenic effects of FK is controversial. Hand-picked clean fresh islets (WKA/Qdj:RT1u) were transplanted either beneath the renal capsule or into the liver via the portal vein of the diabetic (STZ, 60 mg/kg) rats (Lewis: RT11). FK506 was administered s. c. for 7 days after transplantation. The mean survival times (MST)* of the renal subcapsular grafts receiving 0 (control), 0.32 or 1.0 mg/ kg FK were 7.2 ± 1.1 (mean ± SD, n = 5), 13.8 ± 4.8 (n = 4), and 20.2 ± 8.0 days (n = 5), respectively. The MST of the intrahepatic grafts receiving 0, 0.1, 0.32, or 1.0 mg/kg FK were 4.4 ± 1.1 (n = 5), 7.2 ± 0.8 (n = 5), > 45.3 ± 23.1 (n = 6) or > 54.4±8.8 days (n = 5), respectively. Histologically, islets were found easily in the liver of normoglycemic recipients for more than 60 days after transplantation and appeared intact, with well-granulated beta cells. Foci of mononuclear cells were occasionally seen adjacent to the islet cells. The plasma glucose of the recipients with 1.0 mg/kg FK fluctuated between 150 and 350 mg/dl without rejection. In the recipients treated with 3.2 mg/kg FK the plasma glucose of all the recipients (n = 3) returned to pretransplant levels by 21 days after transplantation. However, islet cells were present in the liver of all these recipients without mononuclear cell infiltration. Immunohisto-chemically islet grafts stained weakly for insulin, but to the same extent as the controls for glucagon and somatostatin. These findings clearly demonstrate the immunosuppressive effect of FK506 on islet allografts and the importance of the transplant site for prolongation of graft survival by FK, and also suggest that FK has toxic effects on the islet grafts (B cells) when used in high dosages.

Diabetogenic effects of FK506 on renal subcapsular islet isografts in rat

Previously we demonstrated prevention of immune rejection in rat islet allografts by continuous subcutaneous (s.c.) administration of FK506 and also showed that FK506 might have diabetogenic effects (Ryu and Yasunami (1991) Transplantation, 52, 599-605). The purpose of the present study was to characterize further diabetogenic effects of FK506 on renal subcapsular islet isografts in rat. Continuous s.c. administration of FK506 (3 mg/kg/day) for 35 days produced glucose intolerance in the recipients as demonstrated by intravenous (i.v.) glucose tolerance test at the end (35 days) and after discontinuation (90 days) of FK506 administration. Morphologically, beta cells in the grafts of FK506-treated group were degranulated at 35 and 120 days after transplantation. Electron microscopically, degranulation, marked swelling of rough endoplasmic reticulum, Golgi apparatus and mitochondria were detected in beta cells of the grafts treated with FK506 at 35 days, and at 120 days there was moderate structural recovery in the organella. These findings clearly demonstrate that FK506 has diabetogenic effects on renal subcapsular islet isografts in rat and also suggests potential reversibility of damages by FK506 in beta cells of the grafts.

Modulation of the kinetics of the initial leukocyte migration into renal allografts by 16,16-dimethyl PGE2.

Host sensitization to vascular allografts is induced by the interaction between host lymphocytes, antigen-presenting cells, and the allograft. However, little is known concerning the nature or kinetics of the initial host leukocyte migration into the transplanted organ prior to immune sensitization. Employing a model of donorirradiated renal allografts and isografts, we have characterized the participating cell types and the kinetics of the leukocyte influx during the first 96 hr after engraftment. Both isografts and allografts experience a marked initial influx of host leukocytes into the renal interstitium, peaking at 48 hr after transplantation. Concomitant glomerular accumulation of leukocytes is much less marked. By 96 hr, the leukocyte influx into isografts has significantly diminished, while allografts demonstrate a subsequent additional rise in interstitial leukocytes coincident with the development of allosensitization. In allografts, the predominant cell type in the influx of the first 24–48 hr of the leukocyte influx is the monocyte/macrophage, with a smaller component of T lymphocytes. Neutrophils and B lymphocytes are not found in this initial infiltrate. Intragraft infusion of dimethyl PGE2 markedly inhibits the monocyte influx during the first 24–48 hr into the renal interstitium, but not the glomeruli, of allografts, while having relatively little effect on the migration of leukocytes into the renal glomerulus or renal interstitium of isografts. The results suggest that one mechanism by which PGE may inhibit host sensitization to allografts may be suppression of the initial influx of donor monocytes into the newly allografted organ.

