Impact of muscle volume loss on acute oral mucositis in patients undergoing concurrent chemoradiotherapy after oral cancer resection.

This study evaluated the association between skeletal muscle mass depletion and severe oral mucositis in patients undergoing concurrent chemoradiotherapy after oral cancer resection. Skeletal muscle mass was evaluated in 60 patients using the skeletal muscle index, which was based on skeletal muscle cross-sectional area (on computed tomography) at the level of the third lumbar vertebra. In accordance with the grading criteria of the Radiation Therapy Oncology Group, patients with a grade ≥3 were defined as having severe oral mucositis. Multivariate logistic regression analysis was used to evaluate independent risk factors for severe oral mucositis. Eleven patients (18.3%) were diagnosed with low skeletal muscle mass. Severe oral mucositis occurred in 17 (28.3%) patients, and the mean skeletal muscle index was 42.8 cm2/m2. A low skeletal muscle mass (hazard ratio 18.1; P=0.001) and a chemotherapy regimen consisting of 5-fluorouracil and cisplatin (versus cisplatin only) (hazard ratio 5.5; P=0.015) were independent risk factors for severe oral mucositis. Future prospective studies are warranted to identify effective pre- and perioperative exercises and nutrition programmes to increase low skeletal muscle mass and reduce the incidence of severe oral mucositis in patients undergoing concurrent chemoradiotherapy after oral cancer resection.

Inter-observer reproducibility of endometrial cytology by the Osaki Study Group method: utilising the Becton Dickinson SurePath™ liquid-based cytology.

OBJECTIVE: The purpose of the present study was to evaluate the reproducibility of the cytological diagnosis of endometrial lesions by the Osaki Study Group (OSG) method of new cytological diagnostic criteria using BD SurePath™ (SP)-liquid-based cytology (LBC). METHODS: This cytological classification using the OSG method consists of six categories: (i) normal endometrium (NE), (ii) endometrial glandular and stromal breakdown (EGBD), (iii) atypical endometrial cells, cannot exclude atypical endometrial hyperplasia or more (ATEC-A), (iv) adenocarcinoma including atypical endometrial hyperplasia or malignant tumour (Malignancy), (v) endometrial hyperplasia without atypia (EH) and (vi) atypical endometrial cells of undetermined significance (ATEC-US). For this study, a total 244 endometrial samplings were classified by two academic cytopathologists as follows: 147 NE cases , 36 EGBD cases , 47 Malignant cases, eight ATEC-A cases, two EH cases and four ATEC-US cases. To confirm the reproducibility of the diagnosis and to study the inter- and intra-observer agreement further, a second review round followed at 3-month intervals, which included three additional cytopathologists. RESULTS: The inter-observer agreement of NE classes improved progressively from 'good to fair' to 'excellent', with values increasing from 0.70 to 0.81. Both EGBD and Malignancy classes improved progressively from 'good to fair' to 'excellent', with values increasing from 0.62-0.63 to 0.84-0.95, respectively. The overall intra-observer agreement between the first and the second rounds was 'good to fair' to 'excellent', with values changing from 0.79 to 0.85. All kappa improvements were significant (P < 0.0001). CONCLUSION: In this study, it seemed that the use of the OSG method as the new diagnostic criteria for SP-LBC preparation, may be a valid method to improve the precision (reproducibility) of endometrial cytology.

Survival rates and prognostic factors of Epstein-Barr virus-associated hydroa vacciniforme and hypersensitivity to mosquito bites.

