Phase III randomised controlled trial of neoadjuvant chemotherapy plus radical surgery vs radical surgery alone for stages IB2, IIA2, and IIB cervical cancer: a Japan Clinical Oncology Group trial (JCOG 0102).

BACKGROUND: A phase III trial was conducted to determine whether neoadjuvant chemotherapy (NACT) before radical surgery (RS) improves overall survival. METHODS: Patients with stage IB2, IIA2, or IIB squamous cell carcinoma of the uterine cervix were randomly assigned to receive either BOMP (bleomycin 7 mg days 1-5, vincristine 0.7 mg m(-2) day 5, mitomycin 7 mg m(-2) day 5, cisplatin 14 mg m(-2) days 1-5, every 3 weeks for 2 to 4 cycles) plus RS (NACT group) or RS alone (RS group). Patients with pathological high-risk factors received postoperative radiotherapy (RT). The primary end point was overall survival. RESULTS: A total of 134 patients were randomly assigned to treatment. This study was prematurely terminated at the first planned interim analysis because overall survival in the NACT group was inferior to that in the RS group. Patients who received postoperative RT were significantly lower in the NACT group (58%) than in the RS group (80%; P=0.015). The 5-year overall survival was 70.0% in the NACT group and 74.4% in the RS group (P=0.85). CONCLUSION: Neoadjuvant chemotherapy with BOMP regimen before RS did not improve overall survival, but reduced the number of patients who received postoperative RT.

Radiation therapy for primary vaginal carcinoma.

Brachytherapy plays a significant role in the management of cervical cancer, but the clinical significance of brachytherapy in the management of vaginal cancer remains to be defined. Thus, a single institutional experience in the treatment of primary invasive vaginal carcinoma was reviewed to define the role of brachytherapy. We retrospectively reviewed the charts of 36 patients with primary vaginal carcinoma who received definitive radiotherapy between 1992 and 2010. The treatment modalities included high-dose-rate intracavitary brachytherapy alone (HDR-ICBT; two patients), external beam radiation therapy alone (EBRT; 14 patients), a combination of EBRT and HDR-ICBT (10 patients), or high-dose-rate interstitial brachytherapy (HDR-ISBT; 10 patients). The median follow-up was 35.2 months. The 2-year local control rate (LCR), disease-free survival (DFS), and overall survival (OS) were 68.8%, 55.3% and 73.9%, respectively. The 2-year LCR for Stage I, II, III and IV was 100%, 87.5%, 51.5% and 0%, respectively (P = 0.007). In subgroup analysis consisting only of T2-T3 disease, the use of HDR-ISBT showed marginal significance for favorable 5-year LCR (88.9% vs 46.9%, P = 0.064). One patient each developed Grade 2 proctitis, Grade 2 cystitis, and a vaginal ulcer. We conclude that brachytherapy can play a central role in radiation therapy for primary vaginal cancer. Combining EBRT and HDR-ISBT for T2-T3 disease resulted in good local control.

Safety and efficacy of a splenectomy during debulking surgery for Müllerian carcinoma.

PURPOSE: This study was designed to assess the safety and efficacy of a splenectomy and to analyze the prognostic factors of Müllerian carcinoma with spleen metastasis. METHODS: We reviewed the medical records of 11 patients with Müllerian carcinoma who underwent a splenectomy between 1997 and 2007. The treatment outcome of these patients was examined and the possible prognostic factors were investigated by univariate analysis. RESULTS: Four and seven patients underwent a splenectomy for primary and recurrent disease, respectively. A complete resection was achieved in eight patients. A blood transfusion was not required and only two mild postoperative complications were observed. The median and five-year survivals of all patients following treatment were 39 months and 39%, respectively. Older patients (> or = 60 years old) and patients with a poor performance status (PS2) had a poorer prognosis by univariate analysis. CONCLUSIONS: A splenectomy can be performed safely and effectively during debulking surgery for appropriately selected patients with primary or recurrent Müllerian carcinoma.

Interleukin-10 gene polymorphism reflects the severity of chronic immune thrombocytopenia in Japanese patients.

