Toyomi Satoh

Extended Clavien-Dindo classification of surgical complications: Japan Clinical Oncology Group postoperative complications criteria.

PurposePrior to publication of the Clavien-Dindo classification in 2004, there were no grading definitions for surgical complications in either clinical practice or surgical trials. This report establishes supplementary criteria for this classification to standardize the evaluation of postoperative complications in clinical trials.MethodsThe Japan Clinical Oncology Group (JCOG) commissioned a committee. Members from nine surgical study groups (gastric, esophageal, colorectal, lung, breast, gynecologic, urologic, bone and soft tissue, and brain) specified postoperative complications experienced commonly in their fields and defined more detailed grading criteria for each complication in accordance with the general grading rules of the Clavien-Dindo classification.ResultsWe listed 72 surgical complications experienced commonly in surgical trials, focusing on 17 gastroenterologic complications, 13 infectious complications, six thoracic complications, and several other complications. The grading criteria were defined simply and were optimized for surgical complications.ConclusionsThe JCOG postoperative complications criteria (JCOG PC criteria) aim to standardize the terms used to define adverse events (AEs) and provide detailed grading guidelines based on the Clavien-Dindo classification. We believe that the JCOG PC criteria will allow for more precise comparisons of the frequency of postoperative complications among trials across many different surgical fields.

Outcomes of fertility-sparing surgery for stage I epithelial ovarian cancer: a proposal for patient selection.

PURPOSE The objective of this study was to assess clinical outcomes and fertility in patients treated conservatively for unilateral stage I invasive epithelial ovarian cancer (EOC). PATIENTS AND METHODS A multi-institutional retrospective investigation was undertaken to identify patients with unilateral stage I EOC treated with fertility-sparing surgery. Favorable histology was defined as grade 1 or grade 2 adenocarcinoma, excluding clear cell histology. RESULTS A total of 211 patients (stage IA, n = 126; stage IC, n = 85) were identified from 30 institutions. Median duration of follow-up was 78 months. Five-year overall survival and recurrence-free survival were 100% [corrected] and 97.8% for stage IA and favorable histology (n = 108), 100% and 100% for stage IA and clear cell histology (n = 15), 100% and 33.3% for stage IA and grade 3 (n = 3), 96.9% and 92.1% for stage IC and favorable histology (n = 67), 93.3% and 66.0% for stage IC and clear cell histology (n = 15), and 66.7% and 66.7% for stage IC and grade 3 (n = 3). Forty-five (53.6%) of 84 patients who were nulliparous at fertility-sparing surgery and married at the time of investigation gave birth to 56 healthy children. CONCLUSION Our data confirm that fertility-sparing surgery is a safe treatment for stage IA patients with favorable histology and suggest that stage IA patients with clear cell histology and stage IC patients with favorable histology can be candidates for fertility-sparing surgery followed by adjuvant chemotherapy.

Tissue factor expression as a possible determinant of thromboembolism in ovarian cancer

Ovarian cancer, and clear cell carcinoma in particular, reportedly increases the risk of venous thromboembolism (VTE). However, the mechanisms remain unclear. Tissue factor (TF) supposedly represents a major factor in the procoagulant activities of cancer cells. The present study examined the involvement of TF expression in VTE for patients with ovarian cancer. Subjects comprised 32 consecutive patients (mean age 49.8 years) with histologically confirmed ovarian cancer. Presence of VTE was examined using a combination of clinical features, D-dimer levels and venous ultrasonography. Immunohistochemical analysis was used to evaluate TF expression into 4 degrees. Venous thromboembolism was identified in 10 of the 32 patients (31%), including five of the 11 patients with clear cell carcinoma. Tissue factor expression was detected in cancer tissues from 24 patients and displayed significant correlations with VTE development (P=0.0003), D-dimer concentration (P=0.003) and clear cell carcinoma (P<0.05). Multivariate analysis identified TF expression as an independent predictive factor of VTE development (P<0.05). Tissue factor (TF) expression is a possible determinant of VTE development in ovarian cancer. In particular, clear cell carcinoma may produce excessive levels of TF and is more likely to develop VTE.

