A first-in-human phase I study of TAS-117, an allosteric AKT inhibitor, in patients with advanced solid tumors.

PURPOSE: TAS-117 is a highly potent and selective, oral, allosteric pan-AKT inhibitor under development for advanced/metastatic solid tumors. The safety, clinical pharmacology, pharmacogenomics and efficacy were investigated. METHODS: This phase I, open-label, non-randomized, dose-escalating, first-in-human study enrolled patients with advanced/metastatic solid tumors and comprised three phases (dose escalation phase [DEP], regimen modification phase [RMP], and safety assessment phase [SAP]). The SAP dose and regimen were determined in the DEP and RMP. Once-daily and intermittent dosing (4 days on/3 days off, 21-day cycles) were investigated. The primary endpoints were dose-limiting toxicities (DLTs) in Cycle 1 of the DEP and RMP and incidences of adverse events (AEs) and adverse drug reactions (ADRs) in the SAP. Secondary endpoints included pharmacokinetics, pharmacodynamics, pharmacogenomics, and antitumor activity. RESULTS: Of 66 enrolled patients, 65 received TAS-117 (DEP, n = 12; RMP, n = 10; SAP, n = 43). No DLTs were reported with 24-mg/day intermittent dosing, which was selected as a recommended dose in SAP. In the SAP, 98.5% of patients experienced both AEs and ADRs (grade ≥ 3, 67.7% and 60.0%, respectively). In the dose range tested (8 to 32 mg/day), TAS-117 pharmacokinetics were dose proportional, and pharmacodynamic analysis showed a reduction of phosphorylated PRAS40, a direct substrate of AKT. Four patients in the SAP had confirmed partial response. CONCLUSION: Oral doses of TAS-117 once daily up to 16 mg/day and intermittent dosing of 24 mg/day were well tolerated. TAS-117 pharmacokinetics were dose proportional at the doses evaluated. Antitumor activity may occur through AKT inhibition. TRIAL REGISTRATION: jRCT2080222728 (January 29, 2015).

Human papillomavirus vaccine impact on invasive cervical cancer in Japan: Preliminary results from cancer statistics and the MINT study.

The first prophylactic vaccine against human papillomavirus (HPV) 16 and HPV18 was licensed in Japan in 2009. HPV vaccine effectiveness against high-grade cervical lesions has been demonstrated among young Japanese women, but evidence of its effects on invasive cervical cancer (ICC) is lacking. Using data from two different cancer registries, we compared recent trends of new ICC cases by age group using Poisson regression analysis. We also analyzed time trends in HPV16/18 prevalence among 1414 Japanese women aged <40 years newly diagnosed with ICC in the past decade. Based on the population-based cancer registry, the incidence of ICC among young women aged 20-29 years showed a significant decline from 3.6 to 2.8 per 100 000 women-years during 2016-2019, but no similar decline was observed for older age groups (p < 0.01). Similarly, using data from the gynecological cancer registry of the Japan Society of Obstetrics and Gynecology, the annual number of ICCs among women aged 20-29 years also decreased from 256 cases to 135 cases during 2011-2020 (p < 0.0001). Furthermore, a declining trend in HPV16/18 prevalence in ICC was observed only among women aged 20-29 years during 2017-2022 (90.5%-64.7%, p = 0.05; Cochran-Armitage trend test). This is the first report to suggest population-level effects of HPV vaccination on ICC in Japan. Although the declining trend in HPV16/18 prevalence among young women with ICC supports a causal linkage between vaccination and results from cancer registries, further studies are warranted to confirm that our findings are attributable to vaccination.

Clinical characteristics and prognostic factors of endometrial stromal sarcoma and undifferentiated uterine sarcoma confirmed by central pathologic review: A multi-institutional retrospective study from the Japanese Clinical Oncology Group.