INTRODUCTION: T-helper cell type 1 (Th1) polarization of the immune response has been documented in patients with chronic immune thrombocytopenia (ITP). Interleukin (IL)-10 is the most important factor regulating Th1 and T-helper type 2 cytokine synthesis. This study evaluated the impact of IL-10 polymorphisms on both susceptibility to, and severity of, chronic ITP. METHODS: We analyzed -1082(G/A), -812(C/T), and -592(C/A) IL-10 polymorphisms in 90 patients with adult chronic ITP and 202 race- and sex-matched healthy controls. RESULTS: No significant differences in the genotype or haplotype frequencies were observed between the patient with chronic ITP and the control group. However, more patients with the -592AA genotype showed a severe thrombocytopenic state (platelet count <10 x 109/l) than those with the -592CC/CA genotypes (44.1%vs. 19.6%, P = 0.01). Furthermore, more patients with the ATA/ATA haplotype showed a severe thrombocytopenic state than those without the ATA/ATA haplotype (44.1%vs. 19.6%, P = 0.01). CONCLUSION: According to our data, patients with low producer type of IL-10 polymorphisms have more severe thrombocytopenia, suggesting that IL-10 gene polymorphisms may reflect the severity of ITP.

Clinical characteristics and outcomes of women with stage IV endometrial cancer.

Treatment strategies for patients with stage IV endometrial cancer (EC) remain controversial. Some studies have suggested that optimal cytoreduction improves survival. We retrospectively analyzed the clinical characteristics and outcomes of 41 women with stage IV EC. The results of preoperative cytologic evaluation and biopsy of the endometrium were reviewed by a single pathologist for patients in whom stage IV EC was diagnosed preoperatively. Of the 41 patients with stage IV EC (median age, 62 years), 31 had surgical stage IV disease and 10 had clinical stage IV disease. Twenty-eight patients were diagnosed of stage IV EC before surgery or without surgery. Progression-free survival and overall survival were 10.4 and 21.3 months, respectively. On univariate analysis, grade 1 or 2 endometrioid subtype, 0 or 1 sites of extraperitoneal metastasis, and hormonal therapy were associated with good outcomes. Multivariate analysis revealed that grade 1 or 2 endometrioid subtype (P=0.005, hazard ratio [HR] 0.23 [0.08-0.65]) and 0 or 1 sites of extraperitoneal metastasis (P=0.001, HR 0.24 [0.10-0.57]) were independent predictors of survival. Neither surgery as primary therapy nor optimal cytoreduction was significantly related to overall survival in either the 28 patients in whom stage IV was diagnosed preoperatively or in all 41 patients. In women with stage IV EC, histologic features and extent of disease are more important determinants of outcomes than any kind of treatment. The indication for surgery should be carefully considered in this subset of patients.

Radical hysterectomy for FIGO stage I-IIB adenocarcinoma of the uterine cervix.

A retrospective analysis was carried out to identify risk factors for survival and relapse in patients with FIGO stage I-IIB cervical adenocarcinoma (AC), who underwent radical hysterectomy, and to compare outcome and spread pattern with those of squamous cell carcinoma (SCC). One hundred and twenty-three FIGO stage I-IIB patients with AC and 455 patients with SCC, who all underwent primary radical hysterectomy, were reviewed. Among the patients with AC, Cox model identified tumour size (95% CI: 1.35-30.71) and node metastasis (95% CI: 5.09-53.44) as independent prognostic factors for survival, and infiltration to vagina (95% CI: 1.15-5.76) and node metastasis (95% CI: 6.39-58.87) as independent prognostic factors for relapse. No significant difference was found in survival or relapse between the AC and SCC groups, after adjusting for other clinicopathological characteristics using Cox model. No significant difference was found in the positive rates of lymph nodes or location of initial failure sites between the two groups, but ovarian metastatic rate was significantly higher in patients with pathologic stage IIB AC (P=0.02). Positive node is a common independent prognostic factor for survival and relapse of patients with AC. FIGO stage I-IIB patients with AC or SCC, who underwent radical hysterectomy, have similar prognosis and spread pattern, but different ovarian metastasis rates.

