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.

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, 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 Menin CD4-Cre (Menin-KO) mice by crossing Menin 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.

HighlightsWe 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.

Abstract. 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. IntroductionDysplasia that is seen on a biopsy of the cervix is called cervical intraepithelial neoplasia (CIN). It is grouped into three categories: CIN I (mild dysplasia), CIN II (moderate to marked dysplasia) and CIN III (severe dysplasia to carcinoma in situ). Treating high-grade (HG)-CIN reduces the incidence and mortality caused by invasive cervical cancer in women with these lesions (1-3). Women treated for CIN are of reproductive age (mean age of approximately 30 years), although the disorder may also arise in much younger women (4,5).Multiple techniques are available for the conservative treatment of HG-CIN in women of fertile age (6-9). These include ablative methods (e.g., cryotherapy, laser vaporization and cold coagulation), with satisfactory colposcopic examination results in women for whom invasion has been ruled out and excisional methods [e.g., the loop electrosurgical excision procedure (LEEP), laser conization and cold-kni...