OBJECTIVES: Low-grade and high-grade endometrial stromal sarcomas (LGESS and HGESS) and undifferentiated uterine sarcomas (UUS) are rare tumors whose pathological classification and staging system have changed recently. These tumors are reported to contain fusion genes. We aimed to clarify the genetic background, clinical features, prognostic factors, and optimal therapy of these tumors using a new classification and staging system. METHODS: We analyzed the clinical features and prognostic information of 72 patients with LGESS, 25 with HGESS, and 16 with UUS using central pathological review. Estrogen and progesterone receptors (PgRs) were examined by immunohistochemistry. JAZF1-SUZ12 and YWHAE-NUTM2A/B gene fusions were tested using real-time polymerase chain reaction. RESULTS: The 5-year overall survival (OS) rates of LGESS, HGESS, and UUS were 94%, 53%, and 25%, respectively. In LGESS, stage IV, incomplete surgery, and absence of PgR were associated with poor OS. The presence of JAZF1-SUZ12 fusion gene was not associated with OS. In HGESS, the relationship between stage and prognosis was unclear. None of the 3 patients with YWHAE-NUTM2A/B fusion gene died during follow-up. Adjuvant chemotherapy was associated with a favorable OS. Incomplete resection of UUS was associated with poor OS; however, residual tumors frequently occurred. Although most patients underwent adjuvant chemotherapy, their prognosis was extremely poor even in stage I disease. CONCLUSIONS: Prognosis of LGESS is generally good; however, stage IV, incomplete surgery, and PgR-negative tumors are associated with poor prognosis. Adjuvant chemotherapy may be useful for HGESS. Prognosis of UUS is extremely poor, even with adjuvant chemotherapy.

Changes in HPV16/18 Prevalence among Unvaccinated Women with Cervical Intraepithelial Neoplasia in Japan: Assessment of Herd Effects following the HPV Vaccination Program.

Since the human papillomavirus (HPV) vaccination program for Japanese girls aged 12-16 years began in 2010, vaccination uptake has been low in women born before 1993 but high (approximately 70%) in those born during 1994-1999. We previously compared the prevalence of vaccine types HPV16 and HPV18 in cervical intraepithelial neoplasia grade 1-3 (CIN1-3) or adenocarcinoma in situ (AIS) between vaccinated and unvaccinated cohorts and found direct protection effects among vaccinated women in Japan. In this study, we focused on changes in HPV16/18 prevalence among "unvaccinated" cohorts with CIN/AIS. We analyzed HPV16/18 prevalence among 5051 unvaccinated women aged <40 years, newly diagnosed with CIN/AIS during 2012-2021 for time trends. Declining trends in HPV16/18 prevalence over 9 years were observed in CIN1 (36.0-10.0%, Ptrend = 0.03) and CIN2-3/AIS (62.5-36.4%, Ptrend = 0.07) among women aged <25 years. HPV16/18 prevalence in CIN1 and CIN2-3/AIS diagnosed at age 20-24 years was lower in 1994-1999 birth cohorts compared with 1988-1993 birth cohorts (4.5% vs. 25.7% for CIN1 and 40.0% vs. 58.1% for CIN2-3/AIS, both p = 0.04). Significant reduction in HPV16/18 prevalence among young unvaccinated women with CIN1 and CIN2-3/AIS suggests herd effects of HPV vaccination in Japan.

Ovarian clear cell carcinoma with an immature teratoma component showing ARID1A deficiency and an identical PIK3CA mutation.

We herein report a case of ovarian clear cell carcinoma with an immature teratoma component that exhibited aggressive behavior. A 47-year-old woman presented with abdominal distention, and computed tomography detected a cystic mass on the right ovary. The resected mass had mural nodules, most of which showed a pale-yellow appearance; some nodules had a heterogeneous cut surface with bright yellow and white areas. Histologically, the former nodules were composed of clear cell carcinoma, while the latter contained teratomatous tissues, such as immature skeletal muscle, adipose tissue, and enteric glands. The tumor was staged as pT1c. Despite adjuvant chemotherapy and additional lymph node dissection, she had local recurrence and multiple liver metastasis 6 months after the first surgery. The disease rapidly progressed, and she died 9 months after the first surgery. Clear cell carcinoma and immature teratoma both showed ARID1A deficiency and an identical PIK3CA mutation, which suggested their clonal relationship.

A randomized phase II/III trial of conventional paclitaxel and carboplatin with or without bevacizumab versus dose-dense paclitaxel and carboplatin with or without bevacizumab, in stage IVB, recurrent, or persistent cervical carcinoma (JCOG1311): Primary analysis.

