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Extramammary Paget's disease (EMPD) is a rare skin cancer with no standard treatment for advanced-stage disease. Although docetaxel-based chemotherapy is common, no standard treatment exists. Pembrolizumab is approved for solid tumors with a high tumor mutation burden (TMB) and/or high microsatellite instability, and nivolumab was approved in Japan in February 2024 for unresectable advanced or recurrent epithelial skin malignancies. However, there is a lack of real-world data regarding the efficacy of anti-programmed cell death protein 1 (PD-1) therapy for EMPD. We present the case details of three EMPD patients treated with anti-PD-1 therapy after docetaxel treatment, with TMB values of 17.8, 14.3, and 5.0 mut/Mb, respectively, and we review similar reported cases. Even in the cases with a high TMB, the response to anti-PD-1 therapy was not sufficient. Most cases involve second-line or later treatments, so further research is needed to determine the precise effectiveness of anti-PD-1 therapy as a first-line treatment., (© 2024 Japanese Dermatological Association.)

Background: This retrospective observational study explored the therapeutic potential of combined androgen blockade (CAB) with bicalutamide (Bic-CAB) as an initial treatment for metastatic hormone-sensitive prostate cancer (mHSPC) in Japan., Methods: The electronic health records of 159 patients with mHSPC from three Japanese institutions who received initial treatment with Bic-CAB between 2007 and 2017 were analyzed. The time to prostate-specific antigen (PSA) progression, duration of Bic-CAB treatment, and overall survival (OS), with various definitions for PSA progression, were assessed. A multivariate Cox proportional hazards model was constructed using clinical parameters to predict time to the end of Bic-CAB treatment and OS., Results: The median observation period was 46.4 months, and the median age of patients at diagnosis was 71 years. A total of 46.5% patients experienced PSA progression with a median survival duration of 29 months (according to Prostate Cancer Clinical Trials Working Group 3 criteria), and 49.1% patients achieved a PSA nadir < 0.2 ng/mL in a median time of 4.7 months. When stratified by PSA nadir and PSA change, patients at low risk for disease progression with a small PSA change due to low initial PSA had a 5-year OS of 100% and a 10-year OS of 75%. The OS during the observation period was 72.9 months., Conclusion: These findings highlight the potential effect of Bic-CAB in patients with mHSPC who were at low risk for disease progression. Initial treatment with Bic-CAB and adjusting treatment early based on PSA dynamics may be a reasonable treatment plan for these patients., (© 2024. The Author(s).)

Familial progressive hyperpigmentation with or without hypopigmentation (FPHH) is an autosomal dominant disorder characterized by widespread skin hyperpigmentation, café-au-lait spots, and hypopigmented circular macules, resulting from KITLG variants. KITLG, expressed by keratinocytes, binds to KIT on melanocytes, stimulating melanogenesis. Disturbances in the KITLG-KIT interaction result in diffuse hyperpigmentation in FPHH. However, the mechanisms behind hypopigmented macule formation remain unclear. This report presents a unique FPHH case in a patient with a novel KITLG mutation (Ser78Leu). Notably, the patient showed multiple hypopigmented macules and striae along the lines of Blaschko. Digital polymerase chain reaction analysis of the DNA from skin and blood tissues indicated a copy-neutral loss of heterozygosity at the KITLG locus, only in the hypopigmented macule. These findings suggest that the hypopigmented macules might result from revertant mosaicism. Conversely, café-au-lait spots do not follow the lines of Blaschko and can superimpose on the hypopigmented striae, indicating a distinct pathogenesis. This case contributes to the understanding of the genetic mechanisms in FPHH., (© 2024 Japanese Dermatological Association.)

