Niraparib in Japanese patients with platinum-sensitive recurrent ovarian cancer: final results of a multicenter phase 2 study.

OBJECTIVE: This study evaluated the long-term safety and efficacy of niraparib in Japanese patients with platinum-sensitive recurrent ovarian cancer. METHODS: This was a follow-up analysis of a phase 2, multicenter, open-label, single-arm study in Japanese women with platinum-sensitive, relapsed ovarian cancer. Participants received niraparib (starting dose 300 mg) once daily in continuous 28-day cycles. The primary endpoint was the incidence of Grade 3 or 4 thrombocytopenia-related events (defined as the overall incidence of the MedDRA Preferred Terms "thrombocytopenia" and "platelet count decreased") occurring in the 30 days after initial administration of niraparib, and secondary endpoints included evaluation of treatment-emergent adverse events and progression-free survival. RESULTS: Nineteen patients (median age, 62 years; median body weight, 53.9 kg) were enrolled. As previously reported, the incidence of Grade 3 or 4 thrombocytopenia-related events during the first 30 days of treatment was 31.6%. At data cutoff, median (range) treatment exposure was 504.0 (56-1,054) days and mean ± standard deviation dose intensity was 154.4±77.5 mg/day. The most common treatment-emergent adverse events were nausea (n=14, 73.7%), decreased platelet count (n=12, 63.2%), decreased neutrophil count (n=11, 57.9%), anemia, vomiting, and decreased appetite (all n=9, 47.4%). One patient was diagnosed with treatment-related leukemia, which resulted in death. Median (95% confidence interval) progression-free survival was 18.0 (5.6-26.7) months. CONCLUSION: Overall, the safety profile of niraparib was considered manageable in this study population of Japanese patients with platinum-sensitive, relapsed ovarian cancer and was consistent with that observed in studies of non-Japanese patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03759587.

Pregnancy outcomes among female childhood, adolescent, and young adult cancer survivors assessed using internet-based nationwide questionnaire surveys in Japan.

OBJECTIVE: Female cancer survivors planning to become pregnant are concerned about the impact of cancer treatment on their ability to maintain normal pregnancy and the negative impact on their offspring. However, studies on the pregnancy outcomes of cancer survivors in Japan are limited. Therefore, this study aimed to investigate the pregnancy outcomes of female cancer survivors by comparing them with women without a history of malignant tumors in Japan. METHODS: This cross-sectional study included 3308 subjects, based on an internet-based questionnaire (self-reported) survey conducted in Japan. Differences in pregnancy outcomes, including multiple pregnancies, stillbirth, preterm birth (PTB), and infant birthweight, between cancer survivors and subjects without a history of malignant tumors, were evaluated using a generalized linear mixed-effects model with adjustment for possible confounding factors. RESULTS: Of 3308 subjects included in this study, 629 (19.0%) were cancer survivors, among whom cervical (40.4%), breast (19.1%), and thyroid (7.0%) malignancies were most frequent. 71 (2.2%) and 53 (1.6%) participants had a history of multiple pregnancies and stillbirth, respectively; 385 (11.8%), 179 (5.5%), and 137 (4.2%) participants, respectively, had histories of PTB at less than 37, 34, and 32 weeks of gestation. Further, 302 (10.7%), 326 (11.6%), and 330 (11.7%) participants delivered to low birthweight (LBW), small-for-gestational-age (SGA), and large-for-gestational-age (LGA) infants, respectively. Subjects with a history of cervical or breast cancers had significantly higher odds of PTB at <37 weeks of gestation (adjusted odds ratios [ORs], 1.87 [95% CI: 1.25-2.81] and 2.61 [95% CI: 1.77-3.86], respectively), preterm LBW infants (adjusted ORs, 2.70 [95% CI: 1.39-5.24] and 2.76 [95% CI: 1.03-7.38], respectively), and LGA infants (1.98 [95% CI: 1.36-2.89] and 1.99 [95% CI: 1.14-3.49], respectively), compared to those without a history of a malignant tumor. Subjects with a history of thyroid cancer had significantly higher odds of stillbirth (adjusted OR, 5.11 [95% CI: 1.11-23.5]). CONCLUSION: Cancer survivors had a higher risk of adverse pregnancy outcomes than those without a history of malignant tumors in Japan. Healthcare providers should consider the high likelihood of adverse pregnancy outcomes during preconception counseling for cancer survivors.

Discrepancies in pathological diagnosis of endometrial stromal sarcoma: a multi-institutional retrospective study from the Japanese clinical oncology group.