OBJECTIVE: To assess the efficacy and safety of dose-dense weekly paclitaxel plus carboplatin (ddTC) with or without bevacizumab compared to conventional, tri-weekly paclitaxel plus carboplatin (cTC) with or without bevacizumab, in metastatic or recurrent cervical carcinoma not amenable to curative local therapy. METHODS: Patients were randomly assigned to either the cTC or ddTC arm. The cTC regimen was paclitaxel 175 mg/m2 and carboplatin at an area under the curve (AUC) of 5 on day 1. The ddTC regimen was paclitaxel 80 mg/m2 on day 1, 8, 15 and carboplatin at AUC of 5 on day 1. Both cTC and ddTC treatments were repeated every 3 weeks for up to 9 cycles. After bevacizumab was approved in Japan, patients in both arms received bevacizumab 15 mg/kg if not contraindicated. The primary endpoint of phase II part was response rate (RR). If the RR of ddTC+bevacizumab was found to be at least 5% better than to cTC + bevacizumab, the study would proceed to phase III part, which had overall survival as its primary endpoint. CLINICAL TRIAL INFORMATION: jRCTs031180007. RESULTS: In total, 122 patients were randomly assigned to either the cTC arm (cTC + bevacizumab: 32; cTC:29) or the ddTC arm (ddTC+bevacizumab: 30; ddTC:31). The RR for patients on cTC + bevacizumab was 67.9%, and for patients on ddTC+bevacizumab 60.7%, cTC: 55.2%, and ddTC: 50.0%. CONCLUSIONS: The study did not meet the primary endpoint of phase II portion. Dose-dense, weekly paclitaxel plus carboplatin is not promising for metastatic or recurrent cervical carcinoma.

Lymphadenectomy issues in endometrial cancer.

OBJECTIVES: This review aims to introduce preoperative scoring systems to predict lymph node metastasis (LNM) and ongoing clinical trials to investigate the therapeutic role of lymphadenectomy for endometrial cancer. METHODS: We summarized previous reports on the preoperative prediction models for LNM and evaluated their validity to omit lymphadenectomy in our recent cohorts. Next, we compared characteristics of two ongoing lymphadenectomy trials (JCOG1412, ECLAT) to examine the survival benefit of lymphadenectomy in endometrial cancer, and described the details of JCOG1412. RESULTS: Lymphadenectomy has been omitted for 64 endometrial cancer patients who met low-risk criteria to omit lymphadenectomy using our scoring system (LNM score) and no lymphatic failure has been observed. Other two models also produced comparable results. Two randomized phase III trials to evaluate survival benefit of lymphadenectomy are ongoing for endometrial cancer. JCOG1412 compares pelvic lymphadenectomy alone with pelvic and para-aortic lymphadenectomy to evaluate the therapeutic role of para-aortic lymphadenectomy for patients at risk of LNM. For quality assurance of lymphadenectomy, we defined several regulations, including lower limit of the number of resected nodes, and submission of photos of dissected area to evaluate thoroughness of lymphadenectomy in the protocol. The latest monitoring report showed that the quality of lymphadenectomy has been well-controlled in JCOG1412. CONCLUSION: Our strategy seems reasonable to omit lymphadenectomy and could be generalized in clinical practice. JCOG1412 is a high-quality lymphadenectomy trial in terms of the quality of surgical procedures, which would draw the bona-fide conclusions regarding the therapeutic role of lymphadenectomy for endometrial cancer.

Propensity score-matched analysis of systemic chemotherapy versus salvage hysterectomy for persistent cervical cancer after definitive radiotherapy/concurrent chemoradiotherapy.

