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Purpose: Precision medicine plays an important role in the treatment of patients with advanced melanoma. Despite its high incidence in White patients, advanced melanoma is rare in Asian countries, hampering prospective clinical trials targeting the Asian population. This retrospective study aimed to elucidate the real-world molecular diagnoses and outcomes of Japanese patients with melanoma using comprehensive genome profiling (CGP)., Materials and Methods: Patients with melanoma who completed standard anticancer medical treatments (including those expected to complete the treatments) underwent CGP, which is covered by the National Health Insurance. We analyzed the results and clinical annotations of 569 patients registered before August 2023 in a national database., Results: Skin, mucosal, and uveal melanomas accounted for 64%, 28%, and 7% of cases, respectively. Patients with BRAF , NRAS , NF1 , and KIT variants represented 25%, 20%, 17%, and 17%, respectively. Eighty-two percent of BRAF , 97% of NRAS , 69% of NF1 , and 54% of KIT were actionable alterations (ie, BRAF classes I, II, and III, NRAS Q61, G12, G13, NF1 loss-of-function, KIT gain-of-function variants). BRAF V600E/K variants occurred in 22% of skin and 2% of mucosal melanomas, but not in uveal melanomas. The mean tumor mutation burden in cutaneous melanomas was 4.2 variants/Mb. Patients previously treated with BRAF-targeted therapy harbored amplifications of BRAF and cell cycle genes more frequently than therapy-naive patients. Thirty-six patients (6.3%) were treated following the molecular tumor board (MTB) recommendations., Conclusion: Actionable gene alterations in BRAF , NRAS , NF1 , and KIT are common in Japanese patients with melanoma. However, few patients were treated according to the MTB recommendations, suggesting that there is an unmet need to increase accessibility to gene-matched clinical trials in Japan.

Background: Non-small-cell lung cancer (NSCLC) is associated with a high incidence of brain metastasis (BM), and the prognosis of patients with NSCLC and BM is poor. This study aimed to identify the prognostic factors and elucidate the survival rates of Japanese patients with NSCLC and BM at initial diagnosis., Methods: HOT 1701 is a retrospective multicenter study of patients with NSCLC and BM at initial diagnosis. The medical records of all consecutive patients diagnosed with advanced or recurrent NSCLC and BM at 14 institutions of the Hokkaido Lung Cancer Clinical Study Group Trial (HOT) in Japan were reviewed. The participants were categorized based on the presence or absence of driver mutations. The Kaplan-Meier method was used to estimate median overall survival (OS). Univariate and multivariate analyses were performed to identify prognostic factors in these patients., Results: Among 566 patients with NSCLC and BM, the median OS was 11.8 months. Patients with driver mutations survived longer than those without driver mutations. The univariate and multivariate analyses revealed 6 independent prognostic factors: age ≥65 years, poor performance status, T factor, absence of driver gene mutations, presence of extracranial metastases, and number of BM. According to the prognostic score based on these 6 factors, the patients were stratified into 3 risk groups: low-, intermediate-, and high-risk, with median OS of 27.8, 12.2, and 2.8 months, respectively., Conclusions: We developed a new prognostic model for patients with NSCLC and BM, which may help determine prognosis at diagnosis., Competing Interests: The authors declare that they have no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Animals sense chemical cues such as nutritious and noxious stimuli through the chemosensory system and adapt their behavior, physiology, and developmental schedule to the environment. In the Drosophila central nervous system, chemosensory interneurons that produce neuropeptides called Hugin (Hug) peptides receive signals from gustatory receptor neurons and regulate feeding behavior. Because Hug neurons project their axons to the higher brain region within the protocerebrum where dendrites of multiple neurons producing developmentally important neuropeptides are extended, it has been postulated that Hug neurons regulate development through the neuroendocrine system. In this study, we show that Hug neurons interact with a subset of protocerebrum neurons that produce prothoracicotropic hormone (PTTH) and regulate the onset of metamorphosis and systemic growth. Loss of the hug gene and silencing of Hug neurons caused a delay in larval-to-prepupal transition and an increase in final body size. Furthermore, deletion of Hug receptor-encoding genes also caused developmental delay and body size increase, and the phenotype was restored by expressing Hug receptors in PTTH-producing neurons. These results indicate that Hug neurons regulate developmental timing and body size via PTTH-producing neurons. This study provides a basis for understanding how chemosensation is converted into neuroendocrine signaling to control insect growth and development., (© 2024 Wiley Periodicals LLC.)

