Chronic inflammatory demyelinating polyneuropathy accompanied by chronic myelomonocytic leukemia: possible pathogenesis of autoimmunity in myelodysplastic syndrome

Paraneoplastic neuropathies have rarely been reported in patients with hematological malignancies. We report herein the case of a 65-year-old Japanese woman with chronic myelomonocytic leukemia (CMML) accompanying chronic inflammatory demyelinating polyneuropathy (CIDP). She had been diagnosed with refractory anemia and subsequently developed CMML with cytogenetic abnormalities including t(3;8)(q26;q24). While regenerating bone marrow following induction chemotherapy, she complained of numbness in the lower legs and then became unable to walk. Clinical and electrophysiological features were consistent with CIDP. Intravenous immunoglobulin treatment was insufficient, although corticosteroids reduced neurological symptoms. This case suggests CIDP as one of the autoimmune phenomena associated with myelodysplastic syndrome and immunosuppressive treatment represents an effective therapy.     

Helices F-G are important for the substrate specificities of CYP3A7.

CYP3A7 is a member of the human CYP3A family and a major form of P450 expressed in human fetal livers. Although CYP3A7 shares nearly 90% base sequence with CYP3A4, CYP3A7 shows striking functional differences in the catalytic preference for several substrates, such as dehydroepiandrosterone (DHEA) or dehydroepiandrosterone 3-sulfate (DHEA-3S). First, to clarify the reason for the differences between CYP3A7 and CYP3A4, a homology model of CYP3A7 was constructed using the CYP3A4 crystal structure. Because these two structures were similar, four kinds of chimeric enzymes were constructed to determine which sequences are important for exhibiting the characteristics of CYP3A7. The results of kinetic analysis of DHEA and DHEA-3S 16alpha-hydroxylations by CYP3A7, CYP3A4, and CYP3A chimeras suggested that the amino acid residues from Leu(210) to Glu(279) were important to express the specificity for substrates as CYP3A7. This region was on the F and G helices of the modeled CYP3A7. Furthermore, to assess which amino acid in this sequence is important for the substrate specificity of CYP3A7, a one-point mutation of CYP3A7 to CYP3A4 was made by site-directed mutagenesis. The mutants of K224T and K244E had lost DHEA and DHEA-3S 16alpha-hydroxylation activities. The mutants also greatly decreased the metabolism of testosterone, erythromycin, nevirapine, and triazolam relative to those activities of CYP3A7 wild-type enzyme. From these results, it is expected that CYP3A7 can recognize specific substrates using the lysines in F-G loops.     

State of Adenomatous Polyposis Coli Gene and ras Oncogenes in Japanese Prostate Cancer

Genetic alterations of ras oncogenes (K-, H- and N- ras ) and adenomatous polyposis coli (APC) gene in tissues of prostate cancer from Japanese patients were examined using PCR-SSCP (polymerase chain reaction-single strand conformation polymorphism) analysis and direct sequencing. Tissues from 8 cases of untreated stage B prostate cancer surgically removed and from 10 cases of endocrine therapy-resistant metastatic disease obtained at autopsy were used in the present study. In four out of 18 cases (22%), ras point mutations were found, two in either codon 12 or 61 of K-ras and two in either 13 or 61 of H- ras . These point mutations were detected in one of the stage B cases (13%) and in three of the autopsy cases (30%). All these cases were poorly differentiated adenocarcinoma. In autopsy cases showing ras mutation in cancerous prostate, the same alteration was observed in metastatic tissues. No APC gene mutation was detected in any sample, although polymorphism was found in some cases. These results indicate that ras oncogene mutations are related to the progression of prostate cancer, whereas APC gene alteration is not involved in tumorigenesis and development of this cancer.     

