三善 陽子

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cancer cell death and contributes to tumor rejection by cytotoxic lymphocytes in cancer immunosurveillance and immunotherapy. TRAIL and TRAIL receptor agonists have garnered wide popularity as promising agents for cancer therapy. We previously demonstrated that the loss of fucosylation in cancer cells impairs TRAIL sensitivity; however, the precise structures of the fucosylated glycans that regulate TRAIL sensitivity and their carrier molecules remain elusive. Herein, we observed that Lewis glycans among various fucosylated glycans positively regulate TRAIL-induced cell death. Specifically, Lewis glycans on lacto/neolacto glycosphingolipids, but not glycoproteins including TRAIL receptors, enhanced TRAIL-induced formation of the cytosolic caspase 8 complex, without affecting the formation of the membranous receptor complex. Furthermore, type I Lewis glycan expression in colon cancer cell lines and patient-derived cancer organoids was positively correlated with TRAIL sensitivity. These findings provide novel insights into the regulatory mechanism of TRAIL-induced cell death and facilitate the identification of novel predictive biomarkers for TRAIL-related cancer therapies in future.

2016〜2021年に当院小児科を受診した慢性肝疾患患者79例を対象に、肝線維化の指標としてM2BPGiを用い、血清IGF-I値との関連について検討した。結果、血清IGF-I SDの変化量と血清M2BPGi値との間に負の相関が認められた。

The Japan Society of Clinical Oncology (JSCO) published the "JSCO Clinical Practice Guidelines 2017 for Fertility Preservation in Childhood, Adolescent, and Young Adult Cancer Patients" in 2017. This was the first guideline in cancer reproductive medicine in Japan. In the field of cancer reproductive medicine, close cooperation between an oncologist and a physician for reproductive medicine is important from before treatment initiation until long after treatment. The guideline takes into consideration disease specificity and provides opinions from the perspective of oncologists and specialists in reproductive medicine that are in line with the current state of the Japanese medical system. It is intended to serve as a reference for medical staff in both fields regarding the availability of fertility preservation therapy before the start of cancer treatment. Appropriate use of this guideline makes it easier to determine whether fertility preservation therapy is feasible and, ultimately, to improve survivorship in childhood, adolescent, and young adult cancer patients. In this article (Part 2), we describe details by organ/system and also for pediatric cancer.

<title>Abstract</title>In 2017, the Japan Society of Clinical Oncology (JSCO) published the JSCO Clinical Practice Guidelines 2017 for Fertility Preservation in Childhood, Adolescent, and Young Adult Cancer Patients. These were the first Japanese guidelines to address issues of oncofertility. In this field of medicine, sustained close cooperation between oncologists and reproductive specialists is essential from the diagnosis of cancer until many years after completion of cancer treatment. These JSCO guidelines were intended to guide multidisciplinary medical staff in considering the availability of fertility preservation options and to help them decide whether to provide fertility preservation to childhood, adolescent, and young adult cancer patients before treatment starts, with the ultimate goal of improving patient survivorship. The guidelines are presented as Parts 1 and 2. This article (Part 1) summarizes the goals of the guidelines and the methods used to develop them and provides an overview of fertility preservation across all oncology areas. It includes general remarks on the basic concepts surrounding fertility preservation and explanations of the impacts of cancer treatment on gonadal function by sex and treatment modality and of the options for protecting/preserving gonadal function and makes recommendations based on 4 clinical questions. Part 2 of these guidelines provides specific recommendations on fertility preservation in 8 types of cancer (gynecologic, breast, urologic, pediatric, hematologic, bone and soft tissue, brain, and digestive).

<title>Abstract</title> <sec id="j_jpem-2021-0205_abs_001_w2aab3b7b4b1b6b1aab1c11b1Aa"> <title>Objectives</title> Iodine deficiency and excess both cause thyroid dysfunction. Few data describe the relationship between iodine status and outcomes of congenital hypothyroidism (CH) in iodine-sufficient areas. We investigated urinary iodine (UI) concentration and its relationship with the clinical course of CH. </sec> <sec id="j_jpem-2021-0205_abs_002_w2aab3b7b4b1b6b1aab1c11b2Aa"> <title>Methods</title> We reviewed and retrospectively analyzed patients with positive newborn screening (NBS) for CH from January 2012 to June 2019 in Japan, obtaining UI and UI-urine creatinine ratio (UI/Cr), serum TSH, free T₄, free T₃ and thyroglobulin (Tg) at the first visit, TSH at NBS, levothyroxine (LT4) dose, and subsequent doses. A UI value of 100–299 μg/L was considered adequate. </sec> <sec id="j_jpem-2021-0205_abs_003_w2aab3b7b4b1b6b1aab1c11b3Aa"> <title>Results</title> Forty-eight patients were included. Median UI and UI/Cr were 325 μg/L and 3,930 µg/gCr, respectively. UI was high (≥300 μg/L) in 26 (54%) and low (≤99 μg/L) in 11 (23%). LT4 was administered to 34 patients. Iodine status was not related to the need for treatment. We found a U-shaped relationship between Tg and UI/Cr. Patients with high Tg (≥400 ng/mL) and abnormal UI levels required significantly lower LT4 doses (≤20 µg/day) at three years of age. Even if they showed severe hypothyroidism initially, they did not need subsequent dose increments. </sec> <sec id="j_jpem-2021-0205_abs_004_w2aab3b7b4b1b6b1aab1c11b4Aa"> <title>Conclusions</title> Abnormal UI levels with Tg elevation were associated with lower LT4 dose requirements. The evaluation of iodine status and Tg concentrations were considered useful in patients suspected of CH. </sec>