n-3 Long-chain polyunsaturated fatty acids (n-3 LC-PUFAs), including eicosapentaenoic acid (EPA), are essential multifunctional nutrients in animals. Microorganisms such as microalgae are known to be n-3 LC-PUFA producers in aquatic environments. Various aquatic invertebrates, including Harpacticoida copepods, and a few terrestrial invertebrates, such as the nematode Caenorhabditis elegans, possess n-3 LC-PUFA biosynthetic enzymes. However, the capacity for n-3 LC-PUFA biosynthesis and the underlying molecular mechanisms in terrestrial insects are largely unclear. In this study, we investigated the fatty acid biosynthetic pathway in the silkworm Bombyx mori and found that EPA was present in silkworms throughout their development. Stable isotope tracing revealed that dietary α-linolenic acid (ALA) was metabolized to EPA in silkworm larvae. These results indicated that silkworms synthesize EPA from ALA. Given that EPA is enriched in the central nervous system, we propose that EPA confers optimal neuronal functions, similar to docosahexaenoic acid, in the mammalian nervous system., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Oligometastasis and oligoprogression (OP) has not been adequately defined in extensive-stage SCLC (ES-SCLC) and may be a good indication for adding local treatment. Therefore, this multicenter study aimed to investigate the prognostic impact of oligometastasis and OP in ES-SCLC., Methods: We enrolled patients who received chemoimmunotherapy between September 2019 and June 2022. Patients were classified into oligometastasis and non-oligometastasis groups by determining the number of original tumor lesions and distant metastases (worsening or newly appearing lesions) at the time of initial diagnosis and disease progression after first-line treatment., Results: We retrospectively analyzed 265 consecutive patients with ES-SCLC. Synchronous oligometastasis (SOM) and OP was defined as less than or equal to five lesions in less than or equal to two organs, including lungs; 21.0% and 53.2% of patients had SOM and OP, respectively. Median progression-free survival was 5.8 months and 4.9 months in patients with and without SOM, respectively (hazard ratio [HR] = 0.72, 95% confidence interval [CI]: 0.51-1.02, p  = 0.065). Median overall survival was 20.5 months and 15.0 months in patients with and without SOM (HR = 0.58, 95% CI: 0.37-0.95, p  = 0.027) from the initiation of first-line treatment. The OP group revealed a better progression-free survival of 5.2 months (versus 3.2 mo, HR = 0.69, 95% CI: 0.50-0.96, p  = 0.026) and overall survival of 15.1 months (versus 7.5 mo, HR = 0.44, 95% CI: 0.29-0.66, p  = 0.027) from the initiation of second-line treatment compared with the non-OP group. The Lung Immune Prognostic Index score was significantly lower in the SOM and OP group., Conclusions: ES-SCLC in patients with SOM and OP may be more indolent than that of the nonoligometastasis group, therefore, new treatment strategies, including the addition of local treatment, should be explored., Clinical Trial Registration: This study was registered at UMIN-CTR (UMIN000053402)., Competing Interests: Dr. Asahina reported receiving grants from 10.13039/100004325AstraZeneca, receiving payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Chugai Pharmaceutical, Merck Sharp & Dohme, Bristol-Myers Squib, Eli Lilly, Taiho Pharmaceutical, AstraZeneca, Ono Pharmaceutical, Merck, KyowaHakko-Kirin and reported participation on a data safety monitoring board or advisory board of AstraZeneca. Dr. Yokouchi reported receiving grants from Chugai Pharmaceuticals Co., Ltd., AstraZeneca, AbbVie, Daiichi Sankyo, Bristol-Myers Squibb Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Sanofi, and personal fees from Chugai Pharmaceutical Co., Ltd. and AstraZeneca during the conduct of the study. Dr. Megumi Furuta reported receiving honoraria from AstraZeneca K.K., Daiichi Sankyo Co, Ltd., Nippon Kayaku Co, Ltd., and Chugai Pharmaceutical Co. during the conduct of the study. Dr. Konno reported receiving grants from 10.13039/100010795Chugai Pharmaceutical. Dr. Hosomi reported receiving payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, and educational events from AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol-Myers Squibb, Kyowa Kirin, Nippon Kayaku, Takeda, Eisai, Novartis, Pfizer, Merck Sharp & Dohme during the conduct of the study. Dr. Oizumi reports receiving grants from 10.13039/100006483AbbVie, 10.13039/100002429Amgen, AstraZeneca, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Merck Sharp & Dohme, Pfizer, Sanofi, Taiho Pharmaceutical, and Takeda Pharmaceutical; honoraria from AstraZeneca, Chugai Pharmaceutical, Merck Sharp & Dohme. The remaining authors declare no conflict of interest., (© 2024 The Authors.)

n-3 polyunsaturated fatty acids (n-3 PUFAs), including eicosapentaenoic acid (EPA), are essential nutrients for vertebrate development and physiology. Microorganisms, such as microalgae, produce n-3 PUFAs that are transferred to higher predators in the aquatic food web. However, recent studies have demonstrated that various aquatic invertebrates possess the biosynthetic enzymes required for n-3 PUFA production, raising the possibility that n-3 PUFAs are also produced in certain aquatic invertebrates. In contrast to aquatic invertebrates, it remains unclear whether and how PUFAs are produced in terrestrial invertebrates, including collembolans, one of the most widespread microarthropods in soil ecosystems. In this study, we investigated the biosynthetic capacity of n-3 PUFAs in litter-dwelling Collembola, Sinella dubiosa. We detected EPA in Sinella dubiosa reared on Brewer's yeast, which produced only saturated and monounsaturated fatty acids. Furthermore, metabolic analysis using isotope-labeled fatty acids revealed that oleic, linolenic, and arachidonic acids were metabolized to EPA in Sinella dubiosa. Given that collembolans are food for predatory arthropods and their nutrients are transferred to higher predatory vertebrates in the soil food web, we propose that Collembola serve as an EPA source in soil ecosystems., Competing Interests: Declaration of Competing Interest The named authors have no financial or other conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

