Chromosomal and microsatellite instability in sporadic gastric cancer

BACKGROUND: Gastric cancer can progress through two pathways of genomic instability: chromosomal (CIN) and microsatellite instability (MSI). It is hypothesized that these two pathways are not always independent and that some tumors show overlap between these two mechanisms. METHODS: A total of 98 sporadic gastric cancers were classified based on their MSI status, using microsatellite assay with BAT26. Evidence for CIN was investigated by identifying loss of heterozygosity (LOH) events on chromosome arms, 5q, 10p, 17p, 17q, and 18q, which are regions harboring tumor suppressor genes that are significant in gastric cancer development. RESULTS: Twelve tumors (12%) showed high-frequency MSI (MSI-H). Overall, 43 of the tumors (44%) had at least one LOH event, with most frequent chromosomal losses observed on 10p and 18q (30%, respectively), followed by 5q (21%), 17p (14%), and 17q (12%). Interestingly, overlap was observed between CIN and MSI pathways. Of 43 cancers with LOH events, four (9%) were also MSI-H. It was also found that 48% of cancers without MSI-H had no LOH events identified, comprising a subgroup of tumors that were not representative of either of these two pathways of genomic instability. CONCLUSION: These results suggest that molecular mechanisms of genomic instability are not necessarily independent and may not be fully defined by either the MSI or CIN pathways in sporadic gastric cancers.     

Prevalence and time of appearance of Brugada electrocardiographic pattern in young male adolescents from a three-year follow-up study

The prevalence of Brugada's electrocardiographic (ECG) pattern in 7,022 male adolescents in the seventh grade was determined, and the same subjects were reexamined 3 years later, while in tenth grade. Two subjects (0.03%) and 7 subjects (0.10%) showed Brugada's ECG pattern by the conventional criterion (J point or ST-segment >/=0.1 mV in leads V(1) to V(3)), and no subjects (0%) and 2 subjects (0.03%) fulfilled the recent criterion (J point or ST-segment >/=0.2 mV) in the seventh and tenth grades, respectively, indicating that Brugada's ECG pattern begins to appear during junior high school and increases until late adulthood.     

Two-stage hepatectomy for multiple bilobular liver metastases from colorectal cancer

BACKGROUND/AIMS: To determine an appropriate surgical treatment for patients with multiple liver metastases, we evaluated the efficacy of two-stage hepatectomy in patients with multiple bilobular liver metastases from colorectal carcinoma. METHODOLOGY: Some patients with multiple liver metastases are not candidates for a complete resection by a single hepatectomy, even when downstaged by chemotherapy, after portal embolization. In two-stage hepatectomy, the highest possible number of tumors is resected in a first, noncurative intervention, and the remaining tumors are resected after a period of liver regeneration. Two-stage hepatectomy was performed in 11 patients. RESULTS: Two-stage hepatectomy was feasible in all of the 11 patients. In 3 of them, the first stage was a major resection (more extensive than a lobectomy). This first hepatectomy was uneventful in all patients. The second hepatectomy was also uneventful in nine patients, but in one of the other two, a perihepatic fluid infection occurred, and in the other, postoperative liver failure developed due to a right subphrenic abscess. However, all patients were discharged. The percentage of the expected resection volume at one time, calculated from CT volumetry, was 75.5+/-1.2% and the prognostic score as surgical risk was 56.6+/-4.5. In two-stage hepatectomy cases, the percentage of the resected volume and the prognostic score in the first hepatectomy were 25.4+/-6.4% and 6.7+/-7.3, and in the second, 45.7+/-4.5% and 28.5+/-5.8. During the follow-up procedures, a residual hepatic recurrence was observed in 6 patients, and pulmonary recurrence in 9. The 1- and 3-year survival rates after the first hepatectomy were 90% and 45%, with median survivals of 18 months from the first hepatectomy. CONCLUSIONS: Two-stage hepatectomy is a surgical modality intended for patients with initial unresectable metastases. However, following such surgery, protective treatment against residual liver recurrence and lung metastasis will be a most important issue.     