Vitamin D deficiency in patients with active systemic lupus erythematosus.

UNLABELLED: We investigated the effects of disease activity on bone metabolism in 36 patients with systemic lupus erythematosus (SLE). Changes in bone remodeling were not explained by corticosteroid use. A high prevalence of 25OHD deficiency in SLE patients indicates the need for vitamin D replacement, mainly during high disease activity periods. INTRODUCTION: We investigated the effects of SLE disease activity on bone metabolism, their relation to inflammatory cytokines and vitamin D levels. METHODS: We performed a cross-sectional analysis of 36 SLE patients classified according to the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) in high activity (group I: 12 patients, mean age 29.6 years) or in minimal activity (group II: 24 patients, mean age 30.0 years), and compared them to normal controls (group III: 26 women, 32.8 years). Serum calcium, phosphorus, parathyroid and sex hormones, bone remodeling markers, interleukin (IL)-6, soluble IL-6 receptor (sIL-6R), IL-1, tumor necrosis factor-alpha (TNF), 25-hydroxivitamin D (25OHD), and 1,25-dihydroxyvitamin D3 were measured, plus bone mineral density. RESULTS: All cytokines were significantly higher in SLE groups; IL-6 could differentiate SLE patients from controls. In group I, 25OHD levels were lower (P < 0.05), which was related to the SLEDAI (R = -0.65, P < 0.001). In multiple regression analysis, the 25OHD level was associated with SLEDAI, osteocalcin and bone-specific alkaline phosphatase. The SLEDAI score was positively correlated with all measured cytokines and especially TNF (R = 0.75, P < 0.001). CONCLUSIONS: SLE patients demonstrated changes in bone remodeling strongly related to disease activity. A high prevalence of 25OHD deficiency was observed in SLE patients, indicating the need for vitamin D replacement.

Genotoxicity studies on green tea catechin.

The beneficial effects of tea catechins are well documented. We evaluated the genotoxic potential of a green tea catechin preparation using established genotoxicity assays, including a bacterial reverse mutation assay (Ames test), a chromosomal aberration assay in cultured Chinese hamster lung cells (CHL/IU), a mouse lymphoma L5178Y/tk assay, and a bone marrow micronucleus (MN) assay in ICR CD mice and SD rats. No significant increases in the number of revertant colonies were observed in the Ames test, but positive responses were observed in two in vitro assays: the chromosomal aberration assay and mouse lymphoma L5178/tk assay. However, the in vivo study demonstrated no significant increase in micronucleated polychromatic erythrocytes (MNPCE) in the bone marrow of both ICR CD mice and SD rats administered a high dose of the green tea catechin preparation up to 2000mg/kg. Combined with favorable epidemiological information suggesting a chemopreventive effect of tea catechins on carcinogenesis, we conclude that green tea catechin presents no significant genotoxic concern under the anticipated conditions of use. These results are consistent with other genotoxicity studies of tea catechins, which show minimal, if any, genotoxic potential.

Surgical treatment for neuroendocrine carcinoma of the uterine cervix.

OBJECTIVE: To identify the best operative approach for neuroendocrine cervical carcinoma (NECC). METHODS: The records of surgically treated patients with stages IB to IIB NECC were reviewed. RESULTS: Of 10 patients who met the study criteria for NECC and underwent radical hysterectomy, 4 had pT1bN0, 4 had pT1bN1, 1 had pT2aN0, and 1 had pT2bN1 disease. Those with pT1bN1 or pT2bN1 disease received postoperative adjuvant radiotherapy and/or chemotherapy, and recurrence occurred in 7 patients (70%). Among these 7 patients, 5 (71%) had a primary NECC tumor with deep stromal invasion and 5 (71%) had extrauterine disease (parametrium and/or lymph node). The recurrences in 6 patients (86%) were located outside the pelvis (lung, liver, or brain). Stromal invasion was 6 mm or less in the 3 patients who did not experience disease recurrence. CONCLUSIONS: Pelvic control by radical hysterectomy may not be beneficial for patients with NECC except for those with an early invasive lesion.