Recent results show that polymorphisms of programmed death ligand 1 (PD-L1, also known as CD274 or B7-H1) might be used as a possible marker for effectiveness of chemotherapy and cancer risk. However, the effect of PD-L1 gene variations on PD-L1 expression remain unclear. Given the post-transcriptional machinery in tumor PD-L1 expression, we investigated single nucleotide polymorphisms (SNPs) in the 3'-untranslated region (3'-UTR) of the PD-L1 gene, rs4143815 and rs4742098, using formalin-fixed paraffin-embedded sections of 154 patients with non-small cell lung cancers (NSCLCs). In rs4143815, the GG genotype showed significant association with PD-L1 expression (P = 0.032). In rs4742098, the AA genotype was significantly associated with histology and PD-L1 expression (P = 0.022 and P = 0.008, respectively). In multivariate logistic regression analysis, the AA genotype in rs4742098 was correlated with PD-L1 expression (odds ratio 0.408, P = 0.048). Interestingly, approximately 10% of the NSCLC cases showed somatic mutation when we compared genotypes of these SNPs between NSCLC tissues and non-tumor tissues from the same patients. In addition, cases with somatic mutation showed higher levels of PD-L1 expression than cases with germline mutation in rs4143815 GG. In conclusion, we demonstrated that the rs4143815 and rs4742098 SNPs in the 3'-UTR of PD-L1 were associated with tumor PD-L1 expression in NSCLCs., (© 2023 Wiley Periodicals LLC.)

n-3 polyunsaturated fatty acids (n-3 PUFAs), including α-linolenic acid and eicosapentaenoic acid (EPA), are essential nutrients for vertebrates including humans. Vertebrates are n-3 PUFA-auxotrophic; hence, dietary intake of n-3 PUFAs is required for their normal physiology and development. Although fish meal and oil have been utilized as primary sources of n-3 PUFAs by humans and aquaculture, these traditional n-3 PUFA sources are expected to be exhausted because of the increasing consumption requirements of humans. Hence, it is necessary to establish alternative n-3 PUFA sources to reduce the gap between the supply and demand of n-3 PUFAs. Here, we investigated whether insects, which are considered as a novel source of essential nutrients, could store n-3 PUFAs by the forced expression of n-3 PUFA biosynthetic enzymes. We utilized Drosophila as an insect model to generate transgenic strains expressing Caenorhabditis elegans PUFA biosynthetic enzymes and examined their effects on the proportion of fatty acids. The ubiquitous expression of methyl-end desaturase FAT-1 prominently enhanced the proportions of α-linolenic acid, indicating that FAT-1 is useful for metabolic engineering to fortify α-linolenic acid in insect. Furthermore, the ubiquitous expression of nematode front-end desaturases (FAT-3 and FAT-4), PUFA elongase (ELO-1), and FAT-1 led to EPA bioproduction. Hence, nematode PUFA biosynthetic genes may serve as powerful genetic tools for enhancing the proportion of EPA in insects. This study represents the first step toward the establishment of n-3 PUFA-producing insects., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Comprehensive genomic profiling (CGP) tests have been covered by public insurance in Japan for patients with advanced solid tumors who have completed or are completing standard treatments or do not have them. Therefore, genotype-matched drug candidates are often unapproved or off-label, and improving clinical trial access is critical, involving the appropriate timing of CGP tests. To address this issue, we analyzed the previous treatment data for 441 patients from an observational study on CGP tests discussed by the expert panel at Hokkaido University Hospital between August 2019 and May 2021. The median number of previous treatment lines was two; three or more lines accounted for 49%. Information on genotype-matched therapies was provided to 277 (63%). Genotype-matched clinical trials were ineligible because of an excess number of previous treatment lines or use of specific agents were found in 66 (15%) patients, with the highest proportion in breast and prostate cancers. Many patients met the exclusion criteria of one to two or more treatment lines across cancer types. In addition, previous use of specific agents was a frequent exclusion criterion for breast, prostate, colorectal, and ovarian cancers. The patients with tumor types with a low median number (two or fewer) of previous treatment lines, including most rare cancers, primary unknown cancers, and pancreatic cancers, had significantly fewer ineligible clinical trials. The earlier timing of CGP tests may improve access to genotype-matched clinical trials, with their proportion varying by cancer type. Each relevant society needs to advocate the desirable timing of CGP testing nationwide., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Lenvatinib is widely used to treat unresectable and advanced thyroid carcinomas. We aimed to determine whether 18 F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) performed 1 week after lenvatinib treatment initiation could predict treatment outcomes., Results: This was a prospective, nonrandomised, multicentre study. Patients with pathologically confirmed differentiated thyroid carcinoma (DTC) and lesions refractory to radioiodine treatment were eligible for inclusion. Patients were treated with 24 mg lenvatinib as the initial dose and underwent PET/CT examination 1 week after treatment initiation. Contrast-enhanced CT was scheduled at least 4 weeks later as the gold standard for evaluation. The primary endpoint was to evaluate the discrimination power of maximum standardised uptake value (SUVmax) obtained by PET/CT compared to that obtained by contrast-enhanced CT. Evaluation was performed using the area under the receiver operating characteristic (ROC-AUC) curve. Twenty-one patients were included in this analysis. Receiver operating characteristic (ROC) curve analysis yielded an AUC of 0.714 for SUVmax after 1 week of lenvatinib treatment. The best cut-off value for the treatment response for SUVmax was 15.211. The sensitivity and specificity of this cut-off value were 0.583 and 0.857, respectively. The median progression-free survival was 26.3 months in patients with an under-cut-off value and 19.7 months in patients with an over-cut-off value (P = 0.078)., Conclusions: The therapeutic effects of lenvatinib were detected earlier than those of CT because of decreased FDG uptake on PET/CT. PET/CT examination 1 week after the initiation of lenvatinib treatment may predict treatment outcomes in patients with DTC., Trial Registration: This trial was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (number UMIN000022592) on 6 June, 2016., (© 2023. The Author(s).)