多発性内分泌腫瘍症(multiple endocrine neoplasia;MEN)2型はRET遺伝子の病的バリアントを原因とする遺伝性腫瘍症である。MEN2型の遺伝性甲状腺髄様癌はほぼ完全浸透率を示す悪性腫瘍で乳幼児期からも発生し、再発が多いため早期発見と治療が重要である。遺伝性甲状腺髄様癌は、海外では予防的甲状腺全摘が推奨されている。一般的に幼少期の甲状腺手術の合併症リスクは高いが、幼少時の甲状腺全摘のみの予防的甲状腺全摘/極早期摘出は、高年齢の進行段階で中央区域以上のリンパ節郭清を伴うよりは手術合併症が少ないことが複数の調査で示されている。日本では予防的甲状腺全摘が保険で認められていない。費用や医療環境も鑑みると、本邦で再発も手術合併症も減らし生涯の質を向上させるためには、現時点ではRET遺伝子の病的バリアント保有者はカルシトニン値上昇後に極早期甲状腺全摘出を行うことが現実的な選択肢であろう。(著者抄録)

Existing guidelines recommend long-term follow-up of childhood cancer survivors (CCS). However, in Japan, transitional care for CCS has not been established. To ascertain the current status in Japan, and to cultivate a better understanding, a questionnaire survey was conducted on transitional care in CCS, and adolescent and young adult (AYA) cancer survivors. Questionnaires were distributed to 183 councilors (137 institutions) of the Japanese Society for Pediatric Endocrinology. A total of 131 responses, representative of 174 councilors, were obtained. The response rate was 95%. Among the respondents, 91% had experience in medical care for cancer patients, while 63% had experience in transitional care; however, the number of patients referred to adult clinics was small. Further, 89% acknowledged the availability of adult endocrinologists who were willing to accept these patients; although their numbers were insufficient. Pediatric endocrinologists highlighted difficulties in medical examinations concerning infertility, obesity, pregnancy/delivery, and gonadal dysfunction, in that order. Staff and time shortages were listed as some of the challenges faced by medical staff, while multisystem morbidity was listed for patients. This nationwide questionnaire survey revealed that Japanese pediatric endocrinologists require cooperation between related departments and collaborative infrastructure to develop transitional care for cancer survivors.

Purpose: Cancer treatment delay due to fertility preservation procedures is a barrier for patients with breast cancer who wish to preserve their fertility. This study aimed to describe the associations between fertility preservation and treatment delay in patients with breast cancer with reproductive concerns and assess the factors related to treatment delay. Methods: Patients with primary breast cancer who visited the reproductive unit at our institution before cancer treatment between 2007 and 2015 were enrolled. The treatment delay cut-off was defined as follows: time to chemotherapy (TTC) >8 weeks for patients intending to receive neoadjuvant chemotherapy, TTC >12 weeks for patients intending to receive adjuvant chemotherapy, time to endocrine therapy (TTE) >12 weeks for patients intending to receive endocrine therapy without radiation therapy and TTE >20 weeks for patients intending to receive endocrine therapy after radiation therapy. Multivariable models were constructed to examine the factors of treatment delay. Results: Overall, 212 patients met the inclusion criteria. Using the defined cut-offs, treatment delay was noted in 18% of the patients. Endocrine therapy was related to treatment delay (OR 4.49, 95% CI 1.02 to 19.7; p=0.05), but fertility preservation by artificial reproductive treatment (ART) was not. Pregnancy and delivery following treatment for breast cancer were achieved in 18 (19%) and 15 (16%) patients who underwent fertility preservation with ART. Conclusion: Fertility preservation with ART was not associated with treatment delay in patients with breast cancer who were referred to reproductive specialists before cancer treatment.