Human papillomavirus infections among Japanese women: age-related prevalence and type-specific risk for cervical cancer

To obtain baseline data for human papillomavirus (HPV) screening and vaccination in Japan, we analyzed HPV DNA data from 2282 Japanese women (1517 normal cytology, 318 cervical intraepithelial neoplasia [CIN] grade 1, 307 CIN2–3, and 140 invasive cervical cancer [ICC]) that visited the University of Tsukuba Hospital or Ibaraki Seinan Medical Center Hospital for screening or treatment of cervical diseases between 1999 and 2007. An L1‐based PCR method was used for individual HPV genotyping. The most common HPV types in ICC were, in order of decreasing prevalence, HPV16 (40.5%), HPV18 (24.4%), HPV52 (8.4%), HPV58 (3.1%), and HPV33 (3.1%). Based on the comparison of HPV type distributions between normal cytology and CIN2–3 and ICC, estimated risk of disease progression varied considerably by genotype: HPV16, HPV18, HPV31, HPV33, HPV35, HPV52, and HPV58 (prevalence ratio, 1.92; 95% confidence interval 1.58–2.34); other oncogenic types (0.31, 95% confidence interval 0.19–0.50); and non‐oncogenic types (0.09, 95% confidence interval 0.03–0.43). HPV16 and/or HPV18, including coinfections with other types, contributed to 67.1% of ICC and 36.2% of CIN2–3 among Japanese women. More importantly, the overall prevalence of HPV16 and/or HPV18 varied greatly according to the womens age: highest in women aged 20–29 years (ICC, 90.0%; CIN2–3, 53.9%), decreasing with age thereafter, and lowest in women aged 60 years or older (ICC, 56.3%; CIN2–3, 25.0%). In conclusion, type‐specific HPV testing may help identify Japanese women at high risk of progression to CIN2–3 and cancer. In Japan, current HPV vaccines are estimated to provide approximately 70% protection against ICC and may be more useful in reducing the incidence of cervical cancer and precancer in young women of reproductive age. (Cancer Sci 2009; 100: 1312–1316)

High incidence of silent venous thromboembolism before treatment in ovarian cancer

Venous thromboembolism (VTE) such as deep-vein thrombosis (DVT) and pulmonary thromboembolism (PTE) often occurs after surgery and rarely occurs even before surgery in patients with ovarian cancer. It is well known that levels of plasma D-dimer (DD) before treatment in most ovarian cancer patients are increased. This study therefore examined whether increased levels of DD are associated with presence of VTE before treatment of ovarian cancer. Between November 2004 and March 2007, DD levels prior to initial treatment were measured in 72 consecutive patients with presumed epithelial ovarian cancer (final diagnosis: epithelial ovarian cancer, n=60; and epithelial ovarian borderline malignancy, n=12). Venous ultrasound imaging (VUI) of the lower extremity was conducted for all patients except for two patients in whom DVT was detected by pelvic computed tomography (CT). When DVT was found, pulmonary scintigraphy was subsequently performed to ascertain presence of PTE. D-dimer levels were above the cut-off value (0.5 μg ml−1) in 65 of 72 patients (90.2%). Venous ultrasound imaging or CT revealed DVT in 18 of 72 patients (25.0%) and pulmonary scintigraphy found PTE in 8 patients (11.1%). All patients with VTE were asymptomatic when VTE was found. D-dimer levels were associated with incidence of VTE (0–1.4 μg ml−1; 0 of 26 (0%), 1.5–7.4 μg ml−1; 9 of 30 (30%) and ⩾7.5 μg ml−1; 9 of 16 (56.3%), P for trend=0.0003). However, even if 1.5 μg ml−1 was used as a cut-off value, this had low specificity and positive predictive value (47.2, 38.3%), though it had high sensitivity and negative predictive value (100, 100%). Therefore, ovarian cancer patients with DD level ⩾1.5 μg ml−1 should be examined using VUI to detect silent DVT. Patients with VTE underwent preventive managements including anticoagulant therapy before initial treatment, chemotherapy or surgery, and after surgery. There was no clinical onset of postoperative VTE in all 72 patients. Measurement of DD levels and subsequent ultrasonography revealed that silent or subclinical VTE frequently occurs before surgery in ovarian cancer. The usefulness of preoperative assessment of VTE needs further confirmation in randomised controlled trials.