Neural plasticity maintained high by activation of cyclic AMP-dependent protein kinase: an age-independent, general mechanism in cat striate cortex.

Adult cats lack ocular dominance plasticity, showing little change in the ocular dominance distribution following monocular deprivation. Ocular dominance plasticity is also lost in kitten visual cortex that has been continuously infused with either catecholaminergic neurotoxin, beta-adrenoreceptor blocker, or inhibitor of cyclic AMP-dependent protein kinase (protein kinase A). Complementarily, in adult cats we showed earlier that pharmacological activation of protein kinase A, albeit partially, restored ocular dominance plasticity. In the present study, we first asked whether, mediated by protein kinase A activation, the same molecular mechanisms could restore ocular dominance plasticity to kitten cortex that once lost the expression of plasticity due to prior pharmacological treatments. Concurrently with monocular deprivation, two kinds of cyclic AMP-related drugs (cholera toxin A-subunit or dibutyryl cyclic AMP) were directly infused in two types of aplastic kitten cortex pretreated with either 6-hydroxydopamine or propranolol. The combined treatment resulted in clear ocular dominance shift to the non-deprived eye, indicating that cortical plasticity was fully restored to aplastic kitten cortex. Next, to directly prove the sensitivity difference in protein kinase A activation between the immature and mature cortex, we compared the thus-obtained data in kittens with the published data derived from adult cats under the comparable experimental paradigm. The extent of ocular dominance changes following monocular deprivation was compared at different drug concentrations in the two preparations: the shifted ocular dominance distribution in aplastic kitten cortex infused with dibutyryl cyclic AMP at the lowest concentration tested and the W-shaped distribution in similarly treated adult cortex at a thousandfold-higher drug concentration that induced nearly maximal changes. We conclude that, irrespective of the animal's age, activation of protein kinase A cascades is a general mechanism to maintain ocular dominance plasticity high, their sensitivity being substantially higher in the immature than mature cortex.

Radical hysterectomy for stage IIB cervical cancer: a review.

Patients with stage IIB cervical cancer in some countries in Europe and Asia especially in Japan are usually treated with radical hysterectomy and pelvic lymphadenectomy. Extrauterine diseases, ie, nodal metastases, parametrial invasion, and intraperitoneal spread, can be readily identified. We present the literature review of radical hysterectomy in stage IIB cervical cancer by searching data since 1980 from Medline, and we found that the parametrial involvement of patients in this stage was only 21-55%, the incidence of pelvic node metastases was about 35-45%, and 5-year survival rate was between 55% and 77%. Lymph node metastases and the number of positive nodes were significant prognostic factors of patients in this stage.

Clinical aspects and prognosis of pelvic recurrence of cervical carcinoma.

OBJECTIVE: To identify which patients with locally recurrent cervical carcinoma are potentially curable. METHOD: A total of 664 stage IB-IVA patients were examined following surgery or radiotherapy. RESULT: Among the 664 patients, 193 (29%) developed recurrence. Sixty-seven (35%) of these recurrences were located in the pelvis alone. Among these 67 recurrences, 24 (35%) were central recurrences and the remaining 43 (65%) were pelvic side-wall recurrences. Of the 24 patients with central recurrences, 8 were salvaged. Of these 8 patients, 3 underwent pelvic exenteration, and 5 received optimal radiotherapy. The recurrent tumor in these 5 survivors who received radiotherapy had consisted of a small (<2 cm) tumor. All 43 patients with pelvic wall recurrence developed progressive disease. CONCLUSION: The following patients are potentially curable: patients with a resectable, centrally located tumor who are candidates for pelvic exenteration, and patients with a small central recurrence for whom complete radiation therapy is feasible.

Genotoxicity studies on dietary diacylglycerol (DAG) oil.