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) elicit potent cell cycle arrest in EGFR-mutant non-small-cell lung cancer (NSCLC) cells. However, little is known about the mechanisms through which these drugs alter the tumor phenotype that contributes to the immune escape of EGFR-mutant cells. Using EGFR-mutant NSCLC cell lines and tissue samples from patients, we investigated the changes in immune checkpoints expressed in tumor cells following EGFR inhibition. Subsequently, we also analyzed the role of soluble factors from the dying tumor cells in the activation of immune signaling pathways involved in therapy resistance. Upon EGFR-TKI treatment, we found that EGFR-mutant cells upregulated the expression of innate immune checkpoint CD24 in vitro. We then analyzed biopsy samples from six patients who developed resistance to a first-generation EGFR-TKI without the acquired T790M mutation. Immunohistochemistry revealed that levels of tumor CD24 expression were increased upon treatment compared with those from pre-treatment samples. Monocyte-derived macrophages facilitated antibody-dependent cellular phagocytosis when EGFR-TKI-treated EGFR-mutant cells were incubated with anti-CD24 antibodies in vitro, suggesting that CD24 may be a therapeutical target for EGFR-mutant lung cancer. Moreover, EGFR inhibition accelerated the release of cell-free DNA (cfDNA) from dying tumor cells, which activated the type I interferon signaling pathways in human THP-1 monocytes in a stimulator of interferon genes-dependent manner. Our study indicates that EGFR inhibition in EGFR-mutant NSCLC cells fosters a tumor microenvironment associated with immune escape. Thus, CD24 targeted therapy and cfDNA monitoring may contribute to improved treatment outcomes in patients with EGFR-mutant NSCLC., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Animals develop from juveniles to sexually mature adults through the action of steroid hormones. In insect metamorphosis, a surge of the steroid hormone ecdysone prompts the transition from the larval to the adult stage. Ecdysone is synthesized by a series of biosynthetic enzymes that are specifically expressed in an endocrine organ, the prothoracic gland. At the late larval stage, the expression levels of ecdysone biosynthetic enzymes are upregulated through the action of numerous transcription factors, thus initiating metamorphosis. In contrast, the mechanism by which chromatin regulators support the expression of ecdysone biosynthetic genes is largely unknown. Here, we demonstrate that Su(var)2-10 and Su(var)205, suppressor of variegation [Su(var)] genes encoding a chromatin regulator Su(var)2-10 and nonhistone heterochromatic protein 1a, respectively, regulate the transcription of one of the heterochromatic ecdysone biosynthetic genes, neverland, in Drosophila melanogaster. Knockdown of Su(var)2-10 and Su(var)205 in the prothoracic gland caused a decrease in neverland expression, resulting in a defect in larval-to-prepupal transition. Furthermore, overexpression of neverland and administration of 7-dehydrocholesterol, a biosynthetic precursor of ecdysone produced by Neverland, rescued developmental defects in Su(var)2-10 and Su(var)205 knockdown animals. These results indicate that Su(var)2-10- and Su(var)205-mediated proper expression of neverland is required for the initiation of metamorphosis. Given that Su(var)2-10-positive puncta are juxtaposed with the pericentromeric heterochromatic region, we propose that Su(var)2-10- and Su(var)205-dependent regulation of inherent heterochromatin structure at the neverland gene locus is essential for its transcriptional activation., (© The Author(s) 2022. Published by Oxford University Press on behalf of Genetics Society of America. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Animals control their developmental schedule in accordance with internal states and external environments. In Drosophila larvae, it is well established that nutrient status is sensed by different internal organs, which in turn regulate production of insulin-like peptides and thereby control growth. In contrast, the impact of the chemosensory system on larval development remains largely unclear. Here, we performed a genetic screen to identify gustatory receptor (Gr) neurons regulating growth and development, and found that Gr28a-expressing neurons are required for proper progression of larval growth. Gr28a is expressed in a subset of peripheral internal sensory neurons, which directly extend their axons to insulin-producing cells (IPCs) in the central nervous system. Silencing of Gr28a-expressing neurons blocked insulin-like peptide release from IPCs and suppressed larval growth during the mid-larval period. These results indicate that Gr28a-expressing neurons promote larval development by directly regulating growth-promoting endocrine signaling in a stage-specific manner., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)

