Analysis of the correlation with KRAS gene mutation status and the benefit of cetuximab plus irinotecan as third- line chemotherapy for the Treatment of unresectable metastatic colorectal cancer

Mutation of the KRAS gene in patients with metastatic colorectal cancer(mCRC)has been established as a predictive marker of poor response to anti-EGFR cetuximab. The Japanese Society of Medical Oncology recommends that the KRAS mutation status at codon 12 and codon 13 should be genotyped by direct-sequencing or allele-specific PCR. In this study, we tested the point mutation of codon 12 and 13 in the KRAS gene by Luminex(xMAP)flow cytometry with sequence-specific oligonucleotide probes for 39 out of 64 unresectable mCRC patients enrolled from Sep 2008 to Oct 2009, who were administered cetuximab in combination with irinotecan(CPT-11)as third-line therapy. We retrospectively analyzed the relationship between KRAS mutation status and responses to combination therapy. Mutations in the KRAS gene were detected in 38. 5% of cases(codon12: 73%, codon 13: 27%), and the median follow-up time was 8. 2 months(range, 1. 4-15. 2 months). The response rates for patients with KRAS wild-type and patients with KRAS mutations were 33. 3%(95%CI 14. 5-52. 2%)and 0%(p=0. 015); the disease control rates were 75%(95%CI 57. 7-92. 3%)and 40%(95%CI, 15. 2-64. 8%; p=0. 044); the median TTF was 7 months(95%CI 4. 6-9. 3)and 2. 3 months(95%CI 1. 3-3. 2; p=0. 0007), and the median OS was 12. 9 months(95%CI 6. 7-19. 1)and 10. 8 months(95%CI 5. 0-16. 7; p=0. 15), respectively. Therefore, we concluded that the KRAS mutation in mCRC is a predictive factor for the lack of response to combination therapy with cetuximab plus CPT- 11, as reported in previous clinical studies.     

Combination chemotherapy using docetaxel, cisplatin, and S-1 for far advanced gastric cancer

Combination of docetaxel, cisplatin, and S-1 (DCS) is expected as a new treatment regimen for far advanced gastric cancer. We performed DCS chemotherapy for six patients, including four cases with invasion to pancreas, three cases with para-aortic lymph node metastasis, and two cases with liver metastasis. Clinical stages were either IIIC or IV for all of the patients. The patients received 2-4 courses of docetaxel (40 mg/m2) and cisplatin (60 mg/m2) on day 1, and S-1 (80 mg/m2) on days 1-14 every 4 weeks. The response rate was 83% (5 PR and 1 SD), and the disease control rate was 100%. Grade 3/4 neutropenia, grade 3 febrile neutropenia, and grade 3 diarrhea were observed in three cases (50%), one case (17%), and one case (17%), respectively. Four of six patients underwent R0 surgery after DCS chemotherapy, and no severe complication was occurred. Histological responses were Grade 2 for two cases, Grade 1b for one case, and Grade 1a for one case, respectively. DCS regimen showed a high objective tumor response, and also is one of the promising regimens as neoadjuvant setting for far advanced gastric cancer.     

Antiobesity effects of <Emphasis Type="Italic">Kaempferia parviflora</Emphasis> in spontaneously obese type II diabetic mice

Kaempferia parviflora Wall. Ex Baker (KP) has been used as a folk medicine in Laos and Thailand to lower blood glucose levels, improve blood flow, and increase vitality. This study investigated the preventive effects of KP on obesity and its downstream symptoms (various metabolic disorders) using Tsumura, Suzuki, Obese Diabetes (TSOD) mice, a multifactorial genetic disease animal model in which metabolic diseases develop spontaneously, similar to metabolic syndrome in humans, and Tsumura, Suzuki, Non-Obesity (TSNO) mice as the corresponding control mice. When feed that was mixed with KP (1 or 3%) was given ad libitum to TSOD and TSNO mice for 8 weeks, body weight increase, visceral fat accumulation, lipid metabolism abnormalities, hyperinsulinemia, glucose intolerance, insulin resistance, hypertension, and peripheral neuropathy were suppressed in TSOD mice, but no marked differences were observed in TSNO mice. Because KP had preventive effects on metabolic diseases, including antiobesity effects, only in obese animals, we propose that KP will be extremely valuable as a medicine or component of food in alternative health care.     

Bmi1 regulates cell fate via tumor suppressor WWOX repression in small-cell lung cancer cells

Mortality from lung cancer is important worldwide. Recently, epigenetic aberration of lung cancer, not only genomic DNA methylation but also chromatin modification, has become an important target for lung cancer research, although previous research has demonstrated that lung cancer develops as a result of both environmental and genetic factors. Here, we demonstrated that an epigenetic regulator/polycomb group protein Bmi1 is more highly expressed in small-cell lung cancer (SCLC) than in non-small-cell lung cancer by immunohistochemical analysis. In vitro experiments indicated that Bmi1 reduction by lentivirus-derived shRNA significantly suppressed proliferation, colony formation and in vivo tumor formation. Importantly, apoptosis was induced by Bmi1 depletion in small-cell lung cancer cells. Furthermore, a tumor suppressor WWOX was identified as a Bmi1 target in the cells by a chromatin immunoprecipitation assay and a quantitative real-time PCR assay; WWOX had a role as a tumor suppressor in SCLC cells; therefore, the Bmi1/WWOX pathway could be a new candidate for a new therapeutic approach for SCLC.     