Dietary diacylglycerol (DAG) oil is an edible oil enriched in DAG (more than 80%). A recent investigation indicated that DAG oil or its components may have beneficial effects on the prevention and management of obesity. We evaluated the genotoxic potential of DAG oil using standard genotoxicity tests. Bacterial reverse mutation assay (Ames test), the chromosomal aberration assay in cultured Chinese hamster lung cells (CHL/IU), and a bone marrow micronucleus assay in ICR CD mice were employed in the present study. In addition we have tested the possibility that genotoxic substances may be formed during cooking, heated DAG oil (HDG) was prepared by batch frying potato slices in the oil at 180 degrees C for 8 h/day for three consecutive days. Therefore, genotoxicity tests were also performed on HDG. Results obtained did not show any genotoxic effect on either unheated DAG oil (UDG) or HDG. We conclude that there are no safety concerns on the genotoxicity of DAG oil under the conditions for normal use.

Prognostic significance of positive peritoneal cytology in endometrial carcinoma confined to the uterus.

A retrospective analysis was performed to evaluate the prognostic significance of peritoneal cytology in patients with endometrial carcinoma limited to the uterus. A total of 280 patients with surgically staged endometrial carcinoma that was histologically confined to the uterus were examined clinicopathologically. The median length of follow-up was 62 (range, 12-135) months. All patients underwent hysterectomy and salpingo-oophorectomy with selective lymphadenectomy, and only three patients received adjuvant postoperative therapy. No preoperative adjuvant therapy was employed. In all, 48 patients (17%) had positive peritoneal cytology. The 5-year survival rate among patients with positive or negative peritoneal cytology was 91 or 95%, respectively, showing no significant difference (log-rank, P=0.42). The disease-free survival rate at 36 months was 90% among patients with positive cytology, compared with that of 94% among patients with negative cytology, and the difference was not significant (log-rank, P=0.52). Multivariate proportional hazards model revealed only histologic grade to be an independent prognostic factor of survival (P=0.0003, 95% CI 3.02 - 40.27) among the factors analysed (age, peritoneal cytology, and depth of myometrial invasion). Multivariate analysis revealed that histologic grade (P=0.02, 95% CI 1.21-9.92) was also the only independent prognostic factor of disease-free survival. We concluded that the presence of positive peritoneal cytology is not an independent prognostic factor in patients with endometrial carcinoma confined to the uterus, and adjuvant therapy does not appear to be beneficial in these patients.

Bone loss at the lumbar spine and the proximal femur in a rural Japanese community, 1990-2000: the Miyama study.

Bone mineral density (BMD) was measured over a ten year period in a cohort study in Miyama village, Wakayama Prefecture, Japan, to provide information on rate of bone loss in the mature and elderly population. Four hundred subjects were selected by sex and age decade from the full list of residents born in 1910-1949, and aged 40-79 years at the end of 1989, with 50 men and 50 women in each age decade. Baseline BMD of the lumbar spine and the proximal femur was measured using dual energy X-ray absorptiometry (DXA) in 1990 and again in 1993, 1997 and 2000. Annual rate of change in BMD (% per year) in the lumbar spine in men in their forties, fifties, sixties and seventies was 0.17, 0.55, 0.01 and -0.16, respectively, and in women, -0.87, -0.83, -0.48 and -0.48, respectively. Thus in men, BMD at the lumbar spine increased in all age strata but the oldest, when it decreased, whereas in women, it decreased in all age strata. On the other hand, BMD at the proximal femur decreased in both sexes in all age strata. Our results show that bone loss rates differ depending on the site involved, demonstrating that different strategies are needed for the prevention of bone loss in the spine and hip.Furthermore, we found evidence of differences in BMD for given age strata between birth cohorts. Data in 1990 and in 2000 showed significant improvements for men in their sixties and for women in their fifties, suggesting that future problems of osteoporosis might be less severe than has previously been predicted in Japan.

Bone mineral density in young women of the city of São Paulo, Brazil: correlation with both collagen type I alpha 1 gene polymorphism and clinical aspects.

