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).

Abnormal Vaginal Cytology after Total Laparoscopic Hysterectomy in Patients with Cervical Intraepithelial Neoplasia.

To explore the incidence of abnormal vaginal cytology after total laparoscopic hysterectomy for the treatment of cervical intraepithelial neoplasia 3, we retrospectively analyzed the medical records of patients treated at NHO Shikoku Cancer Center (Japan) in 2014-2019. The cases of 99 patients who underwent a laparoscopic (n=36) or open (n=63) hysterectomy and postoperative follow-up were examined. Abnormal vaginal cytology was detected in 13.9% (5/36) of the laparoscopic-surgery (LS) group and 14.3% (9/63) of the open-surgery (OS) group. A vaginal biopsy was performed at the physicians' discretion; one LS patient and six OS patients were diagnosed with vaginal intraepithelial neoplasia. The cumulative incidence of abnormal vaginal cytology at 3 years post-hysterectomy was 21.4% (LS group) and 20.5% (OS group), a nonsignificant difference. A multivariate analysis showed that age > 50 years was the only independent risk factor for abnormal vaginal cytology among the covariates examined including age; body mass index; histories of vaginal delivery, abdominal surgery, and smoking; and surgical approach (hazard ratio 8.11; 95% confidence interval 1.73-37.98; p=0.01). These results suggest that the occurrence of abnormal vaginal cytology after a hysterectomy may not be influenced by the laparoscopic procedure but is associated with older age.

Poor Treatment Outcomes of Locally Advanced Cervical Adenocarcinoma of Human Papilloma Virus Independent Type, Represented by Gastric Type Adenocarcinoma: A Multi-Center Retrospective Study (Sankai Gynecology Study Group).

The revised World Health Organization classification of cervical cancer divides adenocarcinomas into human papillomavirus-associated (HPVa) and -independent (HPVi) types; the HPVi type is represented by the gastric type. The treatment outcomes of locally advanced adenocarcinoma (LaAC), based on this classification, are understudied. We investigated the outcomes of patients with HPVa and HPVi LaACs. Data for all consecutive patients with stage IB3 to IIIC1 adenocarcinoma who received treatment at 12 institutions throughout Japan between 2004 and 2009 were retrieved to analyze progression-free and overall survival. Central pathological review classified 103 and 48 patients as having HPVa and HPVi tumors, respectively. Usual- (84%) and gastric- (90%) type adenocarcinomas were the most frequent subtypes. Surgery was the primary treatment strategy for most patients. Progression-free and overall survival of patients with HPVi were worse than those of patients with HPVa (p = 0.009 and 0.032, respectively). Subgroup analysis by stage showed that progression-free survival was significantly different for stage IIB. The current surgical treatment strategy for LaACs is less effective for HPVi tumors than for HPVa tumors, especially those in stage IIB.

Uterine leiomyosarcoma well-controlled with eribulin mesylate.

Uterine leiomyosarcoma is a rare type of malignant gynecological tumor and has a poor prognosis; therefore, this tumor is often difficult to treat. Some new drugs have been approved during the past several years in Japan and are expected to be efficacious. Eribulin, one of these drugs, is a natural product of halichondrin B, which is isolated from a marine sponge. A recent clinical trial comparing eribulin with dacarbazine to target liposarcoma and leiomyosarcoma indicated that overall survival (OS) was prolonged by treatment with eribulin. We report a case of uterine progressive leiomyosarcoma that responded to eribulin. A 57-year-old woman was suspected of having leiomyosarcoma based on an endometrial biopsy and imaging examinations. Although the tumor grew toward the uterine artery on the right side of the uterine cervix, we performed a total abdominal hysterectomy and bilateral salpingo-oophorectomy to obtain an outcome of no gross residual disease. However, the margin of the right side of the uterine cervix was histologically positive, so leiomyosarcoma stage IIB (pT2bcN0cM0, FIGO2008) was diagnosed. Gemcitabine and docetaxel therapy was administered postoperatively. However, after three cycles, the residual tumor progressed. Other anticancer drugs were administered but were ineffective. We administered eribulin (1.4 mg/m2) as a fourth-line regimen, and the mass decreased by 32% after four cycles. However, the residual tumor continued to grow after eight cycles. The only adverse event associated with eribulin treatment was mild, grade 2 neutropenia. For our patient, eribulin was effective for her recurrent leiomyosarcoma. In selecting chemotherapy, there are currently no fixed guidelines; we should consider the characteristics and adverse events associated with each drug and patient performance status and comorbidities. In this patient, eribulin was associated with few adverse events, an easy route of administration and a good quality of life. Therefore, eribulin is expected to be efficacious for the treatment of gynecologic sarcoma.