Mutational Analysis of CDKN2 (CDK4I/MTS1) Gene in Tissues and Cell Lines of Human Prostate Cancer

To study mutation of the CDKN2 gene in prostate cancer, samples from 51 Japanese patients and four human prostate cancer cell lines were examined by single-strand conformation polymorphism analysis and direct sequencing. Only one out of 51 (2%) patients revealed a mutation, which was a 24 bp deletion from the 5'-untranslated region to codon 3, resulting in loss of the initiation site. One of the four cell lines revealed a missense mutation, a GAC→TAC (Asp→Tyr) at codon 84. These results indicate that mutation of the CDKN2 gene is rare in prostate cancer and thus does not contribute significantly to the pathogenesis of human prostate cancer. Prostate cancer cell lines may acquire more frequent abnormality of the CDKN2 gene than tumor tissues.     

Biodegradation and biocompatibility of polyorganophosphazene

We investigated biodegradation and biocompatibility of poly(organophosphazenes). We prepared poly(organophosphazenes) having different side chain groups. The blood compatibility of poly(organophosphazenes) containing fluorinated side groups, poly(bis[trifluoroethoxy]phosphazene) (PbFP) and poly([trifluoroethoxy][ethyl glycinate]phosphazene) (PFGP), without heparinization were evaluated in vitro. The deformation and aggregation of platelets adhered on PbFP and PFGP were not observed and they suppressed platelet activation. Additionally, PbFP and PFGP showed a higher degradation rate, despite their high hydrophobic nature. We found that the high mobility of water in PbFP and PFGP was one of the important factors facilitating their degradation. Their polymer structures were formed in a more open nature, indicating that water easily attacked the backbone of the phosphorus and nitrogen atoms in the poly(organophosphazene). On the other hand, the proliferation of HeLa cells cultured on poly(organophosphazene) was reduced compared with that on the control tissue culture polystyrene.     

Minilaparotomy approach to terminal ileal Crohn's disease

The feasibility and safety of a minilaparotomy approach to terminal ileal Crohn's disease have not been fully elucidated. The purpose of this study was to compare early outcomes utilizing this technique as an alternative to conventional approaches. Nine patients with terminal ileal Crohn's disease (but no complicating enteric fistulas) who underwent minilaparotomy between January 1998 and September 2000 were studied prospectively. The minilaparotomy approach entails a complete surgical procedure performed through a skin incision of less than 7 cm. Ten similar patients who underwent conventional laparotomy between January 1995 and December 1997 served as the control group. Age, gender, body weight, height, body mass index, number of prior laparotomies, operating times, operative blood loss, and types of operative procedure were similar for cases and controls. The length of the laparotomy incision in the minilaparotomy approach group was significantly shorter than that in the conventional approach group (median length 6.0 vs. 16.5 cm; p <0.05). Postoperative intervals until initial standing and walking were significantly shorter for minilaparotomy patients than conventional surgery patients (p <0.05 and p <0.05, respectively), whereas postoperative intervals until passing flatus, urinary catheter removal, and tolerance of liquids and solids did not differ for the two groups, nor did the analgesic requirement or postoperative hospital stay. Postoperative complications developed in two conventional-group patients; none was noted with the minilaparotomy approach. Our data suggest that the minilaparotomy approach to terminal ileal Crohn's disease without an enteric fistula is feasible, safe, and less invasive than the conventional approach.     

Intracranial germinoma with syncytiotrophoblastic giant cells in the cerebellopontine angle--case report

A 23-year-old man presented with a 3-week history of left hearing disturbance and left facial nerve paresis. T1-weighted magnetic resonance (MR) imaging showed an iso-intense mass in the left cerebellopontine angle (CPA), with homogeneous enhancement with gadolinium-diethylenetriaminepenta-acetic acid. T2-weighted MR imaging showed the mass as heterogeneously iso- to hyperintense. Gross total removal of the tumor was achieved. Histological examination revealed that the tumor was a germinoma with syncytiotrophoblastic giant cells. Whole central nervous system irradiation with cisplatin-etoposide chemotherapy was performed postoperatively. He has been in good condition with no sign of recurrence for 7 years. Intracranial germ cell tumors in the CPA are very rare. Total surgical removal followed by irradiation and chemotherapy will provide a good outcome.     