BACKGROUND: Epstein-Barr virus (EBV)-associated T/natural-killer lymphoproliferative disorders form a group of diseases that includes classical and systemic hydroa vacciniforme (HV) and hypersensitivity to mosquito bites (HMB). Patients with systemic HV (sHV) and HMB often have a poor prognosis, although little is known about the prognostic factors. OBJECTIVES: To elucidate the prognostic factors of HV and HMB. METHODS: We studied clinicopathological manifestations, routine laboratory findings, anti-EBV titres, EBV DNA load and EBV-encoded gene expression, including expression of BZLF1, in 50 patients with classical HV (cHV), sHV, HMB only and HMB with HV (HMB + HV), and further analysed 30 patients who were available for follow-up. RESULTS: The median age of disease onset was 5 years (range 1-74). A follow-up study indicated that fatal outcomes were observed in three of eight patients with sHV, two of six patients with HMB only, and two of five patients with HMB + HV. The main causes of death were complications from haematopoietic stem-cell transplantation and multiorgan failure. There were no fatalities among the 11 patients with cHV. Univariate analysis revealed two poor prognostic indicators: (i) onset age > 9 years and (ii) the expression of an EBV-encoded immediate-early gene transcript, BZLF1 mRNA, in the skin lesions (P < 0·001 and P = 0·003, respectively). CONCLUSIONS: No prognostic correlation was observed in EBV-infected lymphocyte subsets, anti-EBV antibody titres or EBV DNA load. Late onset and EBV reactivation are both related to more severe phenotypes of the disease, and thus may predict a poor prognosis.

Phase II study of S-1, an oral fluoropyrimidine, in patients with advanced or recurrent cervical cancer.

BACKGROUND: S-1 is an oral fluoropyrimidine. This phase II study was designed to evaluate the efficacy and safety of S-1 in patients with advanced or recurrent uterine cervical cancer. PATIENTS AND METHODS: S-1 35 mg/m(2) was given twice daily for 28 days repeated every 6 weeks. Eligible patients were women aged 20-74 years, who had Eastern Cooperative Oncology Group performance status of zero or one, who had stage IVB or recurrent uterine cervical cancer, and who had received no more than one platinum-containing chemotherapy regimen for stage IVB or recurrent disease. The primary end point was overall response rate (ORR) determined by RECIST. RESULTS: A total of 37 patients were enrolled in the trial and 36 were eligible. The median number of cycles administered was 4. The confirmed ORR was 30.6% (95% confidence interval 15.5% to 45.6%). The response rate for patients who had received platinum-based treatment including chemoradiotherapy was 31.8% (7 of 22). After a median follow-up duration of 25 months, the median time to progression and the median survival time were 5.2 and 15.4 months, respectively. The most frequent grade 3 or 4 adverse events were anemia (16%), anorexia (16%), and diarrhea (22%). CONCLUSIONS: This phase II study of S-1 in cervical cancer suggests a promising response rate and a contribution toward prolonging survival, with modest toxic effects. Phase III studies of S-1 in patients with advanced or recurrent cervical cancer are thus warranted.

New diagnostic reporting format for endometrial cytology based on cytoarchitectural criteria.

OBJECTIVE: The aim of this study was to develop a new reporting format for endometrial cytology that would standardize the diagnostic criteria and the terminology used for reporting. METHODS: In previous studies, cytoarchitectural criteria were found to be useful for the cytological assessment of endometrial lesions. To apply these criteria, an appropriate cytological specimen is imperative. In this article, the requirements of an adequate endometrial cytological specimen for the new diagnostic criteria are first discussed. Then, the diagnostic criteria, standardized on a combination of conventional and cytoarchitectural criteria, are presented. Third, terminology that could be used, not only for reporting the histopathological diagnosis, but also for providing better guidance for the gynaecologist to determine further clinical action, is introduced. The proposed reporting format was investigated using endometrial cytology of 58 cases that were cytologically underestimated or overestimated compared to the histopathological diagnosis made on the subsequent endometrial biopsy or surgical specimens. RESULTS: Of the 58 cases, 12 were reassessed as being unsatisfactory for evaluation. Among the remaining 46 cases, 25 of the 27 cases, which had been underestimated and subsequently diagnosed as having endometrial carcinoma or a precursor stage on histopathological examination,were reassessed as recommended for endometrial biopsy. On the other hand, 19 cases overestimated by cytology were all reassessed as not requiring biopsy. CONCLUSIONS: The reporting format for endometrial cytology proposed in this article may improve diagnostic accuracy and reduce the number of patients managed inappropriately.

Molecular epidemiological and mutational analysis of DNA mismatch repair (MMR) genes in endometrial cancer patients with HNPCC-associated familial predisposition to cancer.