Background: Cutaneous melanoma (CM) is the most common type in Caucasians, while acral melanoma (AM) and mucosal melanoma (MM), which are resistant to immunotherapies and BRAF/MEK-targeted therapies, are more common in East Asians. Genomic profiling is essential for treating melanomas, but such data are lacking in Japan., Methods: Comprehensive genomic profiling data compiled in the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) were analyzed., Results: A total of 380 melanomas was analyzed, including 136 CM, 46 AM, 168 MM, and 30 uveal melanoma (UM). MM included conjunctival, sinonasal, oral, esophageal, anorectal, and vulvovaginal melanomas. No significant difference in the median tumor mutational burden (TMB) of CM (3.39 mutations/megabase), AM (2.76), and MM (3.78) was the key finding. Microsatellite instability-high status was found in one case. BRAF V600E/K was found in only 45 patients (12%). Key driver mutations in CM were BRAF (38%), NRAS (21%), NF1 (8%), and KIT (10%), with frequent copy number alterations (CNAs) of CDKN2A, CDKN2B, and MYC. AM was characterized by altered KIT (30%), NRAS (26%), and NF1 (11%) and CDKN2A, CDKN2B, CDK4, MDM2, and CCND1 CNAs. MM was characterized by altered NRAS (24%), KIT (21%), and NF1 (17%) and MYC, KIT, and CDKN2A CNAs, with differences based on anatomical locations. UM bore GNAQ or GNA11 driver mutations (87%) and frequent mutations in SF3B1 or BAP1., Conclusion: The distinct genomic profiling in Japanese patients, including lower TMB, compared to Caucasians, is associated with poorer treatment outcomes. This result underscores the need for more effective therapeutic agents., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Multiple hereditary infundibulocystic basal cell carcinoma syndrome (MHIBCC), an autosomal dominant disorder caused by variants in SUFU, is characterized by numerous infundibulocystic basal cell carcinomas (IBCCs). In this report, we present a possible case of mosaic MHIBCC. A 57-year-old woman underwent the removal of four papules on her face, which were diagnosed as IBCCs. Exome sequencing revealed a SUFU c.1022+1G>A mutation within the skin tumor. The same mutation was detected in her blood but at a lower allele frequency. TA cloning revealed that the allele frequency of the mutation in the blood was 0.07. Additionally, tumor assessment revealed loss of heterozygosity (LOH) in chromosome 10, including the SUFU locus. These results indicate the patient had mosaicism for the SUFU mutation in normal tissues, aligning with the mosaic MHIBCC diagnosis. This, combined with LOH, likely contributed to IBCC development. Mosaic MHIBCC may present with milder symptoms. However, it may still increase the risk of developing brain tumors and more aggressive basal cell carcinoma. The possibility of mosaicism should be investigated in mild MHIBCC cases, where standard genetic tests fail to detect SUFU germline variants., (© 2024 Japanese Dermatological Association.)

Background: In cardiac computed tomography (CT), the best image quality is obtained at mid-diastole at low heart rates (HRs) and at end-systole at high HRs. On the other hand, extracellular volume (ECV) measurements may be influenced by the cardiac phase. Therefore, we aimed to clarify the influence of the cardiac phase on the image quality and ECV values obtained using dual-layer spectral computed tomography (DLCT)., Methods: Fifty-five patients (68.0±14.5 years; 26 men) with cardiac diseases who underwent retrospective electrocardiogram-gated myocardial CT delayed enhancement (CTDE) between February 2019 to April 2022 were enrolled. The ECVs at the right ventricle (RV) and left ventricle (LV) walls in the end-systolic and mid-diastolic phases were calculated using iodine-density measurements from CTDE spectral data. Iodine-density image quality was classified on a 4-point scale. ECV and image quality across cardiac phases were compared using the t-test and Wilcoxon signed-rank test, respectively. Inter- and intraobserver variability were evaluated using intraclass correlation coefficient (ICC) values., Results: The ECV of the septal regions during mid-diastole was significantly higher than that during end-systole. Other regions showed similar ECV measurements in both groups (P=0.13-0.97), except for the LV anterior wall and LV posterior wall at the base-ventricular level. The image-quality score in end-systole was significantly higher than that in mid-diastole (systole vs. diastole: 3.6±0.5 vs. 3.2±0.7; P=0.0195). Intra- and interobserver variabilities for RV