Characterization of the genomic landscape of biliary tract cancer (BTC) may lead to applying genotype-matched therapy for patients with this disease. Evidence that comprehensive cancer genomic profiling (CGP) guides genotype-matched therapy to improve clinical outcomes is building. However, the significance of CGP in patients with BTC remains unclarified in clinical practice. Therefore, the purposes of this study were to assess the utility of CGP and identify associations between clinical outcomes and genomic alterations in patients with BTC. In this prospective analysis, detection rates for actionable genomic alterations and access rates for genotype-matched therapy were analyzed in 72 patients with advanced BTC who had undergone commercial CGP. Cox regression analyses assessed relationships between overall survival and genomic alterations detected with CGP. The most common genomic alterations detected were TP53 (41, 56.9%), followed by CDKN2A/B (24, 33.3%/20, 27.8%), and KRAS (20, 27.8%). Actionable genomic alterations were identified in 58.3% (42/72) of patients. Detection rates for FGFR2 fusions, IDH1 mutations, and BRAF V600E were low in this cohort. Eight (11.1%) patients received genotype-matched therapy. For patients with intrahepatic cholangiocarcinoma (ICC), CDKN2A/B loss was associated with shorter overall survival. These real-world data demonstrate that CGP can identify therapeutic options in patients with advanced BTC. CDKN2A/B loss was identified as a poor prognostic factor in patients with ICC. Thus, this study provides a rationale for considering CGP in planning therapeutic strategies for advanced BTC., Competing Interests: YK received a research grant from Takeda Pharmaceutical Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Takada, Kubo, Kikuchi, Yoshida, Murota, Arihara, Nakamura, Nagashima, Tanabe, Sugita, Tanaka, Miura, Ohhara, Ishiguro, Yokouchi, Kawamoto, Mizukami, Ohnishi, Kinoshita and Sakurai.)

Introduction: Karyopherin alpha 2 (KPNA2) and karyopherin beta 1 (KPNB1) constitute nuclear transport protein complexes involved in nuclear import and are significant in tumor progression. Although high KPNA2 expression was associated with poor prognosis in solid tumors, the relationship between KPNA2 and KPNB1 expression and their prognostic role in gastric cancer (GC) remains unclear., Methods: Immunohistochemistry was used to correlate the expression of KPNA2 and KPNB1 with various features, including clinicopathological characteristics in 130 patients with GC and survival in 94 patients with invasive lesions extending to the submucosa or deeper., Results: High expression of KPNA2 and KPNB1 was found in 25% and 36% of the patients, respectively. Both were significantly related to tumor depth, lymph node metastasis, lymphatic invasion, venous invasion, and Ki-67 expression. KPNA2 expression was significantly related to that of KPNB1 (p < 0.001). Patients with high KPNB1 expression had poorer prognosis than those with low expression (p = 0.027), as was also observed in case of KPNA2 (p < 0.001). Patients with high expression of both KPNA2 and KPNB1 accounted for 18% and had a poorer prognosis than those with high expression of either and those with low expression of both (p = 0.001). Multivariate analysis revealed that high expression of both KPNA2 and KPNB1 was an independent prognostic factor in patients with GC (hazard ratio, 3.46; 95% confidence interval, 1.64-2.73, p = 0.001)., Conclusion: KPNA2 expression was correlated with KPNB1 expression, and high co-expression of KPNA2 and KPNB1 may represent a strong prognostic biomarker in GC., (© 2022 S. Karger AG, Basel.)

Introduction: In mammals, circadian rhythms regulate many behavioral and physiological processes. Genetic and epidemiological studies have shown that dysregulation of the circadian rhythm induces chronic metabolic diseases, such as obesity, diabetes, and dyslipidemia. We aimed to know the interactions of genetic variations of seven core circadian clock genes with lifestyle factors on the determination of metabolic parameters., Methods: We have analyzed the impacts of genotype of seven core circadian clock genes (i.e., CLOCK, BMAL1, PER1, PER2, PER3, CRY1, and CRY2) and lifestyle factors (i.e., physical activity and sleep duration) in 575 Japanese males on the determination of metabolic parameters (i.e., body mass index [BMI], serum glucose, glycated hemoglobin [HbA1c], low-density lipoprotein cholesterol [LDL-C], and high-density lipoprotein cholesterol [HDL-C] levels)., Results: We have detected the associations between genotypes of PER3 and serum HbA1c level and genotypes of CRY1 and serum LDL-C level. Additionally, the interactions of the genotypes of PER1 and PER3 with physical activity for determining BMI, the genotypes of CLOCK with physical activity for determining serum HbA1c levels were observed. Furthermore, for determining serum HDL-C levels, the interactions of the genotypes of CRY2 with physical activity or sleep duration were observed., Discussion/conclusion: Our findings indicate that the interactions of genotypes for core circadian clock genes and lifestyle factors (i.e., physical activity and sleep duration) are important for determining metabolic parameters., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Hokkaido University Hospital has been designated as a Core Hospital for Cancer Genomic Medicine and developed a system to provide cancer genomic medicine in Hokkaido with its liaison hospitals. Since being reimbursed in June 2019, comprehensive cancer genome profiling (CGP) testing showed certain therapeutic efficacy in patients with no standard treatment options, but it also revealed some problems such as the small number of patients who can receive therapeutic drugs matched with gene abnormalities. Since candidate drugs are often unapproved or off-label, it is necessary to smoothly introduce clinical trials, advanced medical treatment system, and patient-proposed health care service. At our hospital, we are focusing on sharing information on clinical trials being conducted in Hokkaido, launching investigator-initiated clinical trials, promoting patient-proposed health care service, promoting a registry study of genetic profiling and targeted therapies in patients with rare cancers and accompanying clinical trials, and incorporating pediatric cancer patients. This paper describes Hokkaido's cancer genomic medicine provision system, including its exit strategy, and the human resource development that serve as its foundation.