Recently, a high rate of endometrial cancer has been reported in women with hereditary non-polyposis colorectal cancer (HNPCC), suggesting a relationship between familial endometrial cancers and HNPCC. Familial endometrial cancers constitute only about 0.5% of all endometrial carcinomas and it is essential to examine family histories in detail. A mutational analysis of three DNA mismatch repair (MMR) genes (hMLH1, hMSH2 and hMSH6) in patients with endometrial cancer who meet our criteria for familial predisposition to HNPCC-associated endometrial cancers was performed. Mutations were detected in 18 of the 120 patients (15.0%). Most HNPCC-related endometrial cancers do not meet the New Amsterdam Criteria for HNPCC. These clinical criteria may identify only some HNPCC-associated endometrial cancers. Establishing the correct family history for endometrial cancer patients is important for diagnosing familial endometrial carcinomas. An analysis of MMR genes may be useful for patients with endometrial cancer showing familial aggregation. In addition, gynecologists must be accurately informed, and it is important to perform large-scale, multicenter studies both nationwide and internationally.

[Histoculture drug response assay guided concurrent chemoradiotherapy for non-small cell lung cancer].

Retrospective analysis was done to evaluate concurrent chemoradiotherapy (CCRT) using chemotherapeutic agents judged to be sensitive by histoculture drug response assay (HDRA) for non-small cell lung cancer (NSCLC). We treated 21 NSCLC patients with CCRT using senstivie agents judged by HDRA from 1999 to 2004. Objective response was evaluated in 20 patients. They were consisted of 1 complete response (CR) case, 18 partial response (PR) cases, and 1 stable disease (SD) case. The response rate was 95%. Ten cancer related deaths were observed during 816 +/- 861 (60-2,780) days follow-up. Median survival time was 604 days. One- and 5-year survival rates were 73.9% and 40.3%, respectively. In conclusion, HDRA may improve efficacy of CCRT for NSCLC.

Neuronal specificity of alpha-synuclein toxicity and effect of Parkin co-expression in primates.

Recombinant adeno-associated viral (rAAV) vector-mediated overexpression of alpha-synuclein (alphaSyn) protein has been shown to cause neurodegeneration of the nigrostriatal dopaminergic pathway in rodents and primates. Using serotype-2 rAAV vectors, we recently reported the protective effect of Parkin on alphaSyn-induced nigral dopaminergic neurodegeneration in a rat model. Here we investigated the neuronal specificity of alphaSyn toxicity and the effect of Parkin co-expression in a primate model. We used another serotype (type-1) of AAV vector that was confirmed to deliver genes of interest anterogradely and retrogradely to neurons in rats. The serotype-1 rAAV (rAAV1) carrying alphaSyn cDNA (rAAV1-alphaSyn), and a cocktail of rAAV1-alphaSyn and rAAV1 carrying parkin cDNA (rAAV1-parkin) were unilaterally injected into the striatum of macaque monkeys, resulting in protein expression in striatonigral GABAergic and nigrostriatal dopaminergic neurons. Injection of rAAV1-alphaSyn alone decreased tyrosine hydroxylase immunoreactivity in the striatum compared with the contralateral side injected with a cocktail of rAAV1-alphaSyn and rAAV1-parkin. Immunostaining of striatonigral GABAergic neurons was similar on both sides. Overexpression of Parkin in GABAergic neurons was associated with less accumulation of alphaSyn protein and/or phosphorylation at Ser129 residue. Our results suggest that the toxicity of accumulated alphaSyn is not induced in non-dopaminergic neurons and that the alphaSyn-ablating effect of Parkin is exerted in virtually all neurons in primates.

[Pericardioperitoneal fenestration for chronic exudative pericarditis using a subxiphoidal approach; report of a case].

A 77-year-old woman with a previous history of median sternotomy and collagen disease, presented with chief complaints of resting dyspnea as a result of recurrent pericardial effusions or restrictive ventilatory impairment. She experienced significant symptom amelioration after undergoing pericardioperitoneal fenestration. We weighed the positive against the negative of various pericardial effusion drainage methods in this study. This operative procedure is not innovative, but favorable because it can be carried out conveniently and safely, enabling early rehabilitation without appreciable postoperative complications.