Donor-Specific Unresponsiveness Induced by Intraportal Grafting and FK506 in Rat Islet Allografts: Importance of Low Temperature Culture and Transplant Site on Induction and Maintenance

Previously we demonstrated prolongation of islet allograft survival in rat by administration of FK506 to the recipients. The purpose of the present study was to determine whether specific immune unresponsiveness had been induced and to determine the effects of low temperature culture of donor islets as well as the transplant site on the induction of immune unresponsiveness. At 90 days after transplantation, normoglycemic recipients bearing functional intrahepatic grafts were made diabetic again with streptozotocin (STZ) and donor specific or third party islets were transplanted either into the liver or beneath the kidney capsule. When fresh islets were used as donors in initial transplantation in conjunction with FK506, intrahepatic re-transplants of fresh islets from the donor-specific strain in the absence of FK506 maintained normoglycemia for more than 60 days, while third party transplants (n = 3) were rejected within 1 wk. In contrast to intrahepatic regrafts, all the renal subcapsular regrafts from the donor-specific strain (n = 3) were rejected with mean survival time of 12.7 ± 6.4 days. When cultured (24°C, 7 days) islets were used for initial transplantation in conjunction with FKS06, re-transplants of fresh or cultured islets from the donor specific strain beneath the kidney capsule maintained normoglycemic in 3 out of 6 or all (n = 4) of the recipients, respectively. Cultured third party regrafts beneath the kidney capsule (n = 2) were rejected at 9 days. These findings clearly demonstrate that immune unresponsiveness induced by intraportal grafting of islets in conjunction with FK506 was donor specific and indicate that cultured islets appear more tolerogenic when used at the initial transplant and less immunogenic when used as regrafts. The present study also indicates the importance of transplant site in induction and maintenance of donor specific unresponsiveness.

A case of Meckel's diverticulum adherent to the posterior abdominal wall: the efficacy of small-bowel radiography coupled with barium enema examination

with mild chronic inflammatory infiltrates and foci of ectopic gastric mucosa. The patient’s postoperative course was uneventfull, and he was discharged without complications after the surgical resection. Meckel’s diverticulum is the most common congenital anomaly of the gastrointestinal tract.1 In children, 99mTc scanning is proposed be a sensitive and specific diagnostic procedure, as most bleeding diverticula contain gastric mucosa.2 However, even with bleeding, this method has high false-positive and false-negative rates in adult patients.3 Moreover, a CT scan cannot clearly distinguish a Meckel’s diverticulum from a bowel loop in the abdomen and is thus not practical for preoperative diagnosis. In our patient, the Meckel’s diverticulum was adherent to the posterior abdominal wall, and findings on CT scan alone were insufficient to make the diagnosis of a Meckel’s diverticulum. However, on small-bowel radiography coupled with barium enema examination, the rounded collection of barium at the anal side of the stricture strongly suggested a Meckel’s diverticulum. In adults, obstruction (36.5%) is the most common complication of a Meckel’s diverticulum, followed by intussusception (13.7%), inflammation (12.7%), and hemorrhage (12%).4 Obstructive symptoms may occur when either (1) the diverticulum is attached by a fibrous band to the umbilicus, abdominal wall, or other viscera; or (2) the diverticulum is free and unattached.5 However, in our patient, the findings corresponded to neither situation, as the diverticulum had no fibrous band, but was attached to the posterior abdominal wall. We suggest that chronic inflammation of the Meckel’s diverticulum may have extended to the adjacent intestine, producing the ileal stricture and adhesion.