High prevalence of pulmonary embolism prior to cancer therapies in patients with ovarian and endometrial cancers detected by contrast-enhanced CT using D-dimer as an index.

OBJECTIVE: We aimed to evaluate the prevalence of pulmonary embolism (PE) before cancer therapies in patients with ovarian and endometrial cancers with enhanced computed tomography (CT) using D-dimer (DD), and determine the optimal cut-off level of DD. METHODS: Since 2009, we have performed preoperative venous thromboembolism (VTE) screening of patients with ovarian and endometrial cancer. For patients with DD levels of more than 1.0 µg/ml, enhanced CT images were obtained from the pulmonary apex to the foot to detect PE and deep venous thrombosis (DVT) simultaneously. RESULTS: Among patients with ovarian cancer, 84 of 413 (20.3%) had VTEs (DVT alone, n = 31 [7.5%]; PE with or without DVT, n = 53 [12.8%]; PE alone, n = 12 [2.9%]). Among patients with endometrial cancer, 50 of 455 (11.0%) had VTEs (DVT alone, n = 19 [4.2%]; PE with or without DVT, n = 31 [6.8%], PE alone, n = 14 [3.1%]). The optimal cut-off level of DD was estimated to be ≥1.5 and ≥1.2 µg/ml in ovarian and endometrial cancers, respectively. CONCLUSION: Our study revealed a high prevalence of PE before cancer therapies in patients with ovarian and endometrial cancers by enhanced CT using DD.

Antitumor effects of metformin via indirect inhibition of protein phosphatase 2A in patients with endometrial cancer.

OBJECTIVE: Metformin, an antidiabetic drug, inhibits the endometrial cancer cell growth in vivo by improving the insulin resistance; however, its mechanism of action is not completely understood. Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase associated with insulin resistance and type 2 diabetes, and its inhibition restores the insulin resistance. This study investigated the antitumor effect of metformin on endometrial cancer with a focus on PP2A. METHODS: Metformin (1,500-2,250 mg/day) was preoperatively administered to patients with endometrial cancer for 4 to 6 weeks. Expression of the PP2A regulatory subunits, 4 (PPP2R4) and B (PP2A-B), was evaluated using real-time polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC) using paired specimens obtained before and after metformin treatment. The effect of PPP2R4 inhibition with small interfering RNA was evaluated in the endometrial cancer cell lines HEC265 and HEC1B. P values of < .05 were considered statistically significant. RESULTS: Preoperative metformin treatment significantly reduced the expression of PP2A-B, as determined using IHC, and the mRNA expression of PPP2R4, as determined using RT-PCR, in the patients with endometrial cancer. However, metformin could not directly alter the PPP2R4 mRNA levels in the endometrial cancer cell lines in vitro. PPP2R4 knockdown reduced the proliferation and induced the apoptosis by activating caspases 3/7 in HEC265 and HEC1B cells. CONCLUSIONS: Downregulation of the PP2A-B subunit, including PPP2R4, is an important indirect target of metformin. Inhibition of PP2A may be an option for the treatment of endometrial cancer patients with insulin resistance. TRIAL REGISTRATION: This trial is registered with UMIN-CTR (number UMIN000004852).

Prospective evaluation of abnormal glucose metabolism and insulin resistance in patients with atypical endometrial hyperplasia and endometrial cancer.

PURPOSE: Obesity and diabetes (DM) are known to increase the risk of endometrial cancer (EC). However, little is known about the prevalence of abnormal glucose metabolism and insulin resistance (IR) in EC patients. We aimed to evaluate the prevalence of abnormal glucose metabolism and IR in EC patients. METHODS: We prospectively enrolled atypical endometrial hyperplasia (AEH) and EC patients who had received planned treatment at Chiba University Hospital, Japan. All patients, except those with a confirmed diagnosis of DM, underwent the 75-g oral glucose tolerance test (OGTT) before treatment. We evaluated the prevalence of obesity, defined as body mass index (BMI) ≥25, IR, abnormal glucose metabolism, and the associations between these three factors and the clinical characteristics of AEH and EC patients. RESULTS: We enrolled 279 patients from April 2009 to March 2015. Of these, 56 had a confirmed diagnosis of DM. Abnormal OGTT results, including impaired fasting glucose (n = 7), impaired glucose tolerance (n = 69), and newly identified DM (n = 33), were noted in 109 patients. Obesity, IR, and abnormal glucose metabolism were observed in 49.8, 51.6, and 59.1% of patients, respectively. Abnormal glucose metabolism was significantly associated with age (P < 0.001), body mass index (P = 0.004), and IR status (P < 0.001) in multivariate analysis. CONCLUSION: Abnormal glucose metabolism, IR, and obesity were highly prevalent in patients with AEH and EC. These results indicate that physicians should consider a patient's metabolic status in the postoperative management of AEH and EC patients.

The Efficacy of Palonosetron Plus Dexamethasone in Preventing Chemoradiotherapy-induced Nausea and Emesis in Patients Receiving Daily Low-dose Cisplatin-based Concurrent Chemoradiotherapy for Uterine Cervical Cancer: A Phase II Study.

