Phase II study of carboplatin and weekly paclitaxel combination chemotherapy in advanced non-small cell lung cancer: a Kansai Clinical Oncology Group study

The objective of this phase II study was to evaluate the efficacy and toxicity of carboplatin and weekly paclitaxel combination chemotherapy in previously untreated, advanced non-small cell lung cancer (NSCLC). Patients received paclitaxel at a dose of 70 mg/m(2) on days 1, 8, 15, and carboplatin with the target dose of area under the curve (AUC) of 6 on day 1 every 28 days. Forty-six patients were enrolled. A median of four cycles (range, 1-13) were administered. Complete response was observed in one patient (2.2%) and partial response in 23 patients (50%), yielding an overall intent-to-treat response rate of 52.2% (95% confidence interval, 37.8-66.6%). The median survival time was 395 days and 1-year survival rate was 51.4%. Toxicities were mild. Twelve patients (26%) had grade 3 and three patients (7%) had grade 4 neutropenia. Grade 3 thrombocytopenia was seen in four patients (8%). Massive hematoemesis due to duodenal ulcer was observed in one patient, but no other patients experienced grade 3 or more non-hematological toxicities. There was no treatment-related death. Carboplatin and weekly paclitaxel combination chemotherapy is an efficacious and feasible regimen in patients with advanced NSCLC, and this treatment will be a reasonable alternative to the conventional triweekly regimen of paclitaxel and carboplatin.     

Silencing of imprinted CDKN1C gene expression is associated with loss of CpG and histone H3 lysine 9 methylation at DMR-LIT1 in esophageal cancer

The putative tumor suppressor CDKN1C is an imprinted gene at 11p15.5, a well-known imprinted region often deleted in tumors. The absence of somatic mutations and the frequent diminished expression in tumors would suggest that CDKN1C expression is regulated epigenetically. It has been, however, controversial whether the diminution is caused by imprinting disruption of the CDKN1C/LIT1 domain or by promoter hypermethylation of CDKN1C itself. To clarify this, we investigated the CpG methylation index of the CDKN1C promoter and the differentially methylated region of the LIT1 CpG island (differentially methylated region (DMR)-LIT1), an imprinting control region of the domain, and CDKN1C expression in esophageal cancer cell lines. CDKN1C expression was diminished in 10 of 17 lines and statistically correlated with the loss of methylation at DMR-LIT1 in all but three. However, there was no statistical correlation between CDKN1C promoter MI and CDKN1C expression. Furthermore, loss of CpG methylation was associated with loss of histone H3 lysine 9 (H3K9) methylation at DMR-LIT1. Histone modifications at CDKN1C promoter were not correlated with CDKN1C expression. The data suggested that the diminished CDKN1C expression is associated with the loss of methylation of CpG and H3K9 at DMR-LIT1, not by its own promoter CpG methylation, and is involved in esophageal cancer, implying that DMR-LIT1 epigenetically regulates CDKN1C expression not through histone modifications at CDKN1C promoter, but through that of DMR-LIT1.     

Diamond-Blackfan Anemia in Japan: Clinical Outcomes of Prednisolone Therapy and Hematopoietic Stem Cell Transplantation

The epidemiology and treatment outcomes for Diamond-Blackfan anemia (DBA) were surveyed in a cohort of 54 children (M/F = 26:28) registered in Japan from 1988 to 1998. The annual incidence was 4.02 cases per million births, the median age at diagnosis was 60 days, and 59% of the cases presented by 3 months of age. Three patients had a familial occurrence. All patients received prednisolone (PSL), and cyclosporin A (CsA) was added to the therapy in 17 patients. Forty-seven patients received transfusions, and 13 underwent hematopoietic stem cell transplantation (HSCT). The cumulative probabilities of a medication-free or a transfusion-free state prior to HSCT were 36% and 69%, respectively, at more than 5 years after diagnosis. Thirteen patients were weaned from PSL therapy without HSCT, and CsA was not associated with weaning from therapy. Transfusion and medication were stopped at 249 days and 933 days after diagnosis in 34 and 13 patients, respectively, who achieved a state of independence. No initial findings predicted the treatment dependence. More than 20% of patients experienced sustained hemosiderosis and/or adverse effects of PSL. The ages and reticulocyte counts at diagnosis of the patients who underwent HSCT were lower than in the patients who did not. HSCT led to the highest success (85%) of all previous reports, even though 5 alternative donors were included in our study. Two cord blood transplants from unrelated donors failed. These findings suggest the need for developing an integral treatment strategy including selective HSCT for refractory DBA.     

Differential subcellular distribution of Ca2+/calmodulin-dependent protein kinase II isoforms in the striatum and NG108-15 cells

Four subunits of Ca2+/calmodulin-dependent protein kinase II (CaM KII) have several isoforms, which differ in the variable domain. We previously reported that all subunits were highly expressed in rat striatal neurons. To examine intracellular distributions of CaM KII subunits in the rat striatal neurons, we performed immunoblot analysis with antibodies specific to each subunit in cell extracts from the rat striatum after continuous sucrose density gradient fractionation. The alpha subunit, but not the beta, gamma, or delta subunits, was colocalized with synapsin I, and each subunit showed a distinct distribution pattern in the fractions. To examine further the intracellular distributions of CaM KII isoforms in the same subunit, we established NG108-15 cells stably expressing delta1, delta3, and delta4 isoforms and examined distributions of the delta and gamma isoforms in these cell lines after fractionation. Each of the overexpressed exogenous delta isoforms showed a distinct distribution pattern. The endogenous delta2 was colocalized with the overexpressed delta1, delta3, and delta4 isoforms. However, the endogenous gammaB/gammaC isoforms were not colocalized with the overexpressed delta isoforms. Furthermore, the endogenous delta1 was concentrated in the microsomal fraction from the rat striatum. With the results taken together, it is suggested that CaM KII forms oligomers between isoforms in the same subunit but not in different subunits. The variable domain of CaM KII isoforms might possibly be responsible for targeting to certain intracellular compartments.     