RAS-blocking bisphosphonate zoledronic acid inhibits the abnormal proliferation and differentiation of juvenile myelomonocytic leukemia cells in vitro

Juvenile myelomonocytic leukemia (JMML) is a clonal myeloproliferative/myelodysplastic disorder of early childhood with a poor prognosis. JMML cells are characterized by hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF) caused by a continuously activated GM-CSF receptor-retrovirus-associated sequence (RAS) signal transduction pathway through various molecular mechanisms, resulting in spontaneous GM colony formation in vitro. Bisphosphonate zoledronic acid (ZOL), a RAS-blocking compound, suppressed colony formation from bone marrow (BM) cells of 8 patients with JMML and 5 healthy control subjects without and with GM-CSF (10 ng/mL), respectively, in a dose-dependent manner in clonal culture. At 10 microM ZOL, however, spontaneous GM colony formation from JMML BM cells decreased to 3%, but the formation of G colonies containing granulocytes, but no macrophages, was enhanced, whereas 40% of GM colonies were retained and G colony formation was not affected in culture of normal BM cells with GM-CSF. In suspension culture, cytochemical and flow cytometric analyses showed that 10 microM ZOL also inhibited spontaneous proliferation and differentiation along monocyte/macrophage lineage of JMML BM cells but not the development of normal BM cells by GM-CSF. The inhibitory effect of ZOL on JMML cells was confirmed at a single-clone level and observed even at 3 microM. The current result offers a novel approach to therapy in JMML.     

Comparison of the clinical courses of the opticospinal and conventional forms of multiple sclerosis in Japan

We evaluated the clinical courses of 216 patients with multiple sclerosis (MS) diagnosed according to the recommended diagnostic criteria of McDonald et al (10). Sixty-five patients clinically displaying selective involvement of the optic nerves and spinal cord were classified as opticospinal MS (OS-MS), while the other 151 showing disseminated involvement of the central nervous system were classified as conventional MS (C-MS). The disease duration did not differ significantly between the two subtypes (11.2 years vs. 11.5 years). In addition to a higher age of onset, female preponderance and higher Kurtzke's expanded disability status scale (EDSS) scores, the OS-MS patients showed a markedly lower frequency of secondary progressive MS than the C-MS patients (4.6% vs. 29.1%, p=0.0001). The EDSS scores of the C-MS patients were significantly correlated with the disease duration, while those of the OS-MS patients were not. Among the C-MS patients, the frequency of secondary progressive MS was significantly more common in patients with a disease duration of more than 10 years than in those with a shorter duration. These results suggest that the irreversible disability in OS-MS is determined by relapses, rather than by chronic progression, whereas C-MS has a similar clinical course to MS in Westerners.     

Sphincter of Oddi Motor Activity in Patients with Anomalous Pancreaticobiliary Junction

Sphincter of Oddi motor activity was investigated in seven patients with an anomalous pancreaticobiliary junction and in six controls by endoscopic manometry under fluoroscopy. Characteristic phasic wave activity was observed in the sphincter segment in both groups. Amplitude of the phasic contractions was significantly higher in the disease group than in controls (100.8 +/- 14.1 mm Hg vs. 55.2 +/- 4.3 mm Hg, p less than 0.02). Although those with the anomalous pancreaticobiliary junction had a longer common channel (15-30 mm), the length of the sphincter segment with the phasic wave activity was not different. The phasic activity was not seen at the junction of the pancreatic and bile ducts in disease groups. Bile obtained from within the bile duct showed a very high concentration of amylase. Morphine given to cause spasm of the sphincter increased basal pressure and frequency of the phasic waves in all controls. The response to morphine was similar in two patients in whom the anomalous junction was studied, but the procedure was complicated by acute pancreatitis in one of them. These findings suggest that contractions of the sphincter of Oddi in patients with the anomalous junction may contribute to reflux between the pancreatic and bile ducts, leading to various pathologic conditions associated with this anomaly.     