Endometrial stromal sarcoma (ESS) is a rare uterine malignancy that requires accurate pathological diagnosis for proper treatment. This study aimed to clarify the discrepancies in the pathological diagnosis of ESS and obtain practical clues to improve diagnostic accuracy. Between 2002 and 2015, 148 patients with low-grade ESS (LGESS), high-grade ESS (HGESS), undifferentiated endometrial sarcoma (UES), or undifferentiated uterine sarcoma (UUS) diagnosed at 31 institutions were included. We performed immunohistochemistry, real-time polymerase chain reaction for JAZF1-SUZ12 and YWHAE-NUTM2A/B, and break-apart fluorescent in situ hybridization for JAZF1, PHF1, and YWHAE. Central pathology review (CPR) was performed by six pathologists. After CPR, LGESS, HGESS, UES/UUS, and other diagnoses were confirmed in 72, 25, 16, and 31 cases, respectively. Diagnostic discrepancies were observed in 19.6% (18/92) of LGESS and 34% (18/53) of HGESS or UUS/UES. Adenosarcomas, endometrial carcinomas, carcinosarcomas, and leiomyosarcomas were common diagnostic pitfalls. JAZF1-SUZ12 transcript, PHF1 split signal, and YWHAE-NUTM2A/B transcript were mutually exclusively detected in 23 LGESS, 3 LGESS, and 1 LGESS plus 3 HGESS, respectively. JAZF1-SUZ12 and YWHAE-NUTM2A/B transcripts were detected only in cases with CPR diagnosis of LGESS or HGESS. The CPR diagnosis of LGESS, HGESS, and UUS was a significant prognosticator, and patients with LGESS depicted a favorable prognosis, while those with UUS showed the worst prognosis. Pathological diagnosis of ESS is often challenging and certain tumors should be carefully considered. The accurate pathological diagnosis with the aid of molecular testing is essential for prognostic prediction and treatment selection.

Perioperative management of emergent cesarean section in a patient with peripartum cardiomyopathy and orthopnea: a case report.

Perioperative management of pregnant women with heart failure is difficult. Management of anesthesia in pregnant women is especially difficult because all of the currently available choices present challenges. We report a patient with peripartum cardiomyopathy (PPCM) who required an emergent cesarean section and discuss the possible tactics for managing anesthesia. A 40-year-old primipara with severe cardiac and respiratory failure required an emergent cesarean section at 39+1 gestational weeks. Her left ventricular ejection fraction was between 10% and 15%, and she had orthopnea. General anesthesia was planned after inserting sheaths for percutaneous cardiopulmonary support from the femoral artery and vein. However, when the patient was asked to lie down on the operation bed, she panicked and resisted because of labor pain and dyspnea. Therefore, anesthesia was induced instead of the initial plan. Finally, we successfully managed the anesthesia and delivered the newborn. There are no alternatives to general anesthesia in patients with PPCM presenting with orthopnea. Anesthesia induction in the supine position is impossible in such patients owing to dyspnea. Anesthesia should be started with light sedation in the sitting position, and ketamine or low-dose remifentanil may be an option to maintain maternal hemodynamics and prevent neonatal asphyxia.

Pregnancy outcomes in children, adolescents, and young adults that survived cancer: A nationwide survey in Japan.

AIM: Recent advances in cancer treatment have improved the prognosis of child, adolescent, and young adult (CAYA) cancer survivors. This study aimed to examine the current status of pregnancy outcomes among female cancer survivors in Japan. METHODS: The first questionnaire was sent to 633 major tertiary institutions certified by the Japan Society of Obstetrics and Gynecology to identify institutions managing cases of pregnant cancer survivors between January 2011 and December 2015. The second questionnaire was sent only to institutions with pregnant cancer survivors during the study period. RESULTS: We analyzed 2242 singleton deliveries of cancer survivors based on the responses received in the second questionnaire (199/255 responses; 78.0%). The three most frequent types of malignant tumors were uterine cervical (23.4%), breast (17.6%), and thyroid cancers (17.5%). Conception was aided by the use of assisted reproductive technology in 17.0% of the patients. The proportions of mothers aged 35-39.9 and ≥ 40 years were 36.5% and 11.8%, respectively. The prevalence of preterm birth (PTB) at <37, <34, and < 32 weeks' gestation were 16.7%, 6.8%, and 4.3%, respectively. The proportion of infants with low birth weight (LBW) was 18.9%. CONCLUSION: The present study findings suggest that advanced maternal age was common among pregnant cancer survivors and these survivors often gave birth to PTB and LBW infants in Japan. The likelihood of adverse pregnancy outcomes should be considered by healthcare providers when planning counseling and perinatal care for cancer survivors.

