Cross‐sectional analysis of germline BRCA1 and BRCA2 mutations in Japanese patients suspected to have hereditary breast/ovarian cancer

The prevalence of BRCA1/2 germline mutations in Japanese patients suspected to have hereditary breast/ovarian cancer was examined by a multi‐institutional study, aiming at the clinical application of total sequencing analysis and validation of assay sensitivity in Japanese people using a cross‐sectional approach based on genetic factors estimated from personal and family histories. One hundred and thirty‐five subjects were referred to the genetic counseling clinics and enrolled in the study. Full sequencing analysis of the BRCA1/2 gene showed 28 types of deleterious mutations in 36 subjects (26.7%), including 13 types of BRCA1 mutations in 17 subjects (12.6%) and 15 types of BRCA2 mutations in 19 subjects (14.1%). Subjects were classified into five groups and 22 subgroups according to their personal and family history of breast and/or ovarian cancer, and the prevalence of deleterious mutations was compared with previously reported data in non‐Ashkenazi individuals. Statistical analysis using the Mantel‐Haenszel test for groups I through IV revealed that the prevalence of Japanese subjects was significantly higher than that of non‐Ashkenazi individuals (P = 0.005, odds ratio 1.87, 95% confidence interval 1.22–2.88). Family history of the probands suffering from breast cancer indicated risk factors for the presence of deleterious mutations of BRCA1/2 as follows: (1) families with breast cancer before age 40 within second degree relatives (P = 0.0265, odds ratio 2.833, 95% confidence interval 1.165–7.136) and (2) families with bilateral breast cancer and/or ovarian cancer within second degree relatives (P = 0.0151, odds ratio 2.88, 95% confidence interval 1.25–6.64). (Cancer Sci 2008; 99: 1967–1976)     

High Rates of Ki-ras Point Mutation in Both Intra- and Extra-hepatic Cholangiocarcinomas

The presence of the Ki-ras gene mutations in 14 cases of intrahepaticcholangiocarcinoma (IHC) and nine cases of extrahepatic cholangiocarcinoma(EHC) were investigated by polymerase chain reaction-singlestrand conformation polymorphism analysis. To obtain enrichedtumor cell DNA, the microdissection method was used on formalin-fixedparaffin-embedded tissue sections. Point mutations at codon12 of the Ki-ras gene were detected in seven (50%) of the 14cases of IHC and six (67%) of the nine EHC cases. In all butone of the ras gene mutation cases, G to A transitions in thesecond position of codon 12 were detected, the exception beinga G to T transition in the same position in one IHC. No pointmutations were detected at codon 13 or 61 in either IHC or EHC.Furthermore, there was no demonstrable correlation between Ki-rasmutation and patient age, tumor Stage, histological findingsor prognosis. The present results demonstrated a higherparticipationof Ki-ras gene mutations in EHC than found in previous studies,and provided a confirmation and extension of the results earlierreported by Tada et al, and Tsuda et al, for IHC.     

cDNA and genomic sequences for rat 8-oxo-dGTPase that prevents occurrence of spontaneous mutations due to oxidation of guanine nucleotides

The enzyme, 8-oxo-7,8-dihydrodeoxyguanosine triphosphatase (8-oxo-dGTPase),is present In various organisms and plays an important rolein control of spontaneous mutagenesis. This enzyme degrades8-oxoguamne-contaning deoxyribonucleoside triphosphate, a potentiallymutagenic substrate for DNA synthesis, to the correspondingmonophosphate. To obtain appropriate probes for expression ofthe gene in various tissues and also to construct appropriateexperimental models for carcino genesis, we cloned cDNA forrat 8-oxo-dGTPase and elucidated its structure. The nucleotidesequence of the cDNA revealed that the rat 8-oxo-dGTPase proteinis composed of 156 amino acid residues. The molecular weightof rat 8-oxo-dGTPase, calculated from the predicted amino acidse was 18 006, and the 8-oxo-dGTPase protein of this size wasdetected when the cDNA was expressed in 8-oxo-dGTPase-deficlentEscherichitz coil mutT^– cells. The predicted amino acidsequence of the rat 8-oxo-dGTPase has a close homology withthose of human and bacterial counterparts. Using the cDNA asa probe, part of the rat gene for 8-oxo-dGTPase was isolatedand was found to consist of at least three exons and spannedabout 10 kb. A genomic region containing the pseudogene wasalso isolated.     

