Kaneyuki Kubushiro

Phase II study of neoadjuvant chemotherapy with irinotecan hydrochloride and nedaplatin followed by radical hysterectomy for bulky stage Ib2 to IIb, cervical squamous cell carcinoma: Japanese Gynecologic Oncology Group study (JGOG 1065).

The efficacy and adverse events of neoadjuvant chemotherapy with irinotecan hydrochloride and nedaplatin were evaluated in patients with bulky stage Ib2 to IIb cervical squamous cell carcinoma. Eligibility included patients who received irinotecan (60 mg/m2) on days 1 and 8 and nedaplatin (80 mg/m2) on day 1 of a 21-day cycle. After 1-3 courses of chemotherapy, radical hysterectomy was performed. Sixty-eight patients were enrolled. Sixty-six were included in the full analysis set. Their median age was 47 years (range 22-71), the FIGO stage was Ib2 in 18 patients, IIa in 10, and IIb in 38. Radical hysterectomy was performed after NAC in 63 patients (95.5%). The number of administered courses of NAC was 1 in 13 patients, 2 in 43, and 3 in 10. The response rate, the primary endpoint of this study, was 75.8% (CR in 2 patients, PR in 48, SD in 12, PD in 0, and NE in 4). The mean number of treatment courses required for a response was 1.42 (1 course in 30 patients, 2 courses in 19, and 3 courses in 1). The incidences of grade 3 or 4 hematological toxicities were: neutropenia 72.2%, leukopenia 16.7%, anemia 13.6%, thrombocytopenia 7.6%, febrile neutropenia 1.5%, and elevations of alanine aminotransferase and aspartate aminotransferase 1.5%. Grade 3 or 4 non-hematologic toxicities were as follows: diarrhea 6.1%, nausea 3%, anorexia 1.5%, vomiting 1.5%, fever 1.5%, allergic reactions 1.5%, ileus 1.5% and vesicovaginal fistula 1.5%. Neoadjuvant chemotherapy with irinotecan and nedaplatin was an effective and well-tolerated treatment for patients with bulky stage Ib2 to IIb squamous cell carcinoma of the uterine cervix.

Analytical performance of newly developed multiplex human papillomavirus genotyping assay using Luminex xMAP™ technology (Mebgen™ HPV Kit).

Regional differences in human papillomavirus (HPV) genotypes and the presence of mixed HPV infections may affect adversely the efficacy of the HPV vaccine. Therefore, a simple and high-throughput HPV genotyping system is required. Recently, a novel HPV genotyping kit (the Mebgen™ HPV kit) was developed. This kit uses multiplex PCR and Luminex xMAP™ technology to detect 13 types of high-risk HPVs and an internal control in a 96-well format. In the present study, the analytical performance of the kit was examined using HPV plasmid DNA. All 13 types of HPVs were detected with a minimum detection sensitivity of 250 copies/test, and highly specific signals were observed. HPV 16 plasmid was detected in samples containing mixtures with other HPV-type plasmids in ratios ranging from 1:1 to 1:1000. No cross reactivity was observed with DNA from 27 types of other infectious microbes. A clinical evaluation was carried out using cervical samples from 356 patients with persistent abnormal smears diagnosed at mass public health screenings for cervical cancer. The samples were preserved in Tacas™ medium until analysis. HPV was detected in 162 (45.5%) samples including 110 (67.9%) with single infections and 52 (32.1%) with multiple infections. The type distribution of the 13 high-risk HPVs was as follows: 28.4% HPV 16, 11.7% HPV 18, 6.8% HPV 31, 3.1% HPV 33, 3.7% HPV 35, 9.3% HPV 39, 1.9% HPV 45, 8.6% HPV 51, 37.0% HPV 52, 9.3% HPV 56, 16.7% HPV 58, 3.7% HPV 59, and 1.9% HPV 68. To evaluate sample stability over time, changes in the detection of HPV DNA derived from HeLa and SiHa cells were measured in 3 types of liquid-based cytology media. HPV DNA was detected in Tacas and Thinprep™ samples after storage at 4°C or 30°C for 4 weeks and within 1 week of collection in Surepath™ samples. These results suggest that this newly developed HPV genotyping kit is suitable for use in both clinical applications and large-scale epidemiological studies.

p16INK4a immunohistochemistry is a promising biomarker to predict the outcome of low grade cervical intraepithelial neoplasia: comparison study with HPV genotyping