Cloning of carrier cells infected with oncolytic adenovirus driven by midkine promoter and biosafety studies.

BACKGROUND: A549 carrier cells infected with oncolytic adenovirus can induce complete tumor reduction of subcutaneous ovarian tumors but not intraperitoneal disseminated ovarian tumors. This appears to be a result of the insufficient antitumor effect of A549 carrier cells. Therefore, in the present study, we cloned a novel carrier cell with the aim of improving the antitumor effects. METHODS: Carrier cells infected with oncolytic adenovirus AdE3-midkine with a midkine promoter were cloned by limiting dilution. We examined the antitumor effects of these cells on subcutaneous and intraperitoneal OVHM ovarian tumors in a syngeneic mouse model. Biosafety tests were conducted in beagle dogs and rabbits. RESULTS: We cloned EHMK-51-35 carrier cells with 10-fold higher antitumor effects compared to A549 carrier cells in vitro. EHMK-51-35 carrier cells co-infected with AdE3-midkine and Ad-mGM-CSF induced a 100% complete tumor reduction in subcutaneous tumors and a 60% reduction of intraperitoneal disseminated tumors. Single-dose acute toxicity test on beagle dogs with EHMK-51-35 carrier cells co-infected with AdE3-midkine and Ad-cGM-CSF showed no serious side effects. Biologically active adenoviruses were not detected in the blood, saliva, feces, urine or whole organs. In a chronic toxicity test, VX2 tumors in rabbits were injected five times with EHMK-51-35 carrier cells infected with AdE3-midkine and these rabbits showed no serious side effects. CONCLUSIONS: Significant antitumor effects and safety of cloned EHMK-51-35 carrier cells were confirmed in intraperitoneal ovarian tumors and toxicity tests, respectively. These findings will be extended to preclinical efficacy studies using dogs and cats, with the aim of conducting human clinical trials on refractory solid tumors.

Reinforce the antitumor activity of CD8+ T cells via glutamine restriction.

The antitumor activity of activated CD8+ T cells in the tumor microenvironment seems to be limited due to their being metabolically unfit. This metabolic unfitness is closely associated with T-cell exhaustion and impairment of memory formation, which are barriers to successful antitumor adoptive immunotherapy. We therefore assessed the role of glutamine metabolism in the antitumor activity of CD8+ T cells using a tumor-inoculated mouse model. The adoptive transfer of tumor-specific CD8+ T cells cultured under glutamine-restricted (dGln) conditions or CD8+ T cells treated with specific inhibitors of glutamine metabolism efficiently eliminated tumors and led to better survival of tumor-inoculated mice than with cells cultured under control (Ctrl) conditions. The decreased expression of PD-1 and increased Ki67 positivity among tumor-infiltrating CD8+ T cells cultured under dGln conditions suggested that the inhibition of glutamine metabolism prevents CD8+ T-cell exhaustion in vivo. Furthermore, the transferred CD8+ T cells cultured under dGln conditions expanded more efficiently against secondary OVA stimulation than did CD8+ T cells under Ctrl conditions. We found that the expression of a pro-survival factor and memory T cell-related transcription factors was significantly higher in CD8+ T cells cultured under dGln conditions than in those cultured under Ctrl conditions. Given these findings, our study uncovered an important role of glutamine metabolism in the antitumor activity of CD8+ T cells. The novel adoptive transfer of tumor-specific CD8+ T cells cultured in glutamine-restricted conditions may be a promising approach to improve the efficacy of cell-based adoptive immunotherapy.

Assessment of laparoscopic training for gynecological malignancies using Thiel-embalmed human cadavers.