BACKGROUND: The aim of the current study was to evaluate oncologic outcomes of patients who were treated with salvage hysterectomy (HT), compared to systemic chemotherapy (CT) for persistent cervical cancer after definitive radiotherapy (RT)/ concurrent chemoradiotherapy (CCRT). METHODS: Patients with persistent cervical cancer treated with definitive RT/CCRT at 35 institutions from 2005 to 2014 were reviewed retrospectively (n = 317). Those who underwent a HT for persistent cervical cancer after definitive RT/CCRT were matched with propensity scores for patients who underwent systemic CT. Oncologic outcomes between the two groups using a propensity score matched-cohort analysis were compared. RESULTS: A total of 142 patients with persistent cervical cancer after definitive RT/CCRT were included after matching (HT: 71, systemic CT: 71). All background factors between HT and CT groups were well balanced. Median overall survival was 3.8 and 1.5 years in the HT and CT groups, respectively (p = 0.00193, hazards ratio [HR] 0.41, 95% confidence interval [CI] 0.23-0.73), Increasing residual tumor size was significantly associated with a high incomplete resection rate (p = 0.016, Odds Ratio 1.11, 95%CI 1.02-1.22). Severe late adverse events occurred in 7 patients (9.9%) in the HT cohort. CONCLUSION: The current study demonstrated that, when compared to systemic CT, the adoption of salvage HT for patients with persistent cervical cancer after definitive RT/CCRT reduced mortality rate by about 60%. This indicates that salvage HT could be curative treatment for those patients. Further prospective clinical trials with regard to salvage HT after RT/CCRT are warranted.

Human papillomavirus genotype contribution to cervical cancer and precancer: Implications for screening and vaccination in Japan.

To obtain baseline data for cervical cancer prevention in Japan, we analyzed human papillomavirus (HPV) data from 5045 Japanese women aged less than 40 years and diagnosed with cervical abnormalities at 21 hospitals during 2012-2017. These included cervical intraepithelial neoplasia grade 1 (CIN1, n = 573), CIN2-3 (n = 3219), adenocarcinoma in situ (AIS, n = 123), and invasive cervical cancer (ICC, n = 1130). The Roche Linear Array was used for HPV genotyping. The HPV type-specific relative contributions (RCs) were estimated by adding multiple infections to single types in accordance with proportional weighting attributions. Based on the comparison of type-specific RCs between CIN1 and CIN2-3/AIS/ICC (CIN2+), RC ratios were calculated to estimate type-specific risks for progression to CIN2+. Human papillomavirus DNA was detected in 85.5% of CIN1, 95.7% of CIN2-3/AIS, and 91.2% of ICC. Multiple infections decreased with disease severity: 42.9% in CIN1, 40.4% in CIN2-3/AIS, and 23.7% in ICC (P < .0001). The relative risk for progression to CIN2+ was highest for HPV16 (RC ratio 3.78, 95% confidence interval [CI] 3.01-4.98), followed by HPV31 (2.51, 1.54-5.24), HPV18 (2.43, 1.59-4.32), HPV35 (1.56, 0.43-8.36), HPV33 (1.01, 0.49-3.31), HPV52 (0.99, 0.76-1.33), and HPV58 (0.97, 0.75-1.32). The relative risk of disease progression was 1.87 (95% CI, 1.71-2.05) for HPV16/18/31/33/35/45/52/58, but only 0.17 (95% CI, 0.14-0.22) for HPV39/51/56/59/66/68. Human papillomavirus 16/18/31/33/45/52/58/6/11 included in a 9-valent vaccine contributed to 89.7% (95% CI, 88.7-90.7) of CIN2-3/AIS and 93.8% (95% CI, 92.4-95.3) of ICC. In conclusion, our data support the Japanese guidelines that recommend discriminating HPV16/18/31/33/35/45/52/58 genotypes for CIN management. The 9-valent vaccine is estimated to provide over 90% protection against ICC in young Japanese women.

Changes in the Clinicopathological Demographics of Vulvar Cancer in Japan: Increasing Oldest-Old, Stage Shifting, and Decreasing Cohort-Level Survival †.