Lynch syndrome-associated endometrial carcinoma with MLH1 germline mutation and MLH1 promoter hypermethylation: a case report and literature review.

BACKGROUND: Lynch syndrome is an autosomal dominant inherited disease caused by germline mutations in mismatch repair genes. Analysis for microsatellite instability (MSI) and immunohistochemistry (IHC) of protein expressions of disease-associated genes is used to screen for Lynch syndrome in endometrial cancer patients. When losses of both MLH1 and PMS2 proteins are observed by IHC, MLH1 promoter methylation analysis is conducted to distinguish Lynch syndrome-associated endometrial cancer from sporadic cancer. CASE PRESENTATION: Here we report a woman who developed endometrial cancer at the age of 49 years. She had a family history of colorectal cancer (first-degree relative aged 52 years) and stomach cancer (second-degree relative with the age of onset unknown). No other family history was present, and she failed to meet the Amsterdam II criteria for the diagnosis of Lynch syndrome. Losses of MLH1 and PMS2, but not MSH2 and MSH6, proteins were observed by IHC in endometrial cancer tissues. Because MLH1 promoter hypermethylation was detected in endometrial cancer tissue samples, the epigenetic silencing of MLH1 was suspected as the cause of the protein loss. However, because of the early onset of endometrial cancer and the positive family history, a diagnosis of Lynch syndrome was also suspected. Therefore, we provided her with genetic counseling. After obtaining her consent, MLH1 promoter methylation testing and genetic testing of peripheral blood were performed. MLH1 promoter methylation was not observed in peripheral blood. However, genetic testing revealed a large deletion of exon 5 in MLH1; thus, we diagnosed the presence of Lynch syndrome. CONCLUSIONS: Both MLH1 germline mutation and MLH1 promoter hypermethylation may be observed in endometrial cancer. Therefore, even if MLH1 promoter hypermethylation is detected, a diagnosis of Lynch syndrome cannot be excluded.

Long-term outcomes of postoperative taxane/platinum chemotherapy for early stage cervical cancer: a retrospective study.

BACKGROUND: Taxane/platinum (TP)-based combination chemotherapy is standard for the treatment of metastatic or recurrent cervical cancer. The aim of this study was to investigate the efficacy of postoperative TP therapy in early stage cervical cancer. METHODS: A retrospective review of patients with FIGO IB-IIB stage cervical cancer who were treated with radical hysterectomy and displayed surgical-pathological risk factors was performed. 122 patients were identified between 2003 and 2012. Survival was analyzed by Kaplan-Meier method and compared by the log-rank test. The Cox proportional hazards model was used to investigate predictors of survival. RESULTS: The median follow-up period was 82.4 months. The postoperative adjuvant therapy was TP in 82 (67.2%) patients, other chemotherapies in 10 (8.2%), radiotherapy (RT) in 25 (20.5%), and no further therapy (NFT) in 5 (4.1%). Survival was analyzed using 4 subgroups according to the postoperative adjuvant therapy. The estimated 5-year overall survival was 95.1% in the TP group, 90.0% in the other chemotherapy group, 78.9% in the RT group, and 100% in the NFT group. No significant difference of survival was observed in the subgroups. However, when analyzing only patients who displayed high-risk factors, non-TP adjuvant therapy (including RT and other chemotherapies) was independently associated with shorter survival on multivariate analysis. In the TP group, multivariate analysis revealed that a positive surgical margin was a significant predictor of shorter survival. CONCLUSIONS: Postoperative TP is effective in patients with surgically treated early stage cervical cancer. In these populations, a positive surgical margin could be associated with poor prognosis.