The introduction of laparoscopic surgery has also been beneficial for patients with gynecological malignancies. In this respect, surgeons should receive related training in the context of human resource development. Hands-on training was introduced using Thiel-embalmed human cadavers (THCs) in 2014. To determine the usefulness of THCs, they were evaluated in terms of tissue color, consistency and operative tactility, among others, compared with in vivo laparoscopic training for gynecological malignancies. Hands-on training sessions using THCs were held for a total of 11 times at Ehime University Graduate School of Medicine between March 2014 and October 2017. Training on THCs included advanced laparoscopic procedures for radical hysterectomy type III. At the end of each training session, data were collected using a standardized, anonymous questionnaire termed the Likert scale. THCs ensured flexibility and plasticity of tissues and organs; therefore, the working space was similar to that in the living body under pneumoperitoneum. After analyzing the quality and consistency of tissue and organ color compared with in vivo conditions, most of the participants agreed or strongly agreed regarding the uterus, adnexa and ureter, but not regarding the large blood vessels. The highest scores were observed in the authenticity of the anatomical condition of each organ. Most participants strongly agreed that training using THCs would help improve their laparoscopic skills with a high level of satisfaction. Furthermore, most participants reported that they would recommend this training to other obstetrician-gynecologists. Laparoscopic training for gynecological malignancies using THCs was comparable to the in vivo conditions in terms of surgical view and operative tactility. Therefore, THCs may be an excellent training tool for improving laparoscopic surgical skills for gynecological malignancies.

Menin Plays a Critical Role in the Regulation of the Antigen-Specific CD8+ T Cell Response upon Listeria Infection.

Menin, a tumor suppressor protein, is encoded by the MEN1 gene in humans. Certain germinal mutations of MEN1 induce an autosomal-dominant syndrome that is characterized by concurrent parathyroid adenomas and several other tumor types. Although menin is also expressed in hematopoietic lineages, its role in CD8+ T cells remains unclear. We generated Meninflox/flox CD4-Cre (Menin-KO) mice by crossing Meninflox/flox mice with CD4-Cre transgenic (Tg) mice to determine the role of menin in CD8+ T cells. Wild-type (WT) and Menin-KO mice were infected with Listeria monocytogenes expressing OVA to analyze the immune response of Ag-specific CD8+ T cells. Menin deficiency resulted in an impaired primary immune response by CD8+ T cells. On day 7, there were fewer Menin-KO OVA-specific CD8+ T cells compared with WT cells. Next, we adoptively transferred WT and Menin-KO OT-1 Tg CD8+ T cells into congenic recipient mice and infected them with L. monocytogenes expressing OVA to determine the CD8+ T cell-intrinsic effect. Menin-KO OT-1 Tg CD8+ T cells were outcompeted by the WT cells upon infection. Increased expression of Blimp-1 and T-bet, cell cycle inhibitors, and proapoptotic genes was observed in the Menin-KO OT-1 Tg CD8+ T cells upon infection. These data suggest that menin inhibits differentiation into terminal effectors and positively controls proliferation and survival of Ag-specific CD8+ T cells that are activated upon infection. Collectively, our study uncovered an important role for menin in the immune response of CD8+ T cells to infection.

Clinical investigation of the safety and efficacy of a cervical intraepithelial neoplasia treatment using a hyperthermia device that uses heat induced by alternating magnetic fields.

Multiple techniques have been used for the conservative treatment of high-grade cervical intraepithelial neoplasia (HG-CIN) in women of fertile age. Conization has been associated with stenosis of the cervix and a decrease in cervical mucus secretion, in addition to the increase in the risk of cervical canal shortening and problems during the perinatal period, including premature birth and premature rupture of membranes. Although the laser transpiration technique does not cause shortening of the cervical canal, it is associated with the recurrent risk of deep residual disease. The present study aimed to investigate the therapeutic safety and efficacy of the therapy performed using the transaction magnetic field induction heating device, AMTC400, in fertile patients with HG-CIN (excluding carcinoma in situ). Four premenopausal patients with CIN3 and high-risk human papilloma virus (HPV)-positive were treated using an AMTC400. Chronological colposcopic findings, high-risk HPV, final histological findings with conization and follow-up data were evaluated. All the treatments were successfully performed on the in-patients without anesthesia. Intra- and postoperative complications included minor pain and bleeding in all cases. Two of the cases (50%) were high-risk HPV-negative following the treatments. All cases exhibited a change in the observed color (to white), and subsequent epithelization following treatment. Although cytological analysis at 5 weeks following the treatment confirmed the cases were negative for intraepithelial lesions and malignancies, a definitive histology with conization 6 weeks following the treatment confirmed CIN1 and koilocytosis in all cases. The assessment of treatment effectiveness was determined as a moderate improvement in all cases. In conclusion, thermotherapy applied using AMTC400 represented a safe and effective treatment for HG-CIN in women of fertile age. However, additional improvements associated with the site of puncture needles are required. Further studies are required to confirm the long-term efficacy and reproductive outcomes.

The Transcriptional Repressor Gfi1 Plays a Critical Role in the Development of NKT1- and NKT2-Type iNKT Cells.