Animals can sense internal nutrients, such as amino acids/proteins, and are able to modify their developmental programs in accordance with their nutrient status. In the fruit fly, Drosophila melanogaster , amino acid/protein is sensed by the fat body, an insect adipose tissue, through a nutrient sensor, target of rapamycin (TOR) complex 1 (TORC1). TORC1 promotes the secretion of various peptide hormones from the fat body in an amino acid/protein-dependent manner. Fat-body-derived peptide hormones stimulate the release of insulin-like peptides, which are essential growth-promoting anabolic hormones, from neuroendocrine cells called insulin-producing cells (IPCs). Although the importance of TORC1 and the fat body-IPC axis has been elucidated, the mechanism by which TORC1 regulates the expression of insulinotropic signal peptides remains unclear. Here, we show that an evolutionarily conserved molecular chaperone, heat shock protein 90 (Hsp90), promotes the expression of insulinotropic signal peptides. Fat-body-selective Hsp90 knockdown caused the transcriptional downregulation of insulinotropic signal peptides. IPC activity and systemic growth were also impaired in fat-body-selective Hsp90 knockdown animals. Furthermore, Hsp90 expression depended on protein/amino acid availability and TORC1 signaling. These results strongly suggest that Hsp90 serves as a nutrient-responsive gene that upregulates the fat body-IPC axis and systemic growth. We propose that Hsp90 is induced in a nutrient-dependent manner to support anabolic metabolism during the juvenile growth period., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ohhara, Hoshino, Imahori, Matsuyuki and Yamakawa-Kobayashi.)

Aim: The immunoproteasome is a specific proteasome isoform whose proteolytic activity enhances the generation of antigenic peptides to be presented by major histocompatibility complex class I molecules to CD8 + T cells. Physiologically, it is expressed abundantly in immune cells and is induced in somatic cells by cytokines, especially interferon-γ. Recently, variable expression of immunoproteasomes has been demonstrated in different types of cancers. However, the clinical significance of immunoproteasome expression in malignant tumours is poorly understood. In this study, we performed clinicopathological evaluation of immunoproteasome subunit β5i in non-small cell lung carcinomas (NSCLCs)., Methods: Tumour tissues were collected from 155 patients with NSCLCs, and immunohistochemical analysis for β5i was performed in relation to the prognosis of patients., Results: High expression of β5i was found in about 20% of all NSCLCs and was found significantly more frequently (40%) in the adenocarcinoma subset. High expression of β5i was associated with a better 5-year relative survival rate in patients with pStage I to II adenocarcinoma and was also a significant and independent favourable prognostic factor in adenocarcinoma patients. In addition, when we performed in vitro analysis using NSCLC cell lines, combined treatment with the immunoproteasome-specific inhibitor ONX0914 and the proteasome inhibitor MG132 enhanced cell death in β5i-expressing NSCLC cell lines., Conclusion: The expression of immunoproteasome can be explored as both a prognostic factor and a potential therapeutic target in NSCLCs. Since immunoproteasomes have crucial role in the antigen presentation, further studies may help to provide essential knowledge for therapeutic strategies in anticancer immunotherapy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Comprehensive cancer genomic profiling has been used recently for patients with advanced solid cancers. Two cancer genomic profiling tests for patients with no standard treatment are covered by Japanese public health insurance since June 2019., Methods: We prospectively analyzed data of 189 patients with solid cancers who underwent either of the two-cancer genomic profiling tests at Hokkaido University Hospital and its liaison hospitals and whose results were discussed in molecular tumor board at Hokkaido University Hospital between August 2019 and July 2020., Results: All 189 patients had appropriate results. Actionable gene alterations were identified in 93 patients (49%). Frequent mutations included PIK3CA (12%) mutation, BRCA1/2 alteration (7%), ERBB2 amplification (6%) and tumor mutation burden-High (4%). The median turnaround time from sample shipping to acquisition by the expert panel was 26 days. Although 115 patients (61%) were provided with information for genotype-matched therapies, only 21 (11%) received them. Notably, four of eight patients below the age of 20 years were provided information for genotype-matched therapies, and three received them. Their response rates and disease control rates were 29% and 67%, respectively. Most patients who did not undergo the genotype-matched therapies were provided information for only investigational drugs in phases I and II at distant clinical trial sites in central Japan. Twenty-six patients were informed of suspected germline findings, while 11 patients (42%) received genetic counseling., Conclusions: The publicly reimbursed cancer genomic profilings may lead to the modest but favorable therapeutic efficacy of genotype-matched therapy for solid cancer patients with no standard therapy. However, poor access to genotype-matched therapy needs to be resolved., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Clinical targeted sequencing allows for the selection of patients expected to have a better treatment response, and reveals mechanisms of resistance to molecular targeted therapies based on actionable gene mutations. We underwent comprehensive genomic testing with either our original in-house CLHURC system or with OncoPrime. Samples from 24 patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer underwent targeted sequencing between 2016 and 2018. Germline and somatic gene alterations and patients' prognosis were retrospectively analyzed according to the response to endocrine therapy. All of the patients had one or more germline and/or somatic gene alterations. Four patients with primary or secondary endocrine-resistant breast cancer harbored germline pathogenic variants of BRCA1, BRCA2, or PTEN. Among somatic gene alterations, TP53, PIK3CA, AKT1, ESR1, and MYC were the most frequently mutated genes. TP53 gene mutation was more frequently observed in patients with primary endocrine resistance compared to those with secondary endocrine resistance or endocrine-responsive breast cancer. Recurrent breast cancer patients carrying TP53-mutant tumors had significantly worse overall survival compared to those with TP53-wild type tumors. Our 160-gene cancer panel will be useful to identify clinically actionable gene alterations in breast cancer in clinical practice.