[Safety and Efficacy of Cisplatin Treatment after Carboplatin Hypersensitivity Reactions in Gynecologic Malignancies].

To investigate the safety and efficacy of cisplatin(CDDP)treatment after carboplatin(CBDCA)hypersensitivity reactions (CHSR)in gynecologic malignancies, we retrospectively reviewed the clinical records of 544 patients who underwent paclitaxel and CBDCA therapy(TC therapy). CHSR was observed in 18 patients. Eight patients were administered weekly paclitaxel and CDDP therapy(wTP therapy)continuously, to confirm that there was no CDDP hypersensitivity followingintravenous administration of 10 mgCDDP. At the onset of CHSR, the patients had received a median of 9 TC therapy cycles, and the median number of CBDCA administrations was 14. The frequency of CHSR was significantly higher in patients who received 7 cycles or more of TC therapy and CBDCA administration(p<0.0001). The median number of wTP therapy administrations was 8. Although CDDP hypersensitivity reactions were observed in 2 patients, their symptoms were mild(Grade 2, CTCAE v4.0). Of the 6 patients who received wTP therapy and had evaluable disease sites, 1, 2, 2 and 1 patients showed CR, PR, SD, and PD, respectively. The median progression-free survival in these 6 patients was 9.5 months. For patients with the platinum- sensitive disease who have CHSR, CDDP could improve their prognosis.

[Outcomes of Tertiary Debulking Surgery(TDS)for Re-Recurrent Ovarian Cancer].

The survival of patients with recurrent ovarian cancer who have completed secondary debulking surgery (SDS) has been shown to increase. However, whether tertiary debulking surgery (TDS) aimed at complete surgery is useful in patients with a second recurrence is unclear. Eight patients who had undergone SDS were treated after a second recurrence in our hospital. Their medical records were retrospectively reviewed. Consequently, TDS was performed in 4 of the patients (TDSgr). All 4 patients underwent complete debulking surgery, 2 patients received blood transfusions, and none had serious postoperative complications. The median treatment free interval (TFI) from recurrence surgery to the second recurrence was 16 months (range, 9-23 months), and the median TFI after the second recurrence was 30.5 months (range, 15-69 months). Meanwhile, the median TFI after the second recurrence was 7.5 months (range, 1-31 months) in the 4 patients who did not undergo TDS (non-TDSgr). The median survival times after the second recurrence in TDSgr and non-TDSgr were 53 months (range, 41-69 months) and 12 months (range, 2-30 months), respectively. When complete surgery is indicated in patients with a second recurrent ovarian cancer after SDS, in case of good physical condition with single or multiple recurrent lesions, TDS may increase survival and TFI.

Type C2 radical hysterectomy may improve outcomes of locally advanced mucinous adenocarcinoma of the uterine cervix.

BACKGROUND: It is not known whether radiotherapy or surgery is better as initial treatment for locally advanced mucinous adenocarcinoma of the uterine cervix. METHODS: We reviewed the medical records and pathological materials of 32 patients with International Federation of Gynecology and Obstetrics stage IB2-IIB mucinous adenocarcinoma, who had undergone radiotherapy or radical hysterectomy as primary treatment between 2001 and 2010. p16(INK4a) immunohistochemistry was performed as a marker for human papillomavirus-related adenocarcinoma. RESULTS: Thirteen patients received radiotherapy and 19 patients underwent radical hysterectomy. The cumulative 3-year locoregional control rates in the radical hysterectomy and radiotherapy groups were 79.0 and 46.2 % (P = 0.03), and 5-year overall survival rates were 70.7 and 38.5 % (P = 0.09), respectively. Of patients with p16(INK4a)-positive tumors (n = 19), the cumulative 3-year locoregional control rates in the radical hysterectomy and radiotherapy groups were 100 and 60.0 % (P = 0.01), and 5-year overall survival rates were 88.9 and 40.0 % (P = 0.04), respectively. Conversely, the cumulative 3-year locoregional control rates in the human papillomavirus-negative radical hysterectomy group and radiotherapy group were 20.0 and 37.5 % (P = 0.66), and 5-year overall survival rates were 20.0 and 37.5 % (P = 0.60), respectively. CONCLUSIONS: Radical hysterectomy may significantly improve locoregional control and overall survival compared with radiotherapy for stage IB2-IIB mucinous adenocarcinoma patients, especially those with p16(INK4a)-positive mucinous adenocarcinoma.