BACKGROUND: To examine trends in the clinicopathological characteristics of vulvar cancer in Japan. METHODS: This is a nationwide retrospective study examining consecutive women with vulvar cancer between 2001 and 2010 in Japan (n = 1061). Temporal trends in demographics, tumor characteristics, and survival were assessed by cohort-level analysis. The National Cancer Institute's Surveillance, Epidemiology, and End Result Program was used for external validation (n = 10,154). RESULTS: The number of oldest-old women aged ≥80 years significantly increased (from 18.0% in 2001 to 30.6% in 2010; 70.5% relative increase) in the study period. A stage shift was observed, with stage I disease decreasing from 43.0% to 34.0% (21.0% relative decrease), and tumors with distant metastases increasing from 23.2% to 35.6% (53.3% relative increase, p < 0.05). The number of women who underwent surgical treatment decreased from 84.0% to 69.7% (17.0% relative decrease), whereas utilization of radiotherapy increased from 34.4% to 43.2% (25.7% relative increase) over time (p < 0.05). In the cohort-level analysis, the five-year survival rates significantly decreased from 2001 to 2010 (p < 0.05), specifically, 66.9% to 51.0% for progression-free survival (23.7% relative decrease), 79.5% to 67.9% for cause-specific survival (14.6% relative decrease), and 74.9% to 62.3% for overall survival (16.9% relative decrease). In the patient-level analysis, oldest-old women were less likely to undergo surgical treatment and were independently associated with decreased survival (p < 0.05). In the US cohort, the number of oldest-old women (25.2% to 27.8%) and the five-year cause-specific survival rate (81.8% to 79.9%) remained unchanged during the study period (p > 0.05). CONCLUSION: Demographics and outcomes of vulvar cancer in Japan significantly changed during the study period. An increasing oldest-old population and a stage shift to more metastatic disease resulted in a cohort-level decrease in survival rates.

Reduction in HPV16/18 prevalence among young women with high-grade cervical lesions following the Japanese HPV vaccination program.

The Japanese government began a human papillomavirus (HPV) vaccination program for girls aged 12-16 years in 2010 but withdrew its recommendation in 2013 because of potential adverse effects, leading to drastically reduced vaccination uptake. To evaluate population-level effects of HPV vaccination, women younger than 40 years of age newly diagnosed with cervical intraepithelial neoplasia grade 1-3 (CIN1-3), adenocarcinoma in situ (AIS), or invasive cervical cancer (ICC) have been registered at 21 participating institutes each year since 2012. A total of 7709 women were registered during 2012-2017, of which 5045 were HPV genotyped. Declining trends in prevalence of vaccine types HPV16 and HPV18 during a 6-year period were observed in CIN1 (50.0% to 0.0%, Ptrend  < .0001) and CIN2-3/AIS (83.3% to 45.0%, Ptrend  = .07) only among women younger than 25 years of age. Overall, HPV vaccination reduced the proportion of HPV16/18-attributable CIN2-3/AIS from 47.7% to 33.0% (P = .003): from 43.5% to 12.5% as routine vaccination (P = .08) and from 47.8% to 36.7% as catch-up vaccination (P = .04). The HPV16/18 prevalence in CIN2-3/AIS cases was significantly reduced among female individuals who received their first vaccination at age 20 years or younger (P = .02). We could not evaluate vaccination effects on ICC owing to low incidence of ICC among women aged less than 25 years. We found HPV vaccination to be effective in protecting against HPV16/18-positive CIN/AIS in Japan; however, our data did not support catch-up vaccination for women older than 20 years. Older adolescents who skipped routine vaccination due to the government's suspension of its vaccine recommendation could benefit from receiving catch-up vaccination before age 20 years.

A multi-institutional observational study on the effects of three-dimensional radiotherapy and weekly 40-mg/m2 cisplatin on postoperative uterine cervical cancer patients with high-risk prognostic factors.

BACKGROUND: The aim of this study was to evaluate the effects of treatment with both three-dimensional radiotherapy (3DRT) and weekly 40-mg/m2 cisplatin on postoperative uterine cervical cancer patients with high-risk prognostic factors. METHODS: We conducted a retrospective multi-institutional chart review of postoperative uterine cervical cancer patients with high-risk prognostic factors who had been treated with both 3DRT and weekly 40-mg/m2 cisplatin from 2007 to 2012. Each participating hospital provided detailed information regarding patient characteristics, treatment outcomes, and treatment complications. RESULTS: The eligible 96 patients were analyzed. The median follow-up period was 61 months. The 3-year relapse-free survival, overall survival (OS), and locoregional relapse-free survival (LRFS) rates were 76%, 90%, and 88%, respectively. In multivariate analysis, the histological finding of either adenocarcinoma or adenosquamous carcinoma was a significant risk factor for both OS and LRFS. The percentage of patients with grade ≥ 3 acute hematologic toxicity, acute lower gastrointestinal toxicity (GIT), and late lower GIT were 45%, 19%, and 17%, respectively. CONCLUSIONS: The outcomes of concurrent chemoradiotherapy (CCRT) using weekly 40-mg/m2 cisplatin are similar to those in the previous studies that used several chemotherapy regimens. However, postoperative CCRT using 3DRT had a high level of late GIT.

