For the patient in whom the Kras gene variation appears, cancer cell grow and continue to multiply even if blocked by EGFR inhibitor. A topping the offered figure effect of cetuximab is not accepted. The addition of cetuximab for treatment of metastatic colorectal cancer with Kras wild-type tumors is effective.

Cetuximab is a monoclonal antibody that inhibits human epidermal growth factor receptor, and was approved for metastatic advanced colorectal cancer (mCRC) in 2008 in Japan. Evidences confirming the efficacy of cetuximab have been accumulated in western countries. As the first- and second-line therapy, cetuximab plus chemotherapy showed longer survival compared with chemotherapy alone. As a third-line chemotherapy, among various anti-cancer agents for mCRC, only cetuximab could exhibit survival benefits in monotherapy or combination therapy with irinotecan. Recent studies suggest that the status of KRAS mutation is a predictive marker in colorectal cancer patients treated with cetuximab, and these findings lead to personalized cancer treatment.

The use of cetuximab, a mouse chimeric immunoglobulin G1 monoclonal antibody, is approved as anti-epidermal growth factor receptor(EGFR)therapy for the treatment of metastatic colorectal cancer in Japan. Further, panitumumab, matuzumab, nimotuzumab and zalutumumab which also target EGFR, are currently under clinical development. Cetuximab is the first that has been developed as an anti-EGFR antibody. Approximately 30% of the protein which constructs the mouse chimeric antibodies is from mouse, which yields the possibility that the mouse chimeric antibodies induce host immune-reaction. After cetuximab, the humanized monoclonal antibodies such as matuzumab and nimotuzumab, and fully humanized monoclonal antibodies such as panitumumab and zalutumumab, have been developed. In this article, we will introduce the current status of development of these four anti-EGFR antibodies, by focusing on the individual clinical trials using each anti-EGFR antibody.

The need for multinational clinical studies in the oncology field has grown stronger not only for the purpose of registration but also the creation of scientific evidence for proper use of anti-cancer agents. Now almost all clinical study has been planned and executed under international collaboration, including Japan. Multinational study has several advantages to enhance faster accrual from more sites for patients with common malignancies and even with rare tumors, to provide scientific data for the approvals of participating countries, and to deliver meaningful information to medical sites in a broader range at reasonable cost. On the other hand, because of the close relationship between genetic variance and cancer occurrence, each region, US, EU, and Asia/Japan, has been showing differences in the prevalence of cancer, its management, and consequently the drug responses, both in terms of efficacy and safety. This phenomenon has been more commonly observed in clinical studies of recent molecular targeting agents. From the study management viewpoint, the regulations in each region may differ to some extent, although efforts of harmonization has been initiated. Therefore, at the study planning stage, the ethnic or regional differences and those in regulations should be taken into consideration in the preparation of study protocol, and several measures should be prepared and implemented for the smooth conduction of the study. It is also recommended that Japan be involved in the development activity at an earlier phase, so that appropriate alternatives, including Asian collaborative studies, could be considered when needed.

A 79-year-old female with acute promyelocytic leukemia (APL) presented with second hematological relapse. She had been treated previously with modified AIDA protocol as the front-line therapy and had achieved complete remission. During ATRA maintenance therapy, the first hematological relapse occurred and she was treated with arsenic trioxide (ATO), achieving the second complete remission. After four courses of consolidation therapy of ATO, the second hematological relapse occurred. At this time, except for a transient effect of tamibarotene, neither arsenic trioxide nor combination chemotherapy was effective. The patient was then treated with two courses of gemtuzumab ozogamicin (GO) and achieved the third complete remission. At present, she is maintaining molecular remission more than one year after GO treatment. GO is considered to be a promising agent for elderly patients with relapsed acute promyelocytic leukemia resistant to arsenic trioxide.

Two cases of pediatric orbital rhabdomyosarcoma leading to visual dysfunction with rapid growth.

Descriptive epidemiology, particularly regarding the cancer pattern in Japanese and Koreans in the United States, indicates that lifestyle factors contribute substantially to the development of common cancers such as gastric, colorectal, breast and prostate cancers. Sex and age are important determinants of many cancers, and the variation in cancer incidence according to these factors is also indicative of the role of environmental factors. While cancer of first-degree relatives or parental cancer was related to an approximately 2-fold increased risk for most site-specific cancers, a large Scandinavian twin study suggested that the contribution of genetic factors was generally small and that a statistically significant effect of hereditable factors was observed only for prostate, colorectal and breast cancers. It was roughly estimated in this article that infectious agents contributed to 20% of incident cases of cancer in Japan. In a recent cohort study in Japan, it is estimated that 29% of male cancers and 3% of female cancers can be ascribed to smoking. Among other lifestyle factors, alcohol consumption and obesity have provided convincing evidence as factors conferring increased risks of various cancers. The increased risks of colorectal cancer and breast cancer associated with alcohol drinking have been recently acknowledged internationally. Among dietary factors, red meat, aflatoxin and beta-carotene are considered to increase risks of colorectal, liver and lung cancers, respectively. Vegetables and fruits probably decrease the risk of cancer at various sites, and calcium specifically decreases the risk of colorectal cancer. Evidence for increased risk of gastric cancer associated with salted foods is judged to be not sufficient, although a high-salt diet enhanced gastric cancer in animals infected with Helicobacter pylori. The role of dietary factors in cancer development will be more clearly established by research on gene-environment interaction focusing on functional genetic polymorphisms.