Gfi1 plays an important role in the development and maintenance of many hematopoietic linage cells. However, the impact of Gfi1-deficiency on the iNKT cell differentiation remains unclear. We herein demonstrate a critical role of Gfi1 in regulating the development of iNKT cell subsets. In the thymus of T cell-specific Gfi1-deficient mice, iNKT cells normally developed up to stage 2, while the number of stage 3 NK1.1pos iNKT cells was significantly reduced. Furthermore, CD4pos iNKT cells were selectively reduced in the peripheral organs of T cell-specific Gfi1-deficient mice. The α-GalCer-dependent production of IFN-γand Th2 cytokines, but not IL-17A, was severely reduced in T cell-specific Gfi1-deficient mice. In addition, a reduction of the α-GalCer-induced anti-tumor activity was observed in Gfi1-deficient mice. These findings demonstrate the important role of Gfi1 in regulating the development and function of NKT1- and NKT2-type iNKT cell subsets.

Atypical carcinoid of the uterine cervix with aggressive clinical behavior: A case report.

•We herein report a case of a 44-year-old Japanese woman diagnosed with stage IB1 atypical carcinoid of the uterine cervix.•After radical hysterectomy, she developed recurrence with aggressive clinical behavior, resistance to CPT-11 + cisplatin and paclitaxel + CBDCA chemotherapy.

Concurrent chemoradiotherapy with nedaplatin in patients with stage IIA to IVA cervical carcinoma.

The present study aimed to evaluate the efficacy and toxicities of nadaplatin-based concurrent chemoradiotherapy (CCRT) in patients with stage IIA to IVA cervical carcinoma. Patients with an International Federation of Gynecology and Obstetrics (FIGO) stage IIA to IVA cervical carcinoma were treated with nadaplatin-based CCRT, using high-dose rate intracavitary brachytherapy (HDR-ICBT) or radiotherapy (RT) alone, in patients with FIGO stage IIA to IVA cervical carcinoma. CCRT with nedaplatin (80 mg/m2) was administered on Days 1 and 29. The records of 17 women treated either with nadaplatin-based CCRT using HSR-ICBT (n=8) or RT alone (n=9), for stage IIA to IVA cervical carcinoma were retrospectively reviewed. The activity and toxicity were compared in the two treatment groups. Progression-free survival (PFS) and overall survival (OS) were the main endpoints. The 5-year overall survival rates in the CCRT and RT groups were 68.6 and 77.8%, respectively. The median OS of the CCRT and RT groups was 38.5 and 27.3 months, respectively. There was no significant difference in either PFS (P=0.618) or OS (P= 0.231). The most common grade 3-4 or higher toxicities in the CCRT groups were leuko-/neutropenia (37.5%). The frequency of acute grade 3-4 toxicity was higher in the CCRT compared to the RT group. However, no statistically significant difference was observed. Nedaplatin-based CCRT was safely performed. Although the prognosis of patients with FIGO stage IIA to IVA cervical carcinoma was not significantly improved, fewer distant relapses were observed in this treatment. Consequently, nedaplatin-based CCRT may be considered as a potential alternative to cisplatin-based CCRT in this patient population.

[Longer working hours of pharmacists in the ward resulted in lower medication-related errors--survey of national university hospitals in Japan].

It is obvious that pharmacists play a critical role as risk managers in the healthcare system, especially in medication treatment. Hitherto, there is not a single multicenter-survey report describing the effectiveness of clinical pharmacists in preventing medical errors from occurring in the wards in Japan. Thus, we conducted a 1-month survey to elucidate the relationship between the number of errors and working hours of pharmacists in the ward, and verified whether the assignment of clinical pharmacists to the ward would prevent medical errors between October 1-31, 2009. Questionnaire items for the pharmacists at 42 national university hospitals and a medical institute included the total and the respective numbers of medication-related errors, beds and working hours of pharmacist in 2 internal medicine and 2 surgical departments in each hospital. Regardless of severity, errors were consecutively reported to the Medical Security and Safety Management Section in each hospital. The analysis of errors revealed that longer working hours of pharmacists in the ward resulted in less medication-related errors; this was especially significant in the internal medicine ward (where a variety of drugs were used) compared with the surgical ward. However, the nurse assignment mode (nurse/inpatients ratio: 1 : 7-10) did not influence the error frequency. The results of this survey strongly indicate that assignment of clinical pharmacists to the ward is critically essential in promoting medication safety and efficacy.