Osteoporosis is a multifactorial disease with great impact on morbidity and mortality mainly in postmenopausal women. Although it is recognized that factors related to life-style and habits may influence bone mass formation leading to greater or lower bone mass, more than 85% of the variation in bone mineral density (BMD) is genetically determined. The collagen type I alpha 1 (COLIA1) gene is a possible risk factor for osteoporosis. We studied a population of 220 young women from the city of São Paulo, Brazil, with respect to BMD and its correlation with both COLIA1 genotype and clinical aspects. The distribution of COLIA1 genotype SS, Ss and ss in the population studied was 73.6, 24.1 and 2.3%, respectively. No association between these genotypes and femoral or lumbar spine BMD was detected. There was a positive association between lumbar spine BMD and weight (P<0.0001), height (P<0.0156), and body mass index (BMI) (P<0.0156), and a negative association with age at menarche (P<0.0026). There was also a positive association between femoral BMD and weight (P<0.0001), height (P<0.0001), and BMI (P<0.0001), and a negative correlation with family history for osteoporosis (P<0.041). There was no association between the presence of allele s and reduced BMD. We conclude that a family history of osteoporosis and age at menarche are factors that may influence bone mass in our population.

Bone mineral density in young women of the city of Säo Paulo, Brazil: correlation with both collagen type I alpha 1 gene polymorphism and clinical aspects

Osteoporosis is a multifactorial disease with great impact on morbidity and mortality mainly in postmenopausal women. Although it is recognized that factors related to life-style and habits may influence bone mass formation leading to greater or lower bone mass, more than 85 percent of the variation in bone mineral density (BMD) is genetically determined. The collagen type I alpha 1 (COLIA1) gene is a possible risk factor for osteoporosis. We studied a population of 220 young women from the city of Säo Paulo, Brazil, with respect to BMD and its correlation with both COLIA1 genotype and clinical aspects. The distribution of COLIA1 genotype SS, Ss and ss in the population studied was 73.6, 24.1 and 2.3 percent, respectively. No association between these genotypes and femoral or lumbar spine BMD was detected. There was a positive association between lumbar spine BMD and weight (P<0.0001), height (P<0.0156), and body mass index (BMI) (P<0.0156), and a negative association with age at menarche (P<0.0026). There was also a positive association between femoral BMD and weight (P<0.0001), height (P<0.0001), and BMI (P<0.0001), and a negative correlation with family history for osteoporosis (P<0.041). There was no association between the presence of allele s and reduced BMD. We conclude that a family history of osteoporosis and age at menarche are factors that may influence bone mass in our population

Immature glandular features in squamous cell carcinoma of the uterine cervix as an independent indicator of resistance to radiotherapy.

The aim of this study was to evaluate the significance of "immature glandular features" in cervical squamous cell carcinoma (SCC) as an indicator of tumor radioresistance. Pretreatment biopsied tissue specimens of cervical SCC from 100 patients who were uniformly treated with radiotherapy alone were classified into clinically radioresistant (cR) and radiosensitive (cS) groups. Seven histologic parameters comprising glassy cells, signet ring cells, squamous differentiation, recognizable gland, nuclear atypia, stromal response, and mitotic counts were examined. Glassy cells and signet ring cells were regarded as "immature glandular features". The correlation of these seven parameters with tumor response to radiotherapy and patient prognosis was analyzed by univariate and multivariate analyses. As objective indicators of glandular differentiation, alcian-blue staining and immunostaining of cytokeratins 7 and 20 were also performed. It was revealed that immature glandular features, absence of squamous differentiation, and low nuclear atypia were significant indicators of radioresistance of the tumor and of poorer patient prognosis. Combining those histological parameters, the present SCC cases were classified into 26 pathologically radioresistant (pR) and 74 radiosensitive (pS) groups. In the pR group, 54% (14 of 26) were clinically radioresistant, whereas 20% (15 of 74) of the pS group were clinically radioresistant (P = 0.002). The overall prognosis of the pR group was much poorer than that of the pS group (P < 0.0001). This correlation also held true in cases of identical stage and age. We could not show objectively glandular differentiation of "immature glandular features". Nonetheless, the identification of "immature glandular features" was effective in predicting the radiotherapy resistance of cervical SCC and poorer patient prognosis.