Marfan syndrome (MFS) is caused by mutations in the gene encoding fibrillin. A 35-year-old man with MFS visited a local physician because of a sore throat. His left tonsil gradually became swollen and he was referred to our department. Histopathological examination of tonsil biopsy specimens showed diffuse proliferation of lymphoma cells with large nuclei. The tumor cells showed CD5+, CD10+, CD20+, BCL-6+, and MUM-1-. Based on these findings, the patient was diagnosed with CD5+ CD10+ diffuse large B-cell lymphoma (DLBCL). Chemotherapy combined with rituximab was administered and complete response was achieved. CD5+ DLBCL comprises approximately 5 approximately 10% of DLBCLs. In addition, CD5+ CD10+ DLBCL comprises about 5% of CD5+ DLBCLs. There may be a relationship between MFS and B-cell lymphoma because mutations in the gene encoding the receptor of transforming growth factor-beta (TGF-beta) have been implicated in the pathogenesis of MFS and downregulation of TGF-beta receptor expression has been described in the pathology of B-cell lymphoma.

We retrospectively analyzed the clinical outcome of dasatinib in 7 patients with chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) resistant or intolerant to imatinib. Three patients with chronic phase CML and two patients with Ph+ALL achieved major molecular response, however, two CML patients in accelerated phase (AP)/blast crisis (BC), did not. Grade> or =3 pancytopenia was seen in four patients. Among these, two AP/BC-CML patients required interruption/or dose reduction of dasatinib. As for nonhematologic adverse events, pleural effusion was seen in one patient and cytomegalovirus (CMV) colitis was observed in two patients. No patients who had been intolerant to imatinib experienced the same nonhematologic toxicity following treatment with dasatinib. We identified three patients who developed peripheral lymphocytosis, identified as natural killer cells or cytotoxic T-cells based on their large granular lymphocyte (LGL) morphologies and immunophenotypic profiles, out of six patients receiving dasatinib therapy. All three cases that developed LGL lymphocytosis achieved optimal molecular response, two of the patients, however, had pleural effusion and CMV colitis, respectively. Dasatinib inhibits off-target kinases, which may result in unexpected drug responses.

Although high-dose chemotherapy supported by autologous peripheral blood stem cell transplantation (auto-PBSCT) is the standard approach for younger patients with multiple myeloma, some of them still show a poor prognosis. We attempted to define a high-risk group among 32 patients who received auto-PBSCT between August 2000 and July 2007 in our hospital. In conventional metaphase cytogenetics (G-banding), chromosome abnormalities (CA), hypodiploidy, and 13 or 13q deletion (Gd13) were noted in 27.6, 17.2, and 19.4% of patients, respectively. In a FISH study, del(17p) (Fd17p) and t(4;14) were noted in 12.5 and 9.4% of patients, respectively. Prognostic analyses of patients with these abnormal chromosomes revealed that those with CA, hypodiploidy, Gd13, and t(4;14) showed a poorer survival at 3 years compared to those without them: 42.9 vs. 95.2% (p=0.0072), 25.0 vs. 91.5% (p=0.0056), and 40.0 vs. 91.8% (p=0.0245), 0 vs. 89.3% (p<.0001), respectively. When we defined patients showing at least one of CA, hypodiploidy, Gd13, Fd17p, and t(4;14) as a "high-risk group", they showed a poorer overall (23.9 vs. 106.1 mo., p=0.0011) and progression-free (13.5 vs. 25.6 mo., p=0.0095) survival compared to a non-high-risk group. This study indicated that chromosome analysis has a prognostic value in patients with multiple myeloma receiving auto-PBSCT.

A 68-year-old woman was referred to Oami Hospital for severe leukocytopenia. Laboratory data revealed severe leukocytopenia (0.8x10(9)/l), severe neutropenia (0.22x10(9)/l) and IgM-kappa monoclonal gammopathy. Granular lymphocytes accounted for more than 90% of leukocytes. Surface marker analysis revealed that these lymphocytes were CD3+, CD4-, CD8+ and CD16+, and monoclonal rearrangement of T-cell receptor genes was seen on Southern blot hybridization analysis. She was diagnosed with T-cell lineage granular lymphocyte proliferative disorder (T-GLPD). During 13-year follow-up without granulocyte-colony stimulating factor (G-CSF) administration, except for one hospitalization because of bacterial pneumonia, she has not experienced severe infection, despite severe neutropenia. T-GLPD should be kept in mind as a cause of leukocytopenia with or without monoclonal gammopathy, and surface marker or Southern blot hybridization analysis should be considered for determining the diagnosis. There are many reports about Caucasian patients with T-GLPD suffering from recurrent infections and dying of severe infection, but in Japanese T-GLPD patients, severe infection is very rare, as shown in the present case report.