Paclitaxel Plus Carboplatin Versus Paclitaxel Plus Cisplatin in Metastatic or Recurrent Cervical Cancer: The Open-Label Randomized Phase III Trial JCOG0505

PURPOSE In metastatic or recurrent cervical cancer, cisplatin-based chemotherapy is standard. The JCOG0505 randomized phase III trial evaluated the clinical benefits of carboplatin-based regimen. PATIENTS AND METHODS Eligible patients had metastatic or recurrent cervical cancer and had ≤ one platinum-containing treatment and no prior taxane. Patients were randomly assigned either to conventional paclitaxel plus cisplatin (TP; paclitaxel 135 mg/m(2) over 24 hours on day 1 and cisplatin 50 mg/m(2) on day 2, repeated every 3 weeks) or paclitaxel plus carboplatin (TC; paclitaxel 175 mg/m(2) over 3 hours and carboplatin area under curve 5 mg/mL/min on day 1, repeated every 3 weeks). Primary end point was overall survival (OS). Planned sample size was 250 patients to confirm the noninferiority of TC versus TP with the threshold hazard ratio (HR) of 1.29. RESULTS Between February 2006 and November 2009, 253 patients were enrolled. The HR of OS was 0.994 (90% CI, 0.79 to 1.25; noninferiority P = .032 by stratified Cox regression). Median OS was 18.3 months with TP versus 17.5 months with TC. Among patients who had not received prior cisplatin, OS was shorter with TC (13.0 v 23.2 months; HR, 1.571; 95% CI, 1.06 to 2.32). One treatment-related death occurred with TC. Proportion of nonhospitalization periods was significantly longer with TC (P < .001). CONCLUSION TC was noninferior to TP and should be a standard treatment option for metastatic or recurrent cervical cancer. However, cisplatin is still the key drug for patients who have not received platinum agents.