Prospective study of extended segmentectomy for small lung tumors: the final report

BACKGROUND: Minimal resection of small lung tumors is still controversial. This study was conducted to clarify whether this type of operation is acceptable. METHODS: From January 1992 to December 1994, 73 patients were registered in a multiinstitutional trial of limited resection for peripheral lung tumors less than 2 cm in diameter. The operative procedure consisted of extended segmentectomy in which the cut line of the lung was beyond the burdened segment, confirming N0 disease by intraoperative lymph node examination of frozen sections. The operation was changed to other procedures if the report was positive. RESULTS: All the patients were observed more than 5 years. There were no perioperative deaths and no major complications. A total of 55 patients were finally enrolled in this study. Ten patients died postoperatively, 4 of lung cancer and the remaining 6 died of other diseases, with no signs of recurrence. The 5-year survival rate, excluding these 6 patients, was 91.8%; for all patients including those who died it was 81.8%. A total of 18 patients were not included in this study for various reasons. The decrease in forced vital capacity was 11.3% +/- 9.8% compared with the preoperative value. CONCLUSIONS: Extended segmentectomy is an alternative method as a standard operation for patients with small peripheral lung tumors, and the loss of lung function is minimal. However, patient selection must be strict, with intraoperative pathologic examination, and a wide margin to the lesion beyond the burdened segment is mandatory.     

Impairment of insulin signaling in human skeletal muscle cells by co-culture with human adipocytes

Adipocyte factors play a major role in the induction of insulin resistance in skeletal muscle. To analyze this cross-talk, we established a system of co-culture of human fat and skeletal muscle cells. Cells of three muscle donors were kept in co-culture with cells of various fat cell donors, and insulin signaling was subsequently analyzed in myocytes. Insulin-induced tyrosine phosphorylation of insulin receptor substrate (IRS)-1 was completely blocked, with unaltered expression of IRS-1. Troglitazone increased insulin action on IRS-1 phosphorylation, in both the absence and presence of co-culture. Insulin-regulated activation of Akt kinase in the myocytes was significantly reduced after co-culture, with troglitazone restoring insulin action. Addition of tumor necrosis factor (TNF)-alpha (2.5 nmol/l) to myocytes for 48 h reduced IRS-1 expression and inhibited IRS-1 and Akt phosphorylation comparable to the effect of co-culture. Lower doses of TNF-alpha were ineffective. After co-culture, TNF-alpha in the culture medium was below the detection limit of 0.3 pmol/l. A very low level of resistin was detected in the supernatant of myocytes, but not of adipocytes. In conclusion, the release of fat cell factors induces insulin resistance in human skeletal muscle cells; however, TNF-alpha and resistin appear not to be involved in this process.     

Clinical significance of nm23 expression and chromosome 17 numerical aberrations in primary gastric cancer

The metastasis suppressor gene nm23 located on chromosome 17 might be one of the targets in deletions of chromosome 17. In this study, we analyzed the expression of nm23 and chromosome 17 aberrations in gastric cancer and assessed their clinicopathological and prognostic significance. In 103 gastric cancer patients, we examined nm23 expression by immunohistochemistry and detected chromosome 17 aberrations by fluorescence in situ hybridization. There was a significant difference in the expression of nm23 among differentiated histologic types (well > moderately > poorly) (p < 0.01). Negative expression of nm23 correlated with depth of invasion (p < 0.01), lymph node metastasis (p < 0.05), lymphatic invasion (p < 0.05), venous invasion (p < 0.05), poor prognosis (p < 0.05), and chromosome 17 loss (p < 0.05). Chromosome 17 aberrations broadly correlated with clinicopathological variables and were associated with poor prognosis (p < 0.05). Univariate analyses identified nm23 (p < 0.05), chromosome 17 aberrations (p < 0.05), tumor size (p < 0.01), depth of invasion (p < 0.0001), lymph node metastasis (P < 0.001), hepatic metastasis (p < 0.01), peritoneal dissemination (p < 0.01), and lymphatic invasion (p < 0.01) as significant prognostic factors. Multivariate analysis showed that expression of nm23 and chromosome 17 aberrations were not independent prognostic indicators. Our results indicate that negative expression of nm23 and chromosome 17 numerical aberrations correlate with tumor progression and poor prognosis but are not independent prognostic indicators.