Objective In cervical intraepithelial neoplasia (CIN), p16INK4a immunohistochemistry has been reported to be a useful diagnostic biomarker. However, limited information is available about the association between the p16INK4a immunohistochemistry and the outcomes of CIN. Here, we report p16INK4a immunohistochemistry as an effective biomarker to predict the outcomes of CIN. Methods p16INK4a immunohistochemistry was performed in patients with CIN from January 2000 to August 2009. Among these patients, we have performed a retrospective analysis of the medical records to evaluate the outcome of CIN 1-2 and performed statistical analysis to determine the correlation between p16INK4a expression and the outcomes. We also performed HPV genotyping and analyzed the relation between the infecting human papillomavirus (HPV) genotype and the outcomes. Results A total of 244 patients, including 82 with CIN 1, 60 with CIN 2, and 102 with CIN 3, were examined. The rate of p16INK4a overexpression increased with increasing CIN grade, 20.7% for CIN 1, 80.0% for CIN 2, and 89.2% for CIN 3, with significant differences between CIN 1 and CIN 2-3 group. In the 131 CIN 1-2 patients, the progression rate was significantly higher for the patients showing p16INK4a overexpression than for those not showing p16INK4a overexpression (p=0.005); the regression rate was also found to be significantly lower for the patients showing p16INK4a overexpression (p=0.003). High-risk HPV genotypes were detected in 73 patients (73.7%). Both progression and regression rates were not significantly different between the high-risk HPV-positive and HPV-negative groups (p=0.401 and p=0.381, respectively). Conclusion p16INK4a overexpression was correlated with the outcome of CIN 1-2, and p16INK4a is considered to be a superior biomarker for predicting the outcome of CIN 1-2 compared with HPV genotyping.

Japan Society of Gynecologic Oncology guidelines 2013 for the treatment of uterine body neoplasms

The third version of the Japan Society of Gynecologic Oncology guidelines for the treatment of uterine body neoplasms was published in 2013. The guidelines comprise nine chapters and nine algorithms. Each chapter includes a clinical question, recommendations, background, objectives, explanations, and references. This revision was intended to collect up-to-date international evidence. The highlights of this revision are to (1) newly specify costs and conflicts of interest; (2) describe the clinical significance of pelvic lymph node dissection and para-aortic lymphadenectomy, including variant histologic types; (3) describe more clearly the indications for laparoscopic surgery as the standard treatment; (4) provide guidelines for post-treatment hormone replacement therapy; (5) clearly differentiate treatment of advanced or recurrent cancer between the initial treatment and the treatment carried out after the primary operation; (6) collectively describe fertility-sparing therapy for both atypical endometrial hyperplasia and endometrioid adenocarcinoma (corresponding to G1) and newly describe relapse therapy after fertility-preserving treatment; and (7) newly describe the treatment of trophoblastic disease. Overall, the objective of these guidelines is to clearly delineate the standard of care for uterine body neoplasms in Japan with the goal of ensuring a high standard of care for all Japanese women diagnosed with uterine body neoplasms.

Performance of p16INK4a/Ki-67 immunocytochemistry for identifying CIN2+ in atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesion specimens: a Japanese Gynecologic Oncology Group study

Backgroundp16INK4a immunohistochemistry has revealed a high rate of positivity in cervical intraepithelial neoplasia grade 2 (CIN2) and more severe conditions (CIN2+). The Lower Anogenital Squamous Terminology Standardization project proposed p16INK4a immunohistochemistry as an ancillary test for CIN. Immunocytochemistry involving dual staining for p16INK4a and Ki-67 in the triage of atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesions (LSIL) is reported to be useful in the identification of CIN2+. However, it is unclear whether p16INK4a/Ki-67 immunocytochemistry is of practical relevance for the triage of ASCUS and LSIL in the Japanese screening system.MethodsFrom 427 women fulfilling the eligibility criteria, 188 ASCUS and 239 LSIL specimens were analyzed. The accuracy of p16INK4a/Ki-67 immunocytochemistry and genotyping of high-risk human papillomaviruses (HPVs) in detecting CIN2+ were compared.Resultsp16INK4a/Ki-67 immunocytochemistry was positive in 33.5xa0% (63/188) of ASCUS, and 36.8xa0% (88/239) of LSIL specimens. The sensitivity and specificity of p16INK4a/Ki-67 immunocytochemistry was 87.3xa0% (95xa0% confidence interval 78.0–93.8xa0%) and 76.4xa0% (71.6–80.8xa0%), respectively. The positive and negative predictive values were 45.7xa0% (37.6–54.0xa0%) and 96.4xa0% (93.4–98.3xa0%), respectively; positive and negative likelihood ratios were 3.71 and 0.17, respectively. Using the McNemar test, p16INK4a/Ki-67 immunocytochemistry showed equivalent sensitivity but higher specificity than the HPV genotyping testConclusionsCompared with high-risk HPV genotyping, p16INK4a/Ki-67 immunocytochemistry was a more accurate triage test for identifying CIN2+ in ASCUS and LSIL specimens.

Feasibility study on the effectiveness of Goreisan-based Kampo therapy for lower abdominal lymphedema after retroperitoneal lymphadenectomy via extraperitoneal approach.