Blue nevus of the endometrium.

A 36-year-old woman with a long history of amenorrhea underwent endometrial curettage. An aggregate of short spindle cells containing a finely granular, dark brown pigment with the histochemical characteristics of melanin was detected in the endometrial stroma. This finding is considered analogous to the occurrence of similar cells in the endocervical stroma and is most appropriately designated a "blue nevus" of the endometrium. The occurrence of nonneoplastic, melanin-laden cells in the endometrial stroma is an extremely rare phenomenon, which has been reported only once previously.     

Living donor liver transplantation in a patient with HIV

Highly active anti-retroviral therapy(HAART) for human immunodeficiency virus(HIV) has delayed the disease progression. The advances prompted us to undertake liver transplantation in a 41-year-old man with hemophilia B, HIV infection, and hepatitis C(HCV) end-stage liver disease. The donor was the patient's elderly brother. His right liver was implanted by the standard method. Two months after the operation, interferon alfa and ribavirin were administered for HCV infection. HCV was eradicated two weeks after the treatment. The HIV viral load is persistently negative and HAART has not been started so far. Utilizing a organ from living relatives should be one of the options to resolve the concern around the utilization of a scarce public source from cadavers for patients who may not have an equivalent survival to HIV negative patients.     

Effect of chitosan film containing basic fibroblast growth factor on wound healing in genetically diabetic mice

Basic fibroblast growth factor (bFGF) has been shown to stimulate wound healing. However, consistent delivery of bFGF has been problematic. We studied the stability of bFGF incorporated into a chitosan film as a delivery vehicle for providing sustained release of bFGF. The therapeutic effect of this system on wound healing in genetically diabetic mice was determined as a model for treating clinically impaired wound healing. A chitosan film was prepared by freeze-drying hydroxypropylchitosan (a water-soluble derivative of chitosan) acetate buffer solution. Growth factor was incorporated into films before drying by mixing bFGF solution with the hydroxypropylchitosan solution. bFGF activity remained stable for 21 days at 5 degrees C, and 86.2% of activity remained with storage at 25 degrees C. Full-thickness wounds were created on the backs of diabetic mice, and chitosan film or bFGF-chitosan film was applied to the wound. The wound was smaller in after 5 days in both groups, but the wound was smaller on day 20 only in the bFGF-chitosan group. Proliferation of fibroblasts and an increase in the number of capillaries were observed in both groups, but granulation tissue was more abundant in the bFGF-chitosan group. These results suggest that chitosan itself facilitates wound repair and that bFGF incorporated into chitosan film is a stabile delivery vehicle for accelerating wound healing.     

Prognostic value of overexpression of p53 in human ovarian carcinoma patients receiving cisplatin

A major obstacle to the treatment of ovarian carcinoma is intrinsic/acquired resistance to cisplatin-based chemotherapy. The clinical significance of p53 overexpression in patients with ovarian carcinoma is still controversial. The aim of this study was to investigate the independent prognostic significance of p53 overexpression in patients with ovarian carcinoma who are treated with cisplatin. We retrospectively examined the overexpression of p53 in primary ovarian carcinoma, and its association with chemotherapeutic efficacy. One hundred and thirty four ovarian carcinomas were surgically removed from patients who received adjuvant cisplatin-based chemotherapy. Immunohistochemical analysis of p53 was performed using a DO7 antibody against the p53 protein in 134 ovarian carcinomas. The significance of p53 in the prognosis of patients with ovarian carcinomas was also examined by a survival analysis of mortality follow-up data covering the period from 1988 to 2001. Thirty-three tumors (25%) exhibited p53 overexpression. Overexpression of p53 in grade 2/grade 3 tumors was significantly higher than that seen in grade 1 tumors (P=0.0088, 0.0229). Patients with tumors who also showed overexpression of p53 had a significantly inferior response to chemotherapy compared with the patients with p53-negative tumors (P=0.04). Cox regression analysis revealed that p53 overexpression was prognostic for poor disease outcome after adjustment for FIGO stage, grade and residual tumor. These findings suggest that overexpression of p53 in ovarian carcinoma is associated with unfavorable clinical outcome in patients treated with cisplatin-based chemotherapy. Therefore, detection of p53 overexpression using the DO7 antibody may be considered as a predictive marker of chemoresistance for cisplatin in patients with ovarian carcinoma.     

A case of para-aortic lymph node recurrence of gallbladder cancer completely responding to single drug (UFT) chemotherapy

A 67-year-old man with gallbladder cancer was treated by cholecystectomy and extrahepatic bile duct resection with regional lymph node dissection. At 10 months after surgery, CT demonstrated para-aortic lymph node recurrence. Single drug chemotherapy of UFT at 400 mg was started. After one month, the lymph node recurrence could not be detected by CT. UFT may be the primary candidate for chemotherapy for lymph node recurrence of gallbladder cancer.