Do we need a different strategy for HPV screening and vaccination in East Asia

Dear Sir, Recently, pooled IARC studies and meta-analyses have showed that at least 13 human papillomavirus (HPV) types, including types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68, are commonly associated with invasive cervical cancer (ICC). Based on HPV type prevalence data from these studies, current HPV vaccines against only HPV16/18 are considered to prevent a majority (>70%) of cervical cancer worldwide. However, HPV data in East Asia have not been fully evaluated in previous pooled and meta-analyses. The present study thus focused on HPV type prevalence in Japan. We performed a meta-analysis of published data to obtain the representative results, and investigated HPV type prevalence and type-specific risks for cervical carcinogenesis in Japan. Furthermore, obtained data were compared with those in China, Korea and other regions. Source articles presenting HPV prevalence data among Japanese women were identified from National Library of Medicine (PubMed). For the meta-analysis, the following inclusion criteria were considered: (i) Studies were published between 1995 and 2005. (ii) Studies had to use PCR-based assays to identify at least 16 strains of HPV6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59 and 68. (iii) Studies had to include at least 20 HPV-positive women with squamous intraepithelial lesion (SIL), cervical intraepithelial neoplasia (CIN) or ICC. When data or data subsets from an identical study had been published in more than one article, only the publication with the largest sample size was included. However, data from different studies conducted by the same study group were included. Overall, a total of 14 Japanese studies were identified for the present study. For some articles, additional typespecific data were obtained from the authors. HPV type prevalence data were collected separately for squamous cell carcinoma (SCC) and for adenoand adenosquamous carcinoma (ADC). Where histological data were not reported, ICC cases were classified as unspecified carcinoma (UC). On the basis of the pooled analysis of IARC studies, HPV types were separated into 2 groups. High-risk HPVs considered as carcinogenic or probably carcinogenic included HPV16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 73 and 82; all other HPV types were classified as low-risk types. To evaluate HPV genotype-specific risks for progression from LSIL (low grade SIL) to HSIL (high grade SIL) or more, prevalence ratios [(HSIL 1 ICC):LSIL] and 95% confidence intervals were calculated after adjusting for study area, specimen used for HPV DNA testing, and PCR primers. Logistic regression model was used for statistical adjustment, and the analysis was carried out using JMP 6.0J statistics package (SAS Institute, Cary, NC, USA). The p-values obtained in all tests were considered significant at <0.05. This analysis included 7,262 Japanese women (4,941 normal cytology, 475 LSIL, 720 HSIL and 1,126 ICC) from 14 Japanese HPV studies. Consensus primers for the L1, E6/E7 or E7LCR region or GP5/GP6 primers were employed in these studies. In this meta-analysis, HPV prevalence was 10.2% in women with normal cytology, 79.4% in LSIL, 89.0% in HSIL and 87.4% in ICC. HPV positivity was significantly lower in ADC (69.8%) than in SCC (90.7%). Since overall and typespecific HPV prevalence in UC was very similar to that in SCC, UC cases were combined with SCC cases for comparison of HPV type-specific prevalence by histological type. HPV type distributions by cervical disease were summarized in Table I. In ICC, the most common HPV types were, in order of decreasing prevalence, HPV16 (44.8%), 18 (14.0%), 52 (7.0%), 58 (6.7%), 33 (6.3%), 31 (5.1%), 35 (2.3%), 51 (1.0%) and 56 (0.9%). HPV16 was the predominant type (49.2%) in SCC, although HPV18 was the most prevalent (58.2%) in ADC. On the basis of the comparison of HPV type distributions between LSIL and HSIL/ICC, the type-specific risks for progression from LSIL to HSIL/ICC were analyzed (Table I). HPV16, 18 and 33 conferred a significantly higher risk. Seven types of HPV16/18/31/33/ 35/52/58 (the prevalence ratio; 1.86, 95% CI 1.63–2.15) presented a higher risk of progression than the other high-risk types (0.24, 95% CI 0.17–0.33) and low-risk types (0.18, 95% CI 0.09–0.37). Among Japanese women with ICC, HPV16 and 18 were the most common types, which was consistent with the results from other regions. A pooled analysis demonstrated that HPV16 and 18 were associated with 73.5% of ICC in Southeast Asia, 76.9% in Northern Africa and 71.5% in Europe/ North America, and that HPV52 and 58 were detected in 6.1% of ICC cases in Southeast Asia, 1.5% in Northern Africa and 1.1% in Europe/North America. In Japan, however, HPV16 and 18 were less frequently identified (58.8%), and HPV52 and 58 were more common (13.7%). In China, although HPV16 and 18 were predominant (87.1% of all ICC cases from 5 areas), a multicenter study showed that HPV52 and 58 were locally common in Hong Kong (11.8%) and Guangzhou (southern China, 8.3%). Other small studies also reported

Silent venous thromboembolism before treatment in endometrial cancer and the risk factors