OBJECTIVES: The prevention of chemotherapy-induced and radiotherapy-induced emesis is recommended by several guidelines; however, there are no evidence-based recommendations for the use of antiemetics in concurrent chemoradiotherapy (CCRT). The aim of the present study was to evaluate the efficacy and safety of antiemetic therapy comprising palonosetron and dexamethasone during CCRT. METHODS: This is a nonrandomized, prospective, single-center, open phase II study.Twenty-six consecutive patients with cervical carcinoma were treated with daily low-dose cisplatin (8 mg/m/d)-based CCRT (2 Gy/d, 25 fractions, 5 times a week). All patients received 0.75 mg of palonosetron on day 1 of each week and 4 mg of oral dexamethasone daily. The primary endpoint was the percentage of patients achieving a complete response, which was defined as no emetic episodes and no antiemetic rescue medication during treatment. RESULTS: Planned daily low-dose cisplatin-based CCRT was successful without delay or interruption in 46% (12/26) of the patients. The mean dose of total cisplatin was 184 (range, 136 to 200) mg/m.No patient vomited during the treatment period. The complete response rate during CCRT was 100%. A total of 81% patients were completely free from nausea. All patients tolerated the combination of palonosetron and dexamethasone and completed the scheduled regimen. Five patients exhibited grade 1 Cushingoid features that resolved after treatment. CONCLUSIONS: Antiemetic therapy comprising palonosetron and dexamethasone provided complete protection from nausea and vomiting in patients with cervical cancer receiving daily low-dose cisplatin-based CCRT.

Efficacy of palonosetron plus aprepitant in preventing chemoradiotherapy-induced nausea and emesis in patients receiving daily low-dose cisplatin-based concurrent chemoradiotherapy for uterine cervical cancer: a phase II study.

PURPOSE: Antiemetic recommendations during concurrent chemoradiotherapy (cisplatin-based concurrent chemoradiotherapy (CCRT)) have not been established yet. The aim of this study was to investigate whether the combination of palonosetron plus aprepitant, without routine use of dexamethasone, could alleviate chemoradiotherapy-induced nausea and vomiting (CRINV). METHODS: This was a non-randomized, prospective, single-center, open phase II study. Patients with cervical cancer, who were treated with daily low-dose cisplatin (8 mg/m(2)/day) and concurrent radiation (2 Gy/day, 25 fractions, five times a week), were enrolled in this study. All patients received intravenous palonosetron (0.75 mg on day 1 of each week) and oral aprepitant (125 mg on day 1 and 80 mg on days 2 and 3 of each week). The primary endpoint was the percentage of patients with a complete response, defined as no emetic episodes and no use of antiemetic rescue medication during the treatment. RESULTS: Twenty-seven patients (median age, 50 years; range, 33-72 years) were enrolled in this study between June 2013 and April 2014. A total of 13 (48 %) patients showed a complete response to the antiemetic regimen, while 8 patients (30 %) had emetic episodes and 6 patients (22 %) used rescue medication without emetic episodes. No severe adverse effects caused by palonosetron plus aprepitant were observed. CONCLUSION: The combination of palonosetron plus aprepitant was permissive for the prevention of CRINV. This regimen should be considered for patients in whom dexamethasone is contraindicated or not well tolerated.

Daily low-dose Cisplatin-based concurrent chemoradiotherapy for the treatment of cervical cancer in patients 70 years or older.

OBJECTIVES: It has been established that concurrent chemoradiotherapy (CCRT) is efficacious for cervical cancer, but adherence is unsatisfactory among elderly patients. To improve adherence, we have developed and initiated a daily low-dose cisplatin-based CCRT regimen. Here, we retrospectively evaluated the use of CCRT, especially for elderly patients. METHODS: The study included a total of 53 patients who were 70 years or older, had stage IB-IVA cervical cancer, and were initially treated with daily CCRT. The daily CCRT comprised pelvic external beam radiotherapy (2 Gy/d × 25) with daily low-dose cisplatin (8.0 mg/m(2) per day) and either low- or high-dose-rate intracavitary brachytherapy. RESULTS: The median age was 72 years (range, 70-85 years). The median follow-up duration was 32 months (range, 2-104 months). The 3-year overall survival rate was 79.0%. Daily cisplatin chemotherapy was successfully completed in 32 (60.4%) of the 53 patients. Grade 3 or 4 neutropenia was observed in 19 patients (36%). A late complication of grade 3 rectal hemorrhage occurred in 3 patients who received high-dose-rate brachytherapy. All primary tumors responded to daily CCRT; complete response was observed in 43 patients (91.5%) and partial response was observed in 4 patients (8.5%). CONCLUSIONS: Daily CCRT in patients 70 years and older had acceptable compliance and safety. Daily CCRT is suggested to be a good treatment option for elderly patients who have advanced cervical cancer and require concurrent cisplatin.

Normal human chorionic gonadotropin regression curves in uneventful postmolar patients.

OBJECTIVE: To review current follow-up measures of human chorionic gonadotropin (hCG) in uneventful postmolar patients, and to evaluate criteria for initiating chemotherapy. STUDY DESIGN: Between 1993 and 2011 hCG data from 395 patients with uneventful complete moles (CMs) (195 patients) and partial moles (PMs) (205 patients) were obtained at 4 hospitals in Japan. All patients had been followed regularly at various intervals based on the preceding hCG titers and normal hCG regression curve. RESULTS: All patients achieved hCG normalization spontaneously (range, 3.1-29.7 weeks). Approximately half of the patients with CM and PM had attained an undetectable hCG level at 9.3 and 8.3 weeks after evacuation of mole, respectively. The reconstructed normal hCG regression curve consisted of hCG levels of 1,000 mIU/mL at 5 weeks, 100 mIU/mL at 8 weeks and nondetectable hCG levels at 24 weeks. Plotting preceding hCG titers on this hCG regression curve, the intervals of visits to measure hCG were changing, and the real number of visits was significantly fewer than that of recommended weekly measurement of hCG (p<0.0001). CONCLUSION: The use of the present hCG regression curve after evacuation of a molar pregnancy can aid in estimation of the risk of developing gestational trophoblastic neoplasia, especially in women who have suboptimal compliance and follow-up.