ECV measurements at the end-systolic phase were superior to those at the mid-diastolic phase, whereas the corresponding values for LV ECV measurements were similar., Conclusions: Septal ECV showed small but significant differences while other region ECV showed no difference during the cardiac cycle. RV ECV measurements in the end-systolic phase were more reproducible than those in the mid-diastolic phase., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-23-1647/coif). Y.Y. received research grants from JSPS (KAKENHI), KONICAMINOLTA, Inc., and Konica Minolta Science and Technology Foundation; and Honoraria for lectures from KONICAMINOLTA, Inc. T.H. received a research grant KAKENHI from JSPS. The other authors have no conflicts of interest to declare., (2024 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Background: The occurrence of pulmonary adenocarcinoma coexisting with atypical carcinoid tumors is a rare phenomenon. The presence of EML4-ALK fusion in an atypical carcinoid component of a histologically mixed tumor is even more uncommon. Due to their infrequency, the origin and pathogenesis of these mixed tumors remain largely unknown. The advances of therapy development in such patients are still limited and there is no standard treatment. We present a case of collision tumor in the lung consisting of atypical carcinoid and adenocarcinoma to better understand the clinical characteristics of this disease., Case Description: We report an extremely rare case of EML4-ALK rearrangement in a pulmonary atypical carcinoid tumor that coexisting with adenocarcinoma. A 58-year-old woman, who was asymptomatic, underwent pulmonary lobectomy due to the detection of a gradually enlarging solitary pulmonary nodule in the right upper lung. Histological examination of the resected tumor revealed the presence of both atypical carcinoid (approximately 80%) and adenocarcinoma (approximately 20%) components. Metastases by the carcinoid component were observed in mediastinal lymph nodes (station 2R and 4R) and in the primary tumor. Anaplastic lymphoma kinase ( ALK ) rearrangement was detected in both the primary and metastatic lesions of the carcinoid tumor. Four cycles of chemotherapy with etoposide and carboplatin were dispensed after surgery., Conclusions: This is the first reported case of coexisting pulmonary adenocarcinoma and atypical carcinoid tumor with an ALK fusion only detected in the carcinoid component. The presence of ALK rearrangement in pulmonary carcinoid tumor is very uncommon, and there is currently no standard treatment for advanced stages. Therefore, comprehensive molecular testing, including ALK rearrangement analysis, should be recommended for mixed tumors exhibiting features of atypical carcinoid. ALK inhibitors could represent a potential treatment strategy for selected patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-352/coif). R.A.R. and T.H. serve as unpaid editorial board members of Translational Lung Cancer Research from January 2024 to December 2025. J.S. is from Dagong Law Firm. E.M.U. received grants from Merck and AstraZeneca; honoraria from Janssen, Amgen, AstraZeneca, Novartis; support for attending meetings and travel from AstraZeneca and Roche; payment for participation in Advisory Board from Roche, Takeda, Pfizer, AstraZeneca. E.S.R. received grants from Sanofi and Takeda; honoraria from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Roche, Takeda; payment for participation in Advisory Board from Roche and Takeda. P.C. has received research funding from AstraZeneca, Amgen, Boehringer Ingelheim, Merck, Novartis, Roche, and Takeda, speaker’s honoraria from AstraZeneca, Gilead, Janssen, Novartis, Roche, Pfizer, Thermo Fisher, Takeda, support for attending meetings from AstraZeneca, Eli Lilly, Daiichi Sankyo, Janssen, Gilead, Novartis, Pfizer, Takeda, and personal fees for participating to advisory boards from AstraZeneca, Boehringer Ingelheim, Chugai, Pfizer, Novartis, MSD, Takeda and Roche, all outside the submitted work. R.A.R. has consulting agreements with several companies (TerSera Therapeutics, ITM Radiopharma, Regeneron, Advanced Accelerator Applications, Novartis, Ipsen, Amgen, Astra-Zeneca, Curium, Exelexis, EMD Serono) that manufacture products to treat neuroendocrine tumors and lung cancers, all outside the submitted work. R.A.R. is a Board of Directors member of the North American Neuroendocrine Tumor Society. The other authors have no conflicts of interest to declare., (2024 Translational Lung Cancer Research. All rights reserved.)