Prevention by Methionine of Enhancement of Hepatocarcinogenesis by Coadministration of a Choline-deficient L-Amino Acid-defined Diet and Ethionine in Rats

The effects of methionine on hepatocarcinogenesis induced by Coadministration of a choline-deflcient L-amino acid-defined (CDAA) diet and ethionine were examined. F344 male rats were divided into 4 experimental groups. Groups 1 and 2 received the CDAA diet and a choline-supplemented L-amino acid-defined (CSAA) diet, respectively. Group 3 received the CDAA diet containing 0.05% ethionine, and group 4 the CDAA diet containing 0.05% ethionine and 0.47% methionine. Animals were killed after 12 weeks of treatment. Histologically, the CDAA diet induced intracellular fat accumulation and foci. In contrast, ethionine caused not only foci, but also hyperplastic nodules, cholangiofibrosis and the proliferation of oval cells without such fat accumulation. Methionine abolished the development of all of the liver lesions induced by Coadministration of the CDAA diet and ethionine. To investigate the effects of methionine on induction of c- myc and c-Ha- ras expression, as well as generation of 8-hydroxyguanine (8-OHGua) and 2-thiobarbituric acid-reacting substances (TBARS), by Coadministration of the CDAA diet and ethionine, subgroups of 3 to 5 animals were killed at 2, 4, 8 or 11 days after the beginning of the experiment. Coadministration of the CDAA diet and ethionine markedly enhanced the level of expression of c- myc and c-Ha- ras , 8-OHGua formation and TBARS generation as compared with the CDAA or CSAA diet within 11 days, and methionine blocked these actions. These results indicate that addition of methionine prevents the induction of c- myc and c-Ha- ras expression, 8-OHGua formation and TBARS generation, as well as hepatocellular lesions, by Coadministration of the CDAA diet and ethionine in rats, and suggest a possible involvement of oxidative stress and gene expression in hepatocarcinogenesis by these agents.     

Primary Non-Hodgkin Malignant Lymphoma of the Male Breast

A case of primary non-Hodgkin lymphoma of the male breast isreported. The patient was a 76-year-old Japanese with a historyof bilateral gynecomastia. After the patient had received sexhormone treatment for the gynecomastia, rapid growth of a tumorin the right breast was noted, with regression of a contralateralbreast lesion. Clinically, inflammatory breast cancer was suspected,and right mastectomy with ipsilateral axillary lymph node dissectionwas performed after intraarterial infusion chemotherapy usinga cis-platinum derivative. The histology of the surgical specimenwas non-Hodgkin malignant lymphoma of the diffuse large celltype, with focal tumor necrosis. Immunohistochemically, thetumor cells showed a B-cell nature. The patient is currentlywell without disease 39 months after surgery.     

Successful treatment of a young infant who developed high-titer inhibitors against VWF-cleaving protease (ADAMTS-13): important discrimination from Upshaw-Schulman syndrome

We report herein the case of a 9-month-old female infant with acquired thrombotic thrombocytopenic purpura (TTP), which was initially suspected to be either Upshaw-Schulman syndrome (USS or a congenital TTP) or hemolytic uremic syndrome (HUS) because of onset of clinical signs in infancy and accompanying diarrhea. She received combination therapy of plasma exchange, steroid pulse, and high-dose intravenous immunoglobulin infusion that was initiated before the definitive diagnosis, which resulted in excellent clinical improvement. The retrograde analysis of plasma ADAMTS-13 activity and its inhibitor showed a lack of this enzyme activity and the presence of a high-titer IgG inhibitor (200-320 Bethesda units/mL) to this enzyme activity. From our experience, it was suggested that we should recognize the possibility of the patient with acquired TTP in infancy and the importance of plasma exchange therapy for management of its clinical symptoms.     