Adeno-associated virus vector-mediated anti-angiogenic gene therapy for collagen-induced arthritis in mice.

OBJECTIVE: The goal of this study was to determine the utility of adeno-associated virus (AAV) vectors for anti-angiogenic gene therapy in a mouse model of collagen-induced arthritis (CIA). METHODS: CIA mice were generated by immunization with bovine type-II collagen and Freund's complete adjuvant. AAV vectors containing angiostatin and enhanced green fluorescent protein (eGFP) expression units (AAV-Ang/GFP) or the GFP and neomycin phosphotransferase (NeoR) expression units (AAV-GFP/NeoR) were injected into mouse knee joints before development of arthritis. The expression of transgenes was confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) and immunostaining, and the incidence and severity of arthritis was determined histologically via assessment of synovial hyperplasia, cartilage erosion and bone erosion. Vascularity in the knee joint was evaluated by immunohistochemical staining with anti-von Willebrand factor antibody. RESULTS: AAV vectors were capable of efficient gene transfer into chondrocytes and synovial cells, and the extent of synovial hyperplasia and other parameters of arthritis were significantly reduced in the knee joints injected with AAV-Ang/GFP compared with the joints treated with either AAV-GFP/NeoR or phosphate-buffered solution (PBS). Reduction in the number of vessels was confirmed in AAV-Ang/GFP-treated joints. CONCLUSION: AAV-vector-mediated local expression of angiostatin efficiently inhibited the development of collagen-induced arthritis in the treated joint. Anti-angiogenic gene therapy using AAV vector may provide a new approach for the effective treatment of rheumatoid arthritis.

Closure of a cervical H-type tracheoesophageal fistula.

Congenital H-type tracheoesophageal fistulae in adults are infrequent. In surgery, the essential components (defining, cutting, and suturing the fistula, and preventive interposition of muscle flap) must be performed precisely. We undertook these procedures through a small collar incision. Based on results of preoperative images, the fistula was identified under minimum dissection between the trachea and esophagus. After cutting and suturing the fistula, a sternohyoid muscle flap was interposed.

Influence of microcatheter length on flow rates of disposable infusion kits.

BACKGROUND AND OBJECTIVE: Continuous spinal analgesia (CSA) offers considerable pain relief, and has been used in various procedures such as for surgery and cancer pain control. In Japan, portable and disposable infusion kits are increasingly employed for continuous epidural analgesia and CSA. In CSA, the use of a microcatheter is expected to reduce the incidence of spinal headache previously encountered with larger catheters. However, the flow rate of disposable infusion kits is reduced when used in conjunction with a microcatheter. METHODS: This study aimed to investigate the influence of catheter length on the flow rate of two different devices: 20- or 91-cm 28-G microcatheters connected to balloon- or syringe-type infusion pumps were examined (50 mL, 1 mL h(-1)). There were four groups each of 10 experiments: Group A: balloon-type infuser, 91 cm catheter; Group B: balloon-type infuser, 20 cm catheter; Group C: syringe-type infuser, 91 cm catheter; Group D: syringe-type infuser, 20 cm catheter. RESULTS: The mean flow rate in Group A was significantly less than that in Group B and the mean flow rate in Group C was significantly less than Group D (P < 0.05). CONCLUSION: These results indicated that the use of a shorter microcatheter achieves a better flow rate during CSA.

Peripheral primitive neuroectodermal tumor of the vulva: report of a case with imprint cytology.

BACKGROUND: Peripheral primitive neuroectodermal tumor (PNET) of the vulva is an extremely rare disease, and, to our knowledge, only two cases have been previously reported. CASE: A 45-year-old woman presented with a mass in the right labium major. Three years after removal of the tumor, she noticed a new lesion in the same place and underwent a partial vulvectomy. The imprint cytology of the recurrent tumor showed a monomorphic appearance, composed of small round cells with scant cytoplasm against a hemorrhagic background. These tumor cells were loosely connective, but rosettelike structures were observed focally. On pathologic examination, the neoplasm was composed of small round tumor cells showing sinusoidal, diffuse or micropapillary growth. Immunohistochemically, the neoplastic cells stained positively for neuron-specific enolase, vimentin and HBA 71 and negatively for cytokeratin, HBA 45 and muscle-specific actin. The morphologic characteristics of the disease were well expressed in the imprint cytology, and this influenced the selection of immunohistochemical studies. CONCLUSION: Cytologic examination for vulvar tumors, even imprint cytology, can be a useful tool in obtaining an accurate pathologic diagnosis of a rare disease, such as peripheral PNET.