Background: The standard of care for first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) in patients who cannot tolerate platinum-based regimens has not been clarified. We aimed to develop a new treatment regimen for patients with R/M SCCHN who are ineligible for platinum-based therapy, by evaluating the effects and safety of tegafur/gimeracil/oteracil (S-1) and cetuximab., Methods: Platinum-ineligibility was defined as: elderly (aged ≥ 75 years), poor PS, comorbidity, platinum resistance and refusal to undergo platinum-based therapy. Patients received S-1 (80 mg/m 2 /day for 14 days followed by a seven-day break) and cetuximab (initial dose, 400 mg/m 2 , followed by 250 mg/m 2 weekly) until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR)., Results: Between September 2014 and September 2018, we enrolled 23 patients. Among the 21 patients who were evaluable, 20 were male [median age, 69 years (range 49-82)]. The ORR was 9 (43%) of 21 patients [95% confidence interval (CI) 22-66]. One and eight patients achieved complete response (CR) and partial response (PR), respectively. The median overall survival (OS) was 13.7 months (95% CI 9.0-18.3) and progression-free survival (PFS) was 5.7 months (95% CI 3.1-8.2). Grade 3/4 adverse events included acneiform rash and skin reactions (33%), hypomagnesemia (19%), hand-foot syndrome (14%), fatigue (14%), mucositis (10%), and anorexia (10%)., Conclusions: Combination treatment with S-1 and cetuximab was effective and tolerated well by patients with platinum-ineligible R/M SCCHN. Registered clinical trial number: UMIN000015123.

Most fatty acids in phospholipids and other lipid species carry an even number of carbon atoms. Also odd-chain fatty acids (OCFAs), such as C15:0 and C17:0, are widespread throughout the living organism. However, the qualitative and quantitative profiles of OCFAs-containing lipids in living organisms remain unclear. Here, we show that OCFAs are present in Drosophila phosphatidylcholine (PC) and phosphatidylethanolamine (PE) and that their level increases in accordance with progression of growth. Furthermore, we found that food-derived propionic acid/propanoic acid (C3:0) is utilized for production of OCFA-containing PC and PE. This study provides the basis for understanding in vivo function of OCFA-containing phospholipids in development and lipid homeostasis.

Steroid hormones play key roles in development, growth, and reproduction in various animal phyla [1]. The insect steroid hormone, ecdysteroid, coordinates growth and maturation, represented by molting and metamorphosis [2]. In Drosophila melanogaster, the prothoracicotropic hormone (PTTH)-producing neurons stimulate peak levels of ecdysteroid biosynthesis for maturation [3]. Additionally, recent studies on PTTH signaling indicated that basal levels of ecdysteroid negatively affect systemic growth prior to maturation [4-8]. However, it remains unclear how PTTH signaling is regulated for basal ecdysteroid biosynthesis. Here, we report that Corazonin (Crz)-producing neurons regulate basal ecdysteroid biosynthesis by affecting PTTH neurons. Crz belongs to gonadotropin-releasing hormone (GnRH) superfamily, implying an analogous role in growth and maturation [9]. Inhibition of Crz neuronal activity increased pupal size, whereas it hardly affected pupariation timing. This phenotype resulted from enhanced growth rate and a delay in ecdysteroid elevation during the mid-third instar larval (L3) stage. Interestingly, Crz receptor (CrzR) expression in PTTH neurons was higher during the mid- than the late-L3 stage. Silencing of CrzR in PTTH neurons increased pupal size, phenocopying the inhibition of Crz neuronal activity. When Crz neurons were optogenetically activated, a strong calcium response was observed in PTTH neurons during the mid-L3, but not the late-L3, stage. Furthermore, we found that octopamine neurons contact Crz neurons in the subesophageal zone (SEZ), transmitting signals for systemic growth. Together, our results suggest that the Crz-PTTH neuronal axis modulates ecdysteroid biosynthesis in response to octopamine, uncovering a regulatory neuroendocrine system in the developmental transition from growth to maturation., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Increasing oxidative stress seems to be the result of an imbalance between free radical production and antioxidant defenses. During the course of aging, oxidative stress causes tissue/cellular damage, which is implicated in numerous age-related diseases. Carnosinase (CN or CNDP) is dipeptidase, which is associated with carnosine and/or glutathione (GSH) metabolism, those are the most abundant naturally occurring endogenous dipeptide and tripeptides with antioxidant and free radical scavenger properties. In the present study, we generated Drosophila cndp (dcndp) mutant flies using the CRISPR/Cas9 system to study the roles of dcndp in vivo. We demonstrate that dcndp mutant flies exhibit shorter lifespan and increased sensitivity to paraquat or hydrogen peroxide (H 2 O 2 ) induced oxidative stress. These results suggest that dcndp maintains homeostatic conditions, protecting cells and tissues against the harmful effects of oxidative stress in the course of aging.