Osteoarthrosis of upper extremity--basic conception and knack of diagnosis

Joints of upper extremities are non weight-bearing joints. However, there are various diseases which cause pain in these joints with various frequencies. Elaborate movements of hand are the basis of many activities in daily life and reach function of elbow joint enables washing of faces and eating. Thus, pain in these joints hinders basic daily activities. There are only few cases that we treat as primary osteoarthrosis. Almost all cases are secondary osteoarthrosis which are caused by various trauma or diseases. It is very difficult and almost impossible to recover completely even with appropriate medical treatment once osteoarthrosis occurred. Therefore, it is important that we acknowledge those trauma and diseases which cause osteoarthrosis in these joints. It is also important to educate patients in order to prevent progression of osteoarthrosis.     

Effects of growth hormone on testicular dysfunction induced by cyclophosphamide (CP) in GH-deficient rats

Growth hormone (GH) is known to accelerate spermatogenesis and maintain gonadal function. In this study, we evaluated the effect of GH on recovery from testicular damage induced by cyclophosphamide (CP). Eleven- to fourteen-week-old GH-deficient Lewis rats (dw/dw) were divided into 4 groups (n = 10 each), with one group serving as controls. In the CP group, CP was intravenously administered in daily doses of 50 mg/kg for 2 days, followed by daily doses of 10 mg/kg for the next 3 days. In the GH group, rat GH was subcutaneously administered at a daily dose of 0.3 mg/kg until the rats were sacrificed. In the CP/GH group, GH and CP administration were started simultaneously. In the CP/preGH group, GH administration was started 14 days before CP administration. Five rats from each group were sacrificed at days 14 and 28 after administration of CP. Spermatogenesis was then evaluated morphometrically by counting numbers of cells at several stages of the spermatogenic cycle. On day 14, there were no significant differences in the numbers of the spermatocytes between CP and CP/GH group. On day 28, the numbers of spermatocytes and motility of spermatozoa in CP/GH group were greater than those of CP group were. In the CP/preGH group, these effects of GH administration were not observed. These results suggested that administration of GH improved testicular function damaged by CP under GH-deficient condition, when GH and CP administration are started simultaneously.     

Atlas burst fracture (Jefferson fracture) requiring surgical treatment after conservative treatment--report of two cases

Most cases of atlas burst fracture do not require surgical stabilization, because they can be successfully treated with external immobilization. The authors present two cases of atlas burst fracture in which surgical stabilization was required after external immobilization. The first patient was a 50-year-old male and the second patient was a 34-year-old male. Both presented with neck pain without neurological symptoms after a traffic accident. Neuroradiological examinations revealed atlas burst fracture in both patients. They were initially treated with conservative treatment; one with a rigid collar and the other with a halo vest. However, lateral offset of the atlas on the axis increased and atlanto-axial instability became evident three months later in both patients. They underwent upper cervical arthrodesis with satisfactory results. The authors review surgical indication and its timing in patients with atlas burst fracture.     

The usefulness of 3D-CTA for the diagnosis of a ruptured aneurysm at the origin of the duplicated middle cerebral artery: case report

Duplication of the middle cerebral artery is known as a rare anomalous vessel arising from the internal carotid artery and an aneurysm at the origin of the duplicated middle cerebral artery is very rare. We presented a case of ruptured aneurysm at the origin of the duplicated middle cerebral artery and discussed the usefulness of 3D-CTA (three-dimensional computed tomographic angiography) for its diagnosis. A 34-year-old female suffered from severe headache and was admitted to our hospital. CT scan revealed diffuse subarachnoid hemorrhage and angiography revealed duplication of the right middle cerebral artery and dilatation at its origin. We could not identify it as an aneurysm by angiography, so we performed 3D-CTA. 3D-CTA was able to demonstrate clearly the aneurysm at the origin of the duplicated middle cerebral artery and we performed neck clipping of the ruptured aneurysm. To our knowledge, previously there have been only 14 cases which reported such an aneurysm at the origin of a duplicated middle cerebral artery. We reviewed the 15 cases including ours and found that, in 4 cases, the aneurysm could not be detected by the initial angiography. We suspected that most of these aneurysms were small, so the detection of the aneurysms by angiography was difficult. We conclude that 3D-CTA is useful for diagnosing aneurysms at the origin of the duplicated middle cerebral artery even when thy can't be detected by angiography.