PEUTZ‐JEGHERS SYNDROME ASSOCIATED WITH RENAL AND GASTRIC CANCER THAT DEMONSTRATED AN STK11 MISSENSE MUTATION

A 75‐year‐old male was admitted to the gastroenterology unit of Nagoya City University Hospital due to epigastralgia after surgical treatment for right renal cancer. Endoscopy revealed advanced type 1 gastric cancer in the corpus of the stomach and multiple polypoid lesions in the stomach and duodenum. X‐ray examination of the small intestine using barium showed multiple polyps in the upper jejunum. Faint pigmentation on the palm was also detected. Peutz‐Jeghers syndrome (PJS) was diagnosed, despite a lack of family history. Total gastrectomy, resection of part of the upper jejunum and intraoperative endoscopic polypectomy of duodenal polyps was performed. This is the second reported case of PJS associated with renal cancer. We also detected a missense mutation in the tumor suppressor gene STK11 that, when mutated, is causative for PJS.     

Induction of Cytotoxic Cell Activities by a Novel Cyclic Disulfide Compound, SA3443 in vivo

(4R)-Hexahydro-7, 7-dimethyl-6-oxo-1, 2, 5-dithiazocine-4-carboxylic acid (SA3443) is a newly synthesized cyclic disulfide compound which offers potential hepatoprotective properties.

The effect of SA3443 on the induction of natural killer (NK) and cytotoxic T lymphocyte (CTL) activities was investigated. NK activity in BALB/c mice splenic cells was investigated using YAC-1 cells as target cells. SA3443, at a dose range of 30-300 mg/kg/day, augmented NK activity significantly when administered orally once daily for 4 days before the assay. Alloantigen-specific CTL activity in splenic cells from BALB/c mice was detected 9 days after sensitization with C57BL/6 mice splenic cells. SA3443, at a dose of 100 mg/kg/day, augmented CTL activity significantly when administered orally, once daily for 4 days beginning after the sensitization and for 2 days before the assay, while a high dose of SA3443, at 300mg/kg, suppressed CTL activity.

From these results, it is thought that SA3443 may assist in the elimination of hepatitis viruses from the liver in patients with chronic active hepatitis, by the activation of NK and/or CTL activities.     

Mitochondrial encephalomyopathies: biochemical approach.

Thanks to recent advances in the molecular genetics of mitochondrial encephalomyopathies, we can now begin to correlate genetic lesions with biochemical defects. In the fatal infantile myopathy due to cytochrome c oxidase (COX) deficiency, an autosomal recessive condition, immunocytochemical studies have shown an isolated defect of subunit VIIa, which is 1 of the only 2 tissue-specific subunits of human COX. In muscle biopsies from patients with Kearns-Sayre syndrome, a multisystem disorder characterized by deletions of the mitochondrial DNA (mtDNA), the activities of all mitochondrial enzymes containing mtDNA-encoded subunits are decreased. The results of Northern analysis, in situ hybridization, and immunocytochemistry in muscle, and of mitochondrial protein synthesis in cultured fibroblasts suggest that partially deleted mtDNAs are transcribed but not translated, probably due to lack of indispensable tRNAs.     

Objective definition and measurement method of ground-glass opacity for planning limited resection in patients with clinical stage IA adenocarcinoma of the lung

Objective: The standard operation for patients with stage IA lung adenocarcinoma is considered to be a lobectomy. Recently, some researchers have reported that patients with tumors showing greater proportions of ground-glass opacity (GGO) at computed tomography (CT) could be candidates for limited resection, because of its less aggressive nature. However, the lack of a precise definition or standard measuring method of GGO prevents its general use as an index for planning limited resection. Therefore, we attempted to define GGO based on CT number and measured it more objectively. Methods: Between 1998 and 2001, 90 patients with clinical stage IA adenocarcinoma, who underwent standard or intentional limited resection and whose images of chest high-resolution CT were preserved in Digital Imaging and Communications in Medicine (DICOM) format, constituted the study population. The tumor shadow seen on the solid window (WL, −160 HU; WW, 2 HU) was regarded as the central solid area of the tumor seen on the lung window, and GGO was defined as the whole tumor area with the exception of the central solid area. Each area was measured using Scion Image (Scion Corp., Frederick, MD). We analyzed the relationship between the proportion of GGO and both of pathologic findings and recurrence. Results: Among the 90 tumors, 31 (34.4%) were calculated to have a GGO area greater than or equal to 50%. Of these, 27 (87%) tumors were bronchioloalveolar carcinoma. Lymphatic and vascular invasions, or nodal involvement were found only in patients with a smaller proportion of GGO (<50%) (P<0.05). During the follow-up period (median 36 months), recurrences occurred in eight patients who were diagnosed as having tumors showing smaller proportion of GGO (<50%). Conclusions: Tumors with a greater proportion of GGO measured by our method are thought to have a less invasive nature. Our objective measuring method of GGO could be useful for future multicenter trials to elucidate the value of limited resection for clinical stage IA adenocarcinoma based on the proportion of GGO.     