An elderly woman with chronic myeloid leukemia-chronic phase (CML-CP) aged at 67 underwent imatinib therapy. Ph chromosomes gradually decreased, but imatinib was discontinued after 10 months because of aggravated skin eruptions. Three months later, myeloid blast crisis (MBC) occurred. DXR+VCR+PSL chemotherapy and imatinib therapy was administered, and return to CP (RTC) was achieved with the disappearance of Ph chromosomes and a marked decrease of BCR/ABL (FISH). Although imatinib therapy was continued, a second MBC was diagnosed, 13 months after RTC. Chemotherapy, using mainly VCR+PSL was performed and imatinib was discontinued. RTC was achieved, and Ph chromosomes and BCR/ABL again disappeared. One year later, a 3rd MBC developed, and chemotherapy using Ara-C+DNR was performed. A 3rd RTC was achieved, and BCR/ABL decreased. This CML case was resistant to imatinib, but chemotherapy was effective in all 3 episodes of MBC, and BCR/ABL decreased or disappeared.

Targeted therapy refers to anticancer treatment which specifically targets key molecules of cancer cells. The higher levels of expression of the epidermal growth factor receptor (EGFR) have also been shown to be correlated with non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC). Potential biomarkers should be investigated for the selection of patients with NSCLC most likely to benefit from epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib. Cetuximab is a monoclonal antibody that binds with high affinity to the EGFR, which is a prime target for new anticancer therapy. However, the predictive value of EGFR expression and mutation of the K-ras gene has been assessed in response to cetuximab. Many molecular techniques are available to assay for these biomarkers. In this review, we present the current assessments of evidence for using these methods as biomarkers for molecular target-based therapy.

Birt-Hogg-Dubé (BHD) syndrome is a rare disorder inherited in an autosomal dominant manner. The affected patients are predisposed to the development of cutaneous fibrofolliculomas, renal cell tumors and lung cysts with recurrent pneumothorax. The responsible gene for this syndrome is named BHD gene which is mapped in the region of chromosome 17p11.2. Based on the neoplastic changes in the skin and the kidney, BHD gene is regarded as a tumor-suppressor gene. However, detailed mechanism of tumorigenesis is not well understood. In this review, we summarize current understanding of BHD syndrome with special attention to the pathophysiology of lung cysts formation. Recent findings of the roles of BHD gene and its-encoding protein folliculin (FLCN) using rodent models are also discussed.

Cervical cancer is the second leading cause of cancer death in women worldwide; approximately 500,000 women develop cervical cancer every year, and more than half of them die from the disease. While the incidence of cervical cancer in developed countries is decreasing due to the widespread use of cervical cytology screening, the incidence among those in their 20's and 30's in Japan is rapidly increasing because of gradually younger sexual debut. High-risk human papilloma viruses (HPVs) such as HPV16 and 18 are thought to be responsible for more than 90% of cervical cancers. HPVs reach and infect the basal layer of the stratified epithelia via small epithelial injuries produced by sexual intercourse, and the viral DNAs are maintained as episomes in the basal cells. When the host cells initiate terminal differentiation, the viral DNAs start to replicate by reactivating the DNA synthesis machinery through degrading p53 by E6 and inactivating Rb by E7. Viral propagation results in the host cells' death, whereas on rare occasions HPV genomes are integrated into the host chromosomes. The cells constantly over expressing E6 and E7 from the integrated viral genomes develop multiple steps towards carcinogenesis through numerous E6 and E7 oncoprotein functions. However, the over-expressions of E6 and E7 are known to be insufficient for carcinogenesis; additional accumulation of genetic and epigenetic abnormalities in oncogenes and tumor suppressors are required. In this review, we outline the current understanding of the molecular mechanisms of high-risk HPV-induced cervical carcinogenesis.

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem neurocutaneous syndrome characterized by the development of multiple hamartomas distributed throughout the body, skin, brain, eyes, heart, kidney and lung. The affected genes are TSC1 and TSC2, encoding hamartin and tuberin respectively. The hamartin-tuberin complex inhibits the mammalian target of rapamycin pathway, which controls cell growth and proliferation. The most common neurological manifestations of TSC are epilepsy, mental retardation, and autistic behavior. Epilespsy usually occurs during childhood and they need anticonvulsant medications through their life. In adulthood, multiple hamartomas is distributed in the kidney and lung. Individuals with lesions more than 4 cm in diameter or with extensive renal involvement should be referred to a nephrologist or urologist. Understanding variable phenotype expression improve management of TSC.

Neurofibromatosis type 1(NF1) is an autosomal dominant disorder with variable expression. The complications are age specific. Serious complication during early childhood is rare but optic glioma, brain tumors or leukemia may appear. Learning difficulties and attention deficit hyperactive disorders occur in as many as 60% of patients during school age. Overall, intelligence in neurofibromatosis is normal and mental retardation occurs in 6-7%. Managements for learning difficulties and attention deficit hyperactive disorders are especially important for quality of life in these patients. Skin neurofibromas or subcutaneous plexiform neurofibromas appear during childhood and may cause pain or spinal cord involvement. Malignant peripheral nerve sheath tumors that arise from plexiform neurifibromas are a particularly devastating complication during middle age.