Immunoglobulin G1 antibody response to Helicobacter pylori heat shock protein 60 is closely associated with low-grade gastric mucosa-associated lymphoid tissue lymphoma.

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is related to Helicobacter pylori infection. Specifically, it has been pointed out that pathogenesis of MALT lymphoma involves the 60-kDa heat shock protein (hsp60). To investigate humoral immune responses to the H. pylori hsp60 in patients with gastroduodenal diseases and patients with MALT lymphoma, the hsp60 of H. pylori was expressed with a glutathione S-transferase fusion protein and was purified (recombinant hsp60). Sera were obtained from H. pylori-positive patients with gastroduodenal diseases (MALT lymphoma, n = 13; gastric ulcer, n = 20; duodenal ulcer, n = 20; gastritis, n = 20) and from H. pylori-negative healthy volunteers (n = 9). Sera from patients with MALT lymphoma were also obtained at two times: before and after eradication therapy. Antibodies to hsp60 and H. pylori were assessed by enzyme-linked immunosorbent assay. The levels of immunoglobulin G (IgG) antibodies to the hsp60 of H. pylori-positive patients with gastroduodenal diseases were significantly elevated compared to those in the controls. The levels of IgG1 antibodies to hsp60 were elevated and correlated with the levels of anti-H. pylori antibodies in patients with MALT lymphoma. Humarol immunity against hsp60 may be important and relevant to gastroduodenal diseases induced by H. pylori infection.

The interplay of matrix metalloproteinases, morphogens and growth factors is necessary for branching of mammary epithelial cells.

The mammary gland develops its adult form by a process referred to as branching morphogenesis. Many factors have been reported to affect this process. We have used cultured primary mammary epithelial organoids and mammary epithelial cell lines in three-dimensional collagen gels to elucidate which growth factors, matrix metalloproteinases (MMPs) and mammary morphogens interact in branching morphogenesis. Branching stimulated by stromal fibroblasts, epidermal growth factor, fibroblast growth factor 7, fibroblast growth factor 2 and hepatocyte growth factor was strongly reduced by inhibitors of MMPs, indicating the requirement of MMPs for three-dimensional growth involved in morphogenesis. Recombinant stromelysin 1/MMP3 alone was sufficient to drive branching in the absence of growth factors in the organoids. Plasmin also stimulated branching; however, plasmin-dependent branching was abolished by both inhibitors of plasmin and MMPs, suggesting that plasmin activates MMPs. To differentiate between signals for proliferation and morphogenesis, we used a cloned mammary epithelial cell line that lacks epimorphin, an essential mammary morphogen. Both epimorphin and MMPs were required for morphogenesis, but neither was required for epithelial cell proliferation. These results provide direct evidence for a crucial role of MMPs in branching in mammary epithelium and suggest that, in addition to epimorphin, MMP activity is a minimum requirement for branching morphogenesis in the mammary gland.

An anatomic study of the extensor tendons of the human hand.

A total of 548 upper limbs (276 right and 272 left hands) from Japanese cadavers were dissected. The arrangements of extensor indicis proprius, extensor digitorum communis (EDC), and extensor digiti minimi tendons and the intertendinous connections were studied. The most common pattern of extensor tendons was as follows: the index finger had a single EDC tendon, the middle finger had a single EDC tendon, the ring finger had a single EDC tendon, and the small finger had a single EDC tendon or a single common EDC tendon distributed to the ring and small finger. A single extensor indicis proprius tendon ran along the ulnar side of the EDC, and the extensor digiti minimi tendon consisted of 2 slips. Intertendinous connections were classified into 3 types: type 1 with a filamentous band, type 2 with a fibrous band, and type 3 with a tendinous band subdivided to r-shaped and y-shaped. The most common patterns were type 1 in the second intermetacarpal space (IMCS), type 3r in the third IMCS, and type 3y in the fourth IMCS.