Successful function-preserving therapy for chondroblastoma of the temporal bone involving the temporomandibular joint

We present a case involving a late diagnosis of chondroblastoma of the temporal skull base involving the temporomandibular joint (TMJ). Following an initial misdiagnosis and unsuccessful treatment over a period of 5 years, the patient was referred to our department for further evaluation and possible surgical intervention for occlusal abnormalities, trismus, clicking of the TMJ, and hearing impairment. Based on preoperative immunochemical studies showing positive reaction of multinucleated giant cells for S-100 protein, the final diagnosis was chondroblastoma. The surgical approach - postauricular incision and total parotidectomy, with complete removal of the temporal bone, including the TMJ via the extended middle fossa - was successful in preserving facial nerves and diminishing clinical manifestations. This study highlights a misdiagnosed case in an effort to underline the importance of medical examinations and accurate differential diagnosis in cases involving any tumor mass in the temporal bone.     

Aberrant DNA methylation of T-cell leukemia, homeobox 3 modulates cisplatin sensitivity in bladder cancer

The development of resistance to cisplatin during treatment of bladder cancer constitutes a major obstacle to curing bladder cancer. The identification of epigenetic biomarker molecules for cisplatin resistance and the elucidation of the function of the identified genes in bladder cancer will provide useful information. We found that the candidate gene TLX3 was unmethylated in cisplatin sensitive cells and methylated in resistant cells. The suppression of TLX3 expression using TLX3-specific shRNA in parental cells increased cisplatin resistance. Contrarily, overexpression of TLX3 in resistant cells induced increased sensitivity to cisplatin. We found that 22 (21%) out of 110 clinical samples of bladder cancer showed the methylated pattern using the COBRA assay in TLX3. We found a correlation between TLX3 methylation and the sensitivity to cisplatin in the clinical samples by SDI test. Cisplatin sensitivity was closely associated with the methylation status of TLX3. These findings showed that the TLX3 methylation may be useful as a novel biomarker for cisplatin resistance and can be used to design therapies to counteract the resistance against cisplatin in bladder cancer.     

MicroRNA miR-125b is a prognostic marker in human colorectal cancer

MicroRNAs (miRNAs) are small, non-coding RNAs that can function as oncogenes or tumor suppressors in human cancer. Recent reports have highlighted the oncogenic aspects of microRNA miR-125b. However, the clinical significance of miR-125b in gastrointestinal cancers has not been sufficiently investigated. To this end, we analyzed miR-125b expression in colorectal cancer cases. Quantitative RT-PCR was used to evaluate miR-125b expression in 89 colorectal cancer cases to determine the clinicopathological significance of miR-125b expression. The high miR-125b expression group showed a greater incidence of advanced tumor size and tumor invasion compared to the low miR-125b expression group (P<0.05). In addition, the high miR-125b expression group had a significantly poorer prognosis compared to the low expression group (P<0.05). Multivariate analysis indicated that high miR-125b expression was an independent prognostic factor for survival. Our analysis of miR-125b focused on the miR-125b/p53 pathway. In vitro assays revealed that overexpression of miR-125b repressed the endogenous level of p53 protein in human colorectal cancer cells. These data show that miR-125b is directly involved in cancer progression and is associated with poor prognosis in human colorectal cancer. Our findings suggest that miR-125b could be an important prognostic indicator for colorectal cancer patients.     

Usage of granulocyte colony-stimulating factor every 2 days is clinically useful and cost-effective for febrile neutropenia during early courses of chemotherapy

Background  

In order to analyze the clinical activity and cost-effectiveness of granulocyte colony-stimulating factors (G-CSF), the prophylactic usage of G-CSF in patients treated with a single chemotherapy regimen during early courses was prospectively evaluated.     

Crk-associated substrate lymphocyte type regulates myeloid cell motility and suppresses the progression of leukemia induced by p210Bcr/Abl

The p210Bcr/Abl and p190Bcr/Abl fusion oncoproteins are known to cause chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL). Bcr/Abl phosphorylates several proteins that can lead to leukemogenesis. Crk-associated substrate lymphocyte type (Cas-L)/human enhancer of filamentation-1 (HEF1)/neural precursor cell expressed, developmentally down-regulated 9 (NEDD9) is an adapter protein at focal adhesions known to be associated with solid tumor metastasis. Crk-associated substrate lymphocyte type has also been reported to be tyrosine phosphorylated by p190Bcr/Abl. We demonstrated that Cas-L was expressed in murine granulocytes, as well as in lymphocytes, and that Cas-L-deficient (Cas-L(-/-) ) granulocytes had increased migratory activity and decreased adhesiveness. To examine whether Cas-L was involved in leukemogenesis by p210Bcr/Abl, we generated Cas-L(-/-) p210Bcr/Abl transgenic mice. The mice displayed early development of myeloproliferative neoplasm seen in the chronic phase of CML, which resulted in the early death of the mice. Pathologically, increased infiltration of myeloid cells into several tissues was detected in the absence of Cas-L. In a hematopoietic reconstitution assay, Cas-L(-/-) p210Bcr/Abl transgenic cells showed a low population in the spleen, although only their myeloid cell population was normal. Thus, Cas-L seems to regulate the progression of CML in a negative way, presumably by attenuating extramedullary hyperplasia.