Introduction: The JAVELIN Lung 101 phase 1b/2 trial evaluated avelumab (immune checkpoint inhibitor) combined with lorlatinib or crizotinib (tyrosine kinase inhibitors) in ALK -positive or ALK -negative advanced NSCLC, respectively., Methods: Starting doses of lorlatinib 100 mg once daily or crizotinib 250 mg twice daily were administered with avelumab 10 mg/kg every 2 weeks. Primary objectives were assessment of maximum tolerated dose (MTD) and recommended phase 2 dose in phase 1 and objective response rate in phase 2. Primary end points were dose-limiting toxicity (DLT) and confirmed objective response per Response Evaluation Criteria in Solid Tumors, version 1.1., Results: In the avelumab plus lorlatinib group ( ALK -positive; n = 31; 28 in phase 1b; three in phase 2), two of 28 assessable patients (7%) had DLT, and the MTD and recommended phase 2 dose was avelumab 10 mg/kg every 2 weeks plus lorlatinib 100 mg once daily. In the avelumab plus crizotinib group ( ALK -negative; n = 12; all phase 1b), five of 12 assessable patients (42%) had DLT, and the MTD was exceeded with avelumab 10 mg/kg every 2 weeks plus crizotinib 250 mg twice daily; alternative crizotinib doses were not assessed. Objective response rate was 52% (95% confidence interval, 33%-70%) with avelumab plus lorlatinib (complete response, 3%; partial response, 48%) and 25% (95% confidence interval, 6%-57%) with avelumab plus crizotinib (all partial responses)., Conclusions: Avelumab plus lorlatinib treatment in ALK -positive NSCLC was feasible, but avelumab plus crizotinib treatment in ALK -negative NSCLC could not be administered at the doses tested. No evidence of increased antitumor activity was observed in either group., Clinicaltrialsgov Identifier: NCT02584634., Competing Interests: Dr. Solomon reports providing a consulting or advisory role for Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Cancer Council of Victoria, D3 Bio, Janssen, Lilly, the healthcare business of Merck KGaA, Darmstadt, Germany, Pfizer, Roche/Genentech, Takeda, and Thoracic Oncology Group of Australasia; has provided speaker services for Amgen, AstraZeneca, Pfizer, and Roche/Genentech; and has received institutional research funding from 10.13039/100017239BeiGene, 10.13039/100002491Bristol Myers Squibb, 10.13039/100020536Lilly, 10.13039/100004336Novartis, Nuvalent, 10.13039/100004319Pfizer, 10.13039/100004337Roche/10.13039/100004328Genentech, and 10.13039/100004339Sanofi. Prof. Dagogo-Jack reports providing a consulting or advisory role for AstraZeneca, Bayer, Boehringer Ingelheim, BostonGene, Catalyst Pharmaceuticals, Genentech, Janssen, Novocure, Pfizer, Sanofi, Syros Pharmaceuticals, and Xcovery; has received travel, accommodations, or expenses from Array BioPharma, Creative Educational Concepts, DAVA Oncology, Medscape, OncLive/MJH Life Sciences, Pfizer, The ASCO Post, and Total Health Conferencing; and has received institutional research funding from 10.13039/100007174Array BioPharma, 10.13039/100017658Calithera Biosciences, Genentech, Pfizer, 10.13039/100004336Novartis, and Vivace Therapeutics. Prof. Lee reports providing a consulting or advisory role for AstraZeneca/MedImmune, Bristol Myers Squibb, and Novartis; has received honoraria from AstraZeneca/MedImmune, the healthcare business of Merck KGaA, Darmstadt, Germany, and Roche; and has received travel, accommodations, or expenses from Novartis. Prof. Boyer