Studies on percutaneous transvenous mitral commissurotomy using a modified transseptal approach

Summary A modified version of Brockenbrough's trans-septal catheterization technique was carried out in 11 patients indicated for percutaneous transvenous mitral commissurotomy (PTMC). In 8/11 (72.7%), a coiled guide-wire was successfully inserted through theforamen ovale without atrial septal puncture. The Brockenbrough needle was used merely to maintain stiffness and the orientation of the dilator. PTMC was performed with an Inoue single balloon without incident.Patent foramen ovale was found by transesophageal echocardiography prior to the operation in only 1/11 patients (9.0%); nonetheless, it proved not to be a critical factor for the success of the procedure. This procedure seems to have much potential to enable the treatment of mitral stenosis with a lowered risk to the patient, as long as it is performed with precision and caution.     

Advances in transesophageal echocardiography for the evaluation of atherosclerotic lesions in thoracic aorta--the effects of hypertension, hypercholesterolemia, and aging on atherosclerotic lesions.

We assessed atherosclerotic lesions in the thoracic aorta in 166 consecutive patients (aged 56 +/- 13 years) by transesophageal echocardiography, and investigated the influences of hypertension, hypercholesterolemia and age on the prevalence of such lesions. Satisfactory images were obtained of all the thoracic aorta, except for a small part of the ascending aorta, by use of a biplane transesophageal probe. We defined atherosclerotic lesions as increased echogenicity of the intima (intimal thickening), raised plaque, calcification, ulceration, or aneurysms. Lesions were observed in 97 patients (58%). The incidence of lesions in patients with hypertension (81%) or hypercholesterolemia (80%) was significantly greater than in those without both conditions (37%, p less than 0.005). The incidence of lesions was significantly increased among patients over 60 years old compared with that in patients under 60 (76% vs 42%, p less than 0.005). Patients without either hypertension or hypercholesterolemia showed a marked increase in the incidence of lesions with age (16% at less than 60 yrs vs. 67% at greater than 60 yrs), and no significant influence of these conditions on the incidence of lesions was found in patients over 60. We conclude that hypertension and hypercholesterolemia might be important risk factors for the development of atherosclerotic lesions in the thoracic aorta in relatively younger patients. Age appears to become a more important determinant of such lesions in Japanese patients over 60 years old irrespective of blood pressure and serum cholesterol levels.     

Chromosome spreading techniques for primary gastrointestinal tumors

The requirement for well spread out chromosomes for the cytogenetic analysis of primary gastrointestinal tumors led us to develop new techniques. These techniques involved two main procedures: (1) preliminary incubation with culture medium in the presence of collagenase, Dispase, and colcemid, for 3h, and (2) treatment with an extremely hypotonic solution (0.044 M KCl) for 30 min. The techniques were applied to 11 gastrointestinal malignancies (including 1 early gastric cancer and 1 metastatic liver lesion of colon cancer) and significant increases (P<0.01) in the number of metaphases of analyzable karyotypes were obtained, compared with a previous method in which the standard hypotonic molarity of KCL (0.075 M) was employed. The mean value for metaphase numbers of the analyzable karyotypes was 37.0±3.7% in the 5 gastric cancers and 44.7±4.8% in the 5 colon cancers and 1 metastatic lesion. These values were three times and more than twice, respectively, the values obtained by the previous method. A fluorescence in situ hybridization (FISH) study was carried out on one cologenic tumor, the α-satellite centromere-specific probe 17 being used. Deletion of the long arm of chromosome 17 was demonstrated. The method proposed here could yield a sufficient number of metaphases without the use of tissue culture that might cause alteration of karyotype. It can be employed with small biopsy specimens and in studies utilizing the FISH technique.