All-or-none augmentation of Ca2+ sensitivity in alpha-toxin-permeabilized single smooth muscle cells from guinea-pig taenia caecum.

1. Isolated smooth muscle cells from guinea-pig taenia caecum were permeabilized by use of Staphylococcus aureus alpha-toxin, and the sarcoplasmic reticulum Ca2+ store was depleted by exposure to 0.1 microM A23187. 2. Shortening of alpha-toxin-permeabilized single smooth muscle cells was induced by increasing free Ca2+ but was not induced by 0.2 microM free Ca2+. 3. Shortening of the permeabilized cells was caused by application of acetylcholine (ACh) with free Ca2+ concentration held at 0.2 microM. Permeabilized smooth muscle cells responded to 0.3 microM or 1 microM ACh with 0.2 microM Ca2+ with maximal shortening. The concentration-response relationship to ACh had a very steep slope and the cell shortening appeared to be an all-or-none response rather than a graded response, as was the shortening of intact cells to ACh. 4. The shortening of permeabilized cells was also induced by application of guanosine 5''-triphosphate (GTP) with 0.2 microM free Ca2+, showing an all-or-none response. The threshold concentration of GTP that induced an all-or-none response was between 10 microM and 30 microM. 5. These results suggest that Ca2+ sensitivity is augmented by stimulation of the muscarinic receptor or GTP-binding protein(s) in an all-or-none manner. It seems probable that this contributes to the all-or-none response to ACh in intact smooth muscle cells.     

Medical Necessity in Canadian Health Policy: Four Meanings and . . . a Funeral?

Four meanings of medical necessity have emerged, evolved, and dominated past and current health policy debates about the appropriate level of service coverage under Canada's health insurance program. To explore the shift in definition, provincial government and national health care association position papers responding to federal legislative and policy reviews of Canada's health insurance program from 1957 to 1984 were examined, as were more current reports on medical necessity. Four meanings of medical necessity predominated: "what doctors and hospitals do"; "the maximum we can afford"; "what is scientifically justified"; and "what is consistently funded across all provinces." These meanings changed with time as different stakeholder associations and governments redefined the concept of medical necessity to achieve different policy objectives for health service coverage under Canada's health insurance program.     

Reduced-intensity unrelated cord blood transplantation for patients with advanced malignant lymphoma.

We report the results of reduced-intensity unrelated cord blood transplantation (RI-UCBT) in patients with advanced malignant lymphoma. Twenty patients (median age, 46.5 years; range, 27-66 years) underwent RI-UCBT with a preparative regimen consisting of fludarabine 125 mg/m2 , melphalan 80 mg/m 2 , and 4 Gy of total body irradiation. The median infused total cell dose was 2.75 x 10(7)/kg (range, 2.3-3.4 x 10(7)/kg). Graft-versus-host disease (GVHD) prophylaxis was composed of cyclosporine or tacrolimus alone. Fifteen patients achieved primary neutrophil engraftment after a median of 20 days. Eight patients developed grade II to IV acute GVHD, and 2 developed chronic GVHD. Of the 16 patients with evaluable disease, 10 achieved a complete response. Primary disease recurred in 1 patient, and transplant-related mortality within 100 days occurred in 8 of 20 patients. The estimated 1-year probability of progression-free survival was 50%. These data suggest that RI-UCBT is a feasible option for patients with refractory lymphoma who lack an HLA-matched donor.     

Establishment of IL-5-dependent early B cell lines by long-term bone marrow cultures

We established two different IL-5-dependent Ly1+ early B cell lines in long-term bone marrow culture system. One of them (J-87) is stromal cell (ST2) dependent and the other (T-88) is ST2 independent. Both J-87 and T-88 are B220+, Ly1+, sIgM-, Ia-, Thy1-, and IL-2R+, and respond to IL-3 and IL-5 in the presence of ST2. The T-88 can proliferate only in response to IL-5 in the absence of ST2. Southern blot analysis using JH probe revealed that configuration of IgH gene of both cell lines shows rearranged pattern. Binding assay for radiolabeled IL-5 to T-88 demonstrated that T-88 has two classes of IL-5 binding sites (low and high affinity) on the membrane. These data strongly suggest that there are IL-5-sensitive stages at both stromal cell-dependent and stromal cell-independent phases in early B cell development.