Endocycle is a commonly observed cell cycle variant through which cells undergo repeated rounds of genome DNA replication without mitosis. Endocycling cells arise from mitotic cells through a switch of the cell cycle mode, called the mitotic-to-endocycle switch (MES), to initiate cell growth and terminal differentiation. However, the underlying regulatory mechanisms of MES remain unclear. Here we used the Drosophila steroidogenic organ, called the prothoracic gland (PG), to study regulatory mechanisms of MES, which is critical for the PG to upregulate biosynthesis of the steroid hormone ecdysone. We demonstrate that PG cells undergo MES through downregulation of mitotic cyclins, which is mediated by Fizzy-related (Fzr). Moreover, we performed a RNAi screen to further elucidate the regulatory mechanisms of MES, and identified the evolutionarily conserved chaperonin TCP-1 ring complex (TRiC) as a novel regulator of MES. Knockdown of TRiC subunits in the PG caused a prolonged mitotic period, probably due to impaired nuclear translocation of Fzr, which also caused loss of ecdysteroidogenic activity. These results indicate that TRiC supports proper MES and endocycle progression by regulating Fzr folding. We propose that TRiC-mediated protein quality control is a conserved mechanism supporting MES and endocycling, as well as subsequent terminal differentiation., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Lenvatinib, an oral molecular targeted drug, is used to treat patients with unresectable or advanced thyroid carcinoma that is refractory to radioiodine treatment. Effective methods for evaluating molecular targeted drugs are a critical unmet need owing to their expensive costs and unique adverse events. The aim of this study is to determine whether 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT at 1 week after commencing lenvatinib can predict treatment outcomes., Design and Methods: This study is planned as a non-randomised single-arm multicentre study; patients with pathologically confirmed differentiated thyroid carcinoma (DTC) with lesions that are refractory to radioiodine treatment are eligible. The main exclusion criteria are medullary or anaplastic carcinoma, prior treatment with chemotherapy, poor general condition and thromboembolism-requiring treatment. Patients to be included in the study will be treated with lenvatinib and undergo FDG-PET/CT examination twice: before and 1 week after the initiation of treatment. Contrast-enhanced CT, the gold standard for evaluation, will be performed at least 4 weeks after the initiation of treatment. The primary objective is to evaluate the ability of the lesion maximum standard uptake value for FDG PET/CT performed 1 week after the initiation of treatment to predict outcomes compared with the response evaluation obtained via contrast-enhanced CT performed at least 4 weeks after the initiation of treatment., Ethics and Dissemination: This study is conducted in accordance with the Declaration of Helsinki and has received ethical approval from the institutional review board of the Hokkaido University Hospital (approval number: 015-402). The results of this study will be disseminated through a presentation at a conference and the publication of the data in a peer-reviewed journal. The study will be implemented and reported in line with the SPIRIT statement., Trial Registration Number: UMIN000022592., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Solitary fibrous tumor (SFT) is a rare subtype of soft tissue sarcoma (STS). We herein describe a case of late onset of non-islet cell tumor hypoglycemia (NICTH) that was managed via multidisciplinary treatment in a patient with SFT. A 67-year-old man previously diagnosed with SFT 4 years prior to this presentation and treated with several rounds of surgery, presented with massive tumors. Eighteen months following his prescribed chemotherapy, the patient developed hypoglycemia. He was diagnosed with NICTH, after confirming the presence of high molecular weight insulin-like growth factor-2. This case suggests that paraneoplastic syndrome can occur even in cases of rare cancers, such as STS.

Background: Approximately 20% to 30% of non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR)-activating mutations are not responsive to EGFR tyrosine kinase inhibitors (TKIs). Although primary resistance to EGFR-TKIs has been attributed to various genetic alterations, little is known about the clinical and immunopathologic features of patients with primary resistance. The tumor immune microenvironment, including tumor-infiltrating lymphocytes (TILs) and programmed cell death ligand 1 (PD-L1), has been reported to play an important role in tumor progression in those with NSCLC. However, few studies have directly focused on the relationship between the tumor immune microenvironment and primary resistance to EGFR-TKIs., Materials and Methods: The characteristics of 124 NSCLC patients with EGFR mutations who had received EGFR-TKIs were analyzed. Primary resistance was defined as disease progression within 3 months after EGFR-TKI treatment. Tumor specimens obtained before EGFR-TKI treatment were assessed for the density of TILs expressing CD4 or CD8 and for the expression rate of PD-L1 on tumor cells and tumor-infiltrating immune cells, immunohistochemically., Results: Primary resistance was observed in 13.7% of the patients (17 of 124). A significant difference in smoking history was observed between patients with primary resistance and those with non-primary resistance. A lower density of total TILs and negative PD-L1 expression on immunohistochemical analysis correlated significantly with primary resistance, in contrast to that with non-primary resistance. Moreover, the negative PD-L1 expression with low TIL density, indicating immune ignorant phenotype of tumor microenvironment, was observed in those with primary resistance with a significant difference., Conclusion: Smoking and immune ignorance in the tumor microenvironment might result in primary resistance to EGFR-TKIs., (Copyright © 2018 Elsevier Inc. All rights reserved.)