A case of uterine corpus large cell neuroendocrine carcinoma showing prominent myometrial invasion without any macroscopically clear tumor formation.

Large cell neuroendocrine carcinoma (LCNEC) arising in the uterine corpus is a very rare. Here, we report our experience with a primary LCNEC in the uterine corpus that showed prominent myometrial invasion without exhibiting any macroscopically distinct tumor formation in the uterine cavity. The patient was a 54-year-old woman. She had a past medical history of right breast cancer and was referred to our department with irregular genital bleeding, elevated serum carcinoembryonic antigen in periodic medical examinations and computed tomography (CT) findings of uterine cavity dilation. Endometrial biopsy suggested a poorly differentiated tumor. Although magnetic resonance imaging (MRI) showed hematometra-like findings in the uterine cavity, it did not indicate any clear endometrial lesion. The myometrium was unequally thickened, and the entire muscle layer showed a high signal intensity on diffusion-weighted images. Fluorine-18-deoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) showed strong FDG accumulation in the whole uterus, and on the bottom of the uterus, there was a ring-shaped accumulation mainly in the muscle layer. The postoperative resected specimen did not show any tumor formation in the uterine cavity, whereas the myometrium was hard and thickened, and colored white overall. Histopathological examination revealed prominent myometrial invasion in most layers, cervical stromal invasion and pelvic lymph node metastasis. The diagnosis was a LCNEC of the uterine corpus, at FIGO stage IIIC1 and pT2N1M0. With these patients, we found that functional metabolic images, such as MRI diffusion-weighted images and FDG-PET/CT, were useful in identifying the lesion. Preoperatively, when a poorly differentiated tumor is estimated and characteristic myometrial invasion is suspected, the possibility of LCNEC should be considered.

A case of ependymoma arising from the peritoneum.

Ependymoma arising from the peritoneum is extremely rare. We present the case of a 23-year-old woman who underwent urgent laparoscopic surgery because of a pelvic mass and intraperitoneal bleeding. Although peritoneal carcinoma was suspected, pathological re-examination revealed ependymoma with a perivascular pseudorosette and positive for glial fibrillary acidic protein. Residual tumor extraction indicated that the ependymoma had developed from the peritoneum. This case highlights the need to consider ependymoma as a potential diagnosis in young women with suspected ovarian or peritoneal cancer.

The usefulness of 18F-FDG-PET/CT in discriminating benign from malignant ovarian teratomas.