Application of deep learning to the classification of images from colposcopy.

The objective of the present study was to investigate whether deep learning could be applied successfully to the classification of images from colposcopy. For this purpose, a total of 158 patients who underwent conization were enrolled, and medical records and data from the gynecological oncology database were retrospectively reviewed. Deep learning was performed with the Keras neural network and TensorFlow libraries. Using preoperative images from colposcopy as the input data and deep learning technology, the patients were classified into three groups [severe dysplasia, carcinoma in situ (CIS) and invasive cancer (IC)]. A total of 485 images were obtained for the analysis, of which 142 images were of severe dysplasia (2.9 images/patient), 257 were of CIS (3.3 images/patient), and 86 were of IC (4.1 images/patient). Of these, 233 images were captured with a green filter, and the remaining 252 were captured without a green filter. Following the application of L2 regularization, L1 regularization, dropout and data augmentation, the accuracy of the validation dataset was ~50%. Although the present study is preliminary, the results indicated that deep learning may be applied to classify colposcopy images.

Radical hysterectomy with or without para-aortic lymphadenectomy for patients with stage IB2, IIA2, and IIB cervical cancer: outcomes for a series of 308 patients.

BACKGROUND: Although many studies have already shown that lymph node metastasis is one of the major prognostic factors for cervical cancer, the therapeutic significance of para-aortic lymphadenectomy for the surgical treatment of cervical cancer remains controversial. METHODS: A total of 308 patients diagnosed with stage IB2, IIA2, or IIB cervical cancer and treated with radical hysterectomy were retrospectively investigated to assess the incidence of para-aortic lymph node metastasis and the clinicopathological factors linked to cervical cancer prognosis. RESULTS: Para-aortic lymph node metastases were pathologically confirmed in 13 of the 136 patients (9.6 %) who underwent para-aortic lymphadenectomy. The incidence of para-aortic lymph node metastasis was significantly higher in the patients who had common iliac lymph node metastases (odds ratio 31.5, p < 0.001) according to logistic regression analysis. Common iliac lymph node metastasis was related to risk of recurrence (hazard ratio 2.43, p = 0.003) and death (hazard ratio 2.62, p = 0.007) in Cox regression analysis. Kaplan-Meier analysis and Cox regression analysis showed that para-aortic lymphadenectomy did not have a positive impact on survival in 308 patients or 140 pN1 patients, but para-aortic lymphadenectomy was related to better overall survival with a marginal trend toward significance (p = 0.053) in 30 patients with common iliac lymph node metastasis. CONCLUSIONS: Indication for para-aortic lymphadenectomy in the surgical treatment of stage IB2, IIA2, or IIB cervical cancer needs to be individualized. Patients with common iliac lymph node metastasis are possible candidates, and a prospective study is needed to clarify this issue.

Monitoring the impact of a national HPV vaccination program in Japan (MINT Study): rationale, design and methods.

We have developed a collaborative hospital-based approach to monitoring the impact of a human papillomavirus vaccine on cervical cancer, its precursor lesions and human papillomavirus type-specific prevalence in Japan. The monitoring will be conducted for a total period of 21 years on women aged <40 who are newly diagnosed with invasive cervical cancer, cervical intraepithelial neoplasia or adenocarcinoma in situ at 21 participating institutes. Women are monitored to determine their vaccine history and will be human papillomavirus-genotyped each year. The primary endpoint is the human papillomavirus16/human papillomavirus18-positive rate in women aged 16-25 who are diagnosed with invasive cervical cancer, cervical intraepithelial neoplasia grade 2/3 and adenocarcinoma in situ. The major secondary endpoints are the number of women aged <40 who are diagnosed with invasive cervical cancer, cervical intraepithelial neoplasia grade 2/3 and adenocarcinoma in situ, the human papillomavirus type-specific prevalence, and the number of deaths from invasive cervical cancer in women aged <40. Long-term surveillance for human papillomavirus-associated cervical diseases in young females is important for the development of future strategies for cervical cancer prevention in Japan.

Clinical significance of UDP-glucuronosyltransferase 1A1*6 for toxicities of combination chemotherapy with irinotecan and cisplatin in gynecologic cancers: a prospective multi-institutional study.