To evaluate the efficacy and safety of Kampo therapy based on Goreisan for lower abdominal lymphedema after surgical treatment of endometrial cancer or cervical cancer.

Supraclavicular lymph node metastasis as the initial presentation of primary fallopian tube carcinoma

Supraclavicular lymph node metastasis is a rare presentation of primary fallopian tube carcinoma. A 76-year-old woman presented with an enlarged supraclavicular lymph node. A biopsy was performed, and its findings confirmed metastatic adenocarcinoma. Subsequent exploratory laparotomy revealed right fallopian tube carcinoma as the primary lesion; consequently, right salpingo-oophorectomy was performed. After adjuvant chemotherapy, she underwent a laparotomy with total abdominal hysterectomy, left salpingo-oophorectomy, pelvic and para-aortic lymph node sampling, and omentectomy. Supraclavicular lymph node metastasis was thought to be, although rarely, the first manifestation of primary fallopian tube carcinoma (PFTC). When supraclavicular lymph node metastasis of an unknown origin is encountered, the possibility of PFTC should be considered.

Comparison of conventional and liquid-based cytology, and human papillomavirus testing using SurePath preparation in Japan.

We compared the detection rate of cervical neoplasias between a liquid-based cytology (LBC) method using SurePath and the conventional method. We also studied the feasibility of human papillomavirus (HPV) typing by linear array assay. Cytological specimens from 1551 Japanese women were prepared using the conventional and SurePath methods; the cytological and histological results from biopsy samples were compared. HPV typing using an HPV linear array assay was carried out on residual specimens using the SurePath method. The cytodiagnostic results showed a concordance rate of 85.3% (κ = 0.46) between the two methods. The sensitivity of lesions histopathologically diagnosed as CIN1 or above was not significantly different between the two methods (P = 0.575–1.000). The receiver operating characteristic curve analysis of the detectability in CIN2 or above revealed no significant difference between the two methods (P = 0.096). Among the 44 patients who underwent HPV typing using a linear array assay, 33 samples were eligible for HPV testing and were stored at ambient temperature. In conclusion, the SurePath and conventional methods have equivalent abilities for detecting cervical lesions. After preparation for cytological diagnosis, use of the remaining cells from the SurePath specimens to perform HPV typing using the linear array method could be feasible.

Laparoscopically Resected Uterine Adenomatoid Tumor with Coexisting Endometriosis: Case Report

Adenomatoid tumors are rare benign mesothelial tumors of the genital tract, and only a few cases of uterine adenomatoid tumors treated at laparoscopic surgery have been reported. Herein is reported the case of a laparoscopically resected uterine adenomatoid tumor with coexisting endometriosis. A 34-year-old nulliparous woman with suspected uterine fibroma and endometrial cysts underwent laparoscopic surgery in which both the uterine tumor and the endometrial cysts were enucleated. Enucleation of the uterine tumor was difficult, and, therefore, the border between the tumor and normal myometrium was divided using a harmonic scalpel for tumor resection. Microscopic examination of the tumor showed irregularly proliferating smooth muscle cells and many round hiatuses lined by epithelial-like cells. These epithelial-like cells were immunohistochemically positive for mesothelin and podoplanin, and negative for CD34, which suggests that the tumor was an adenomatoid tumor. This may be the fourth reported case of an adenomatoid tumor resected using the laparoscopic approach.

Newly developed liquid-based cytology. TACAS™: cytological appearance and HPV testing using liquid-based sample

Cell profiles determined by the thin-layer advanced cytology assay system (TACAS™), a liquid-based cytology technique newly developed in Japan, were analyzed in this study. Hybrid capture 2 (HC-2) was also performed using the liquid-based samples prepared by TACAS to ascertain its ability to detect human papillomavirus (HPV). Cell collection samples from uterine cervix were obtained from 359 patients and examined cytologically. A HC-2 assay for HPV was carried out in the cell specimens. All specimens were found to show background factors such as leukocytes. After excluding the 5 unsatisfactory cases from the total 354 cases, 82 cases (23.2%) were positive and 272 cases (76.8%) were negative for HPV. Cell specimens from 30 HPV-positive cases and 166 HPV-negative cases were subjected to 4xa0weeks of preservation at room temperature. Then, when subsequently re-assayed, 28 cases (93.3%) in the former group were found to be HPV positive and 164 cases (98.8%) in the latter group were found to be HPV negative. These results supported the excellent reproducibility of TACAS for HPV testing. A reasonable inference from the foregoing analysis is that TACAS may be distinguished from other liquid-based cytological approaches, such as ThinPrep and SurePath, in that it can retain the cell backgrounds. Furthermore, this study raises the possibility that cell specimens prepared using TACAS could be preserved for at least 4xa0weeks prior to carrying out a HC-2 assay for HPV.