Venous thromboembolism (VTE) often occurs after surgery and can even occur before surgery in patients with gynaecological malignancies. We investigated the incidence of VTE before treatment of endometrial cancer and associated risk factors. Plasma D-dimer (DD) levels before initial treatment were examined in 171 consecutive patients with endometrial cancer. Venous ultrasound imaging (VUI) of the lower extremities was performed in patients with DD ⩾1.5 μg ml−1, as the negative predictive value of DD for VTE is extremely high. For patients with deep vein thrombosis (DVT), pulmonary scintigraphy was performed to ascertain the presence of pulmonary thromboembolism (PTE). Risk factors for VTE were analysed using univariate and multivariate analyses for 171 patients. Of these, 37 patients (21.6%) showed DD ⩾1.5 μg ml−1, 17 (9.9%) displayed DVT by VUI and 8 (4.7%) showed PTE on pulmonary scintigraphy. All patients with VTE were asymptomatic. Univariate analysis for various risk factors revealed older age, non-endometrioid histology and several variables of advanced disease as significantly associated with VTE before treatment. Obesity, smoking and diabetes mellitus were not risk factors. Multivariate analysis confirmed extrauterine spread and non-endometrioid histology as independently and significantly associated with risk of VTE. These data suggest that silent or subclinical VTE occurs before treatment in at least around 10% of patients with endometrial cancer. Risk factors for VTE before treatment might not be identical to those after starting treatment.

PIK3CA overexpression is a possible prognostic factor for favorable survival in ovarian clear cell carcinoma

Dysregulated signaling on the PI3-kinase/Akt cascade is reportedly associated with early stage and favorable prognosis in some kinds of malignancies including breast cancer, endometrial cancer, and colorectal cancer. PIK3CA, a catalytic subunit of PI3-kinase, is known to be activated in ovarian clear cell carcinoma (CCC), which is categorized as type I ovarian cancer. The aim of this study was to investigate the clinical significance of PIK3CA overexpression in the disease. We performed immunohistochemical analyses of PIK3CA, PTEN, p-Akt, p27 and p53 expressions in primary ovarian clear cell carcinomas from 62 Japanese patients. Genetic analyses of PIK3CA mutation and amplification were further conducted. PIK3CA was overexpressed in 45 tumors (73%), PTEN expression was negative in 3 (5%), and p53 was positive in 8 (13%). Overexpressed PIK3CA was found to be associated with p-Akt overexpression (P = .007). PIK3CA overexpression tended to be observed in more of stage I disease (73% versus 47%, P = .07) and was associated with absence of residual tumor at the initial surgery (96% versus 71%, P = .01). Furthermore, survival analyses revealed that PIK3CA overexpression correlated with improved overall survival (P = .03). Subsequent genetic analyses demonstrated that PIK3CA overexpression correlated with the presence of mutation or amplification of the PIK3CA gene in tumors (P = .009). Our observations suggest that the subgroup of ovarian clear cell carcinomas harboring activated PIK3CA seems to have better prognosis possibly due to more indolent biological property compared to tumors without PIK3CA activation. PIK3CA may serve as a biomarker for good prognosis and a possible therapeutic target in this lethal subtype of ovarian cancer.

Interleukin-10 −1082 Gene Polymorphism and Susceptibility to Cervical Cancer Among Japanese Women

Polymorphisms in cytokine genes can influence immune responses to human papillomavirus infection, possibly modifying risks of cervical cancer. Using an amplification refractory mutation system-polymerase chain reaction method, we analyzed a single nucleotide polymorphism (A/G) at position -1082 in interleukin-10 promoter region in 440 Japanese women: 173 women with normal cytology, 163 women with cervical intraepithelial neoplasia and 104 women with invasive cervical cancer. The carrier frequency of interleukin-10 -1082 G alleles associated with higher interleukin-10 production increased with disease severity: 9.8% for normal cytology; 19.6% for cervical intraepithelial neoplasia; 29.8% for invasive cervical cancer (P for trend < 0.001). Among cytologically normal women, human papillomavirus infections were more common in those who were positive for an interleukin-10 -1082 G allele (P = 0.04). In conclusion, our data suggest that interleukin-10 -1082 gene polymorphism may serve as a marker of genetic susceptibility to cervical cancer among Japanese women.