BACKGROUND: To investigate the effects of UDP-glucuronosyltransferase 1A1 (UGT1A1) *28, *6 and *27 in patients with gynecologic cancer who received chemotherapy with irinotecan and cisplatin. METHODS: Patients eligible for this study had cervical or ovarian cancer treated with chemotherapy; a course of the regimen consisted of 60 mg/m(2) of irinotecan on days 1, 8 and 15, and 60 mg/m(2) of cisplatin on day 1 every 4 weeks. UGT1A1 polymorphisms and toxicities were analyzed. RESULTS: From March 2007 to December 2007, 30 Japanese patients were enrolled; 24 ovarian carcinoma patients and 6 cervical cancer patients. The following genotypes of UGT1A1 were found: wild type in 17 patients (57%), *28 in 4 patients (13%), *6 in 8 patients (27%), *28*6 in 1 case (3%) and no case of *27 (0%). Grade 3/4 neutropenia, thrombocytopenia and diarrhea were significantly more frequent in *6 patients compared with wild-type patients. Also, in *6 patients irinotecan administration on days 8 or 15 was significantly more often omitted due to toxicities. In patients with *28 or *28*6, side effects were similar to those in patients with *6. CONCLUSION: In addition to UGT1A1*28, UGT1A1*6 might also be a key candidate to determine the dose of combination chemotherapy with irinotecan and cisplatin.

Combined phospho-Akt and PTEN expressions associated with post-treatment hysterectomy after conservative progestin therapy in complex atypical hyperplasia and stage Ia, G1 adenocarcinoma of the endometrium.

Young patients with complex atypical hyperplasia (CAH) or stage Ia, G1 adenocarcinoma (IaG1) of the endometrium, who desire to preserve fertility, can select the conservative therapy by oral progestin, medroxyprogesterone acetate (MPA). However, conservative treatments involve potential risks of progression and recurrence. In an attempt to find out molecular markers for sensitivity to MPA, we performed immunohistochemical analysis of PTEN, phospho-Akt, p53, ER and PgR in MPA-treated 31 cases with CAH or IaG1. Eleven of 12 cases (92%) with CAH and 15 of 19 cases (79%) with IaG1 demonstrated an initial complete response, while five patients underwent hysterectomy due to no response. Four of 11 responders (36%) with CAH and five of 15 responders (33%) with IaG1 later developed relapse. Five of nine patients (56%) with CAH and three of 11 patients (27%) with IaG1 became pregnant after infertility treatment. Immunohistochemical analysis revealed that phospho-Akt expression was significantly decreased by MPA administration (p=0.002). Furthermore, combination of two factors, weak phosho-Akt or PTEN-null expression, was found to be significantly associated with receiving hysterectomy (p=0.04), while each factor showed a trend without statistical significance (p=0.07 and 0.2, respectively). Strong expression of both ER and PgR significantly correlated with successful pregnancy after infertility treatment following complete response to MPA (p=0.02). Our observations in vivo suggest that anti-tumor action of MPA may be mediated by dephosphorylation of Akt, and that immunohistochemical evaluation of phospho-Akt and PTEN may be able to predict the outcome of MPA therapy.

SUMO-1 conjugation to intact DNA topoisomerase I amplifies cleavable complex formation induced by camptothecin.

DNA topoisomerase I (Topo1) manages the topological state of DNA. Cleavable complexes, the covalent Topo1-DNA intermediates, become DNA damaged when the catalytic cycles are inhibited by the anti-tumor drug camptothecin (CPT). Intriguingly, Topo1 is modified rapidly and extensively with SUMO-1, a ubiquitin-like protein, in response to CPT. This study shows that the sumoylation enhances the cleavable complex formation and apoptosis induced by CPT. Indeed, substitutions of Lys117 and Lys153, identified as Topo1 sumoylation sites, reduced the CPT-induced cleavable complexes without influencing its in vitro catalytic activity. Consistent with this observation, CPT-induced cleavable complexes of wild-type Topo1 increased in a sumoylation-dependent manner. We also found that Topo1 sumoylation occurred independently of CPT when Topo1 was inactivated by mutation of the catalytic Tyr723. These findings suggested that Topo1 inactivation by CPT treatment can trigger Topo1 sumoylation, leading to enhanced cleavable complex formation.