Somatic mutations of the PTEN/NMAC1 gene associated with frequent chromosomal loss detected using comparative genomic hybridization in endometrial cancer.

OBJECTIVES: We analyzed the mutational status of the transforming growth factor-beta type II receptor (TGF beta RII), BAX, and PTEN/MMAC1 genes as well as microsatellite instability (MI) in 29 consecutive cases of endometrial carcinoma operated on at the Cancer Institute Hospital (Tokyo, Japan). To identify chromosomal loss associated with significant somatic mutations, we conducted comparative genomic hybridization (CGH) analysis. METHODS: We conducted a direct sequence for mutational analysis of these genes. To examine copy number loss at the chromosomal regions bearing these genes, we used CGH analysis. CGH analysis may provides a genome-wide overview about tumor-associated genomic imbalances. RESULTS: Among nine tumors that showed the MI+ phenotype, four (44%) demonstrated a significant mutation with a definite amino acid change in the PTEN/MMAC1 gene. CGH analysis demonstrated that all four tumors (100%) showed chromosomal copy number loss around the locus of this gene, whereas four (57%) of seven tumors with PTEN/MMAC1 mutations showed chromosomal loss or double mutations in MI- carcinomas. The role of TGF beta RII and BAX genes is limited as a target gene of MI+ phenotype in endometrial cancer, because several mutations of these genes were detected but a chromosomal loss was demonstrated by CGH in only one tumor in MI+ endometrial cancers with mutation. CONCLUSIONS: This report reveals, by using CGH, that most MI+ endometrial cancers with PTEN/MMAC1 mutations as well as MI- tumors showed inactivation of both alleles of this gene, which strongly suggested the involvement of this gene in carcinogenesis.

Mutational analysis of BRCA1 and BRCA2 and clinicopathologic analysis of ovarian cancer in 82 ovarian cancer families: two common founder mutations of BRCA1 in Japanese population.

We analyzed genetic alterations in BRCA1 and BRCA2 genes among 82 ovarian cancer families in Japan. The clinical characteristics of BRCA-associated ovarian cancer patients were compared with cases carrying no mutations as well as with population controls. Using a direct sequencing method, 45 of the 82 ovarian cancer families were found to carry BRCA1 or BRCA2 germ-line mutations (40 with BRCA1 and 5 with BRCA2). In 24 independent mutations of BRCA1, 5 recurrent mutations were found and 2 of them, the L63X and Q934X mutations, were detected in seven and eight independent families, respectively. In addition, 16 mutations of BRCA1 and 3 mutations of BRCA2 have never been described previously. In consideration of clinicopathological features, there was a significantly higher proportion of tumors with serous adenocarcinoma and of cases of advanced stages in the BRCA1 or BRCA2 cases than in those of the controls. On the other hand, there were no differences of mean age at diagnosis between patients with BRCA1 or BRCA2 mutation and those of the controls. Our results indicate that the features of BRCA-associated ovarian cancer in Japan appear to be similar to those in Western countries, and the L63X and Q934X mutations of BRCA1 appear to be common founder mutations unique to the Japanese population.

Identification of a high-risk subgroup in cytology-positive stage IIIA endometrial cancer.

OBJECTIVE: To identify a high-risk subgroup among patients with cytology-positive stage IIIA endometrial cancer. STUDY DESIGN: Fifty-four stage IIIA endometrial cancer patients who were positive only on peritoneal cytology were divided into two groups based on the cytologic pattern of their peritoneal smears. In group A, malignant cell clusters had well-defined edges, while the tumor cell clusters had scalloped edges in group B. The prognostic significance of these findings was investigated. RESULTS: The five-year disease-free survival rate was 97.5% in group A (n=40) versus 50% in group B (n = 14). Multivariate analysis confirmed that the cytologic pattern had an independent influence on survival. CONCLUSION: Positive peritoneal cytology composed of malignant cell clusters with well-defined edges has no impact on survival. Only endometrial cancer patients who show tumor cell clusters with scalloped edges in peritoneal smears are worth considering for upstaging.