BACKGROUND: The present study investigates the usefulness of 18F-FDG-PET/CT (PET/CT) in distinguishing between benign and malignant ovarian teratomas. METHODS: This study includes 4 mature teratomas (MTs) with malignant transformation, 8 immature teratomas (ITs), and 16 MTs that were diagnosed after surgical resection. Preoperative tumor marker values, MRI findings, PET/CT SUVmax values, and other clinical parameters were retrospectively compared with those of 14 patients who had MTs. RESULTS: The median CA125 was significantly higher for ITs than for MTs (P = 0.04). The median AFP was significantly higher for ITs than for MTs (P = 0.0034). The median SUVmax values for MTs with malignant transformation, ITs, and MTs were 18.3 (5.3-23.3), 6.0 (3.6-22.6), and 1.1 (1.0-15.5), respectively. SUVmax was significantly higher in MTs with malignant transformation and ITs than in MTs (P = 0.004, P = 0.0007). With a cut-off SUVmax of 3.6 to distinguish between benign and malignant MTs, sensitivity was 100 %, specificity was 81 %, positive predictive value was 80 %, negative predictive value was 100 %, and diagnostic accuracy was 89 % (AUC 0.94). However, one patient with an MT had a high SUVmax corresponding to values in the central nervous system (CNS). CONCLUSIONS: 18F-FDG-PET/CT has a high diagnostic accuracy in distinguishing between benign and malignant ovarian teratomas. Thus, PET/CT may be useful in cases where the diagnosis is unclear on MRI and other clinical findings. However, some MTs with abundant CNS tissue may have a high SUVmax. Therefore, the diagnosis of a benign or malignant lesion should be made carefully in conjunction with other clinical findings.

[A case of platinum-resistant, recurrent ovarian clear cell adenocarcinoma successfully treated with irinotecan (CPT-11) and paclitaxel (PTX) chemotherapy].

A 40-year-old woman presented to a local clinic with abdominal distension. She was referred to our hospital for suspected ovarian cancer. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed an ovarian tumor with mural nodules, ascites, pleural effusion, and peritoneal dissemination. Laparotomy revealed a 20-cm right ovarian tumor with strong adhesion to the uterus and rectum. Bilateral salpingo-oophorectomy was performed as a primary surgery. The histopathological diagnosis was stage IVovarian clear cell adenocarcinoma, and 6 cycles of postoperative chemotherapy with a combination of TC (paclitaxel [PTX] and carboplatin) and the mTOR inhibitor temsirolimus was administered. During maintenance treatment with temsirolimus, the lesion recurred, and progressive disease was confirmed. Because relapse occurred after 5 months from the last TC treatment, the disease was considered platinum-resistant ovarian cancer, and second-line chemotherapy with 6 cycles of irinotecan (CPT-11 ) and PTX was administered. Partial response was observed after 2 cycles, and the response period was 7 months. We suggest that chemotherapy with CPT-11/PTX could be a treatment option for platinum resistant recurrent ovarian clear cell adenocarcinoma.

Maximum standardized uptake value of fluorodeoxyglucose positron emission tomography/computed tomography is a prognostic factor in ovarian clear cell adenocarcinoma.

BACKGROUND: Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) is useful for diagnosing malignant tumors. Intracellular FDG uptake is measured as the standardized uptake value (SUV), which differs depending on tumor characteristics. This study investigated differences in maximum SUV (SUVmax) according to histologic type in ovarian epithelial cancer and the relationship of SUVmax with prognosis. METHODS: This study included 80 patients with ovarian epithelial cancer based on histopathologic findings at surgery and who had undergone PET/CT before treatment. Maximum SUV on PET/CT of primary lesions and histopathology were compared based on histologic type, and the prognosis associated with different SUVmax was evaluated. RESULTS: Clinical tumor stage was I in 35 patients, II in 8, III in 25, and IV in 12. Histologic type was serous adenocarcinoma (AC) in 33 patients, clear cell AC in 27, endometrioid AC in 15, and mucinous AC in 5. Median SUVmax was lower in mucinous AC (2.76) and clear cell AC (4.9) than in serous AC (11.4) or endometrioid AC (11.4). Overall, median SUVmax was lower in clinical stage I (5.37) than in clinical stage ≥II (10.3). However, in both clear cell AC and endometrioid AC, when histologic evaluation was possible, no difference was seen between stage I and stage ≥II. Moreover, in clear cell AC, the 5-year survival rate was significantly higher in the low-SUVmax group (100%) than in the high-SUVmax group (43.0%, P = 0.009). CONCLUSIONS: Maximum SUV on preoperative FDG-PET/CT in ovarian epithelial cancer differs according to histologic type. In clear cell AC, SUVmax may represent a prognostic factor.