reports providing a consulting or advisory role for AstraZeneca/MedImmune, Bristol Myers Squibb, and Merck & Co., Kenilworth, NJ; has received institutional research funding from 10.13039/100002429Amgen, 10.13039/100019621Ascentage Pharma, 10.13039/100004325AstraZeneca, 10.13039/100017239BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, 10.13039/100004334Merck & Co., Kenilworth, NJ, OncoMed, 10.13039/100012742Peregrine Pharmaceuticals, Pfizer, and Roche/Genentech; and has received travel, accommodations, or expenses from Boehringer Ingelheim, Bristol Myers Squibb, Merck & Co., Kenilworth, NJ, and Roche/Genentech. Prof. Ramalingam reports providing a consulting or advisory role for AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Lilly/ImClone, Roche/Genentech, Takeda, and the healthcare business of Merck KGaA, Darmstadt, Germany. Dr. Carcereny has no relationships to disclose. Prof. Felip reports providing a consulting or advisory role for AbbVie, Amgen, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, GlaxoSmithKline, Janssen, Merck & Co., Kenilworth, NJ, Novartis, Pfizer, Puma Biotechnology, Roche, Sanofi, Genzyme, Takeda, and the healthcare business of Merck KGaA, Darmstadt, Germany; has provided speaker services for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, Medscape, Merck & Co., Kenilworth, NJ, Novartis, PeerVoice, Pfizer, Prime Oncology, Roche, Springer, Takeda, touchIME, and CME Outfitters; has received research funding from grant for Oncology Innovation, Fundación Merck Salud, Madrid, Spain, an affiliate of Merck KGaA, Darmstadt, Germany; and is an independent member of the board of Grifol. Dr. Han reports providing a consulting or advisory role for Merck & Co., Kenilworth, NJ; has received honoraria from Novartis; and has received institutional research funding from Roche. Dr. Hida has received honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharma, Clovis Oncology, Kissei Pharmaceutical, Lilly, Merck & Co., Kenilworth, NJ, Novartis, Ono Pharmaceutical, Pfizer, and Taiho Pharmaceutical; and has received institutional research funding from 10.13039/100006483AbbVie, 10.13039/501100004948Astellas, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharma, Clovis Oncology Daiichi Sankyo, 10.13039/501100002975Dainippon Sumitomo Pharma, 10.13039/501100003769Eisai, 10.13039/100014584Ignyta, 10.13039/100016288Kissei Pharmaceutical, 10.13039/501100004095Kyowa Hakko Kirin, 10.13039/100004334Merck & Co., Kenilworth, NJ, Novartis, Ono Pharmaceutical, Pfizer, Servier, 10.13039/100009954Taiho Pharmaceutical, Takeda, and the healthcare business of Merck KGaA, Darmstadt, Germany. Dr. Hughes reports providing a consulting or advisory role for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eisai, Pfizer, Merck & Co., Kenilworth, NJ, and Roche. Dr. Kim has no relationships to disclose. Dr. Nishio has received lecture fees from Chugai Pharmaceutical, Pfizer, Novartis, and Takeda. Dr. Seto has received honoraria from Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharma, Kissei Pharmaceutical, Kyowa Hakko Kirin, Lilly Japan, Merck & Co., Kenilworth, NJ, Nippon Kayaku, Ono Pharmaceutical, Pfizer, Roche Singapore, Taiho Pharmaceutical, Takeda, and Yakult Honsha; and has received institutional research funding from Astellas Pharma, AstraZeneca, 10.13039/100015731Bayer Yakuhin, Boehringer Ingelheim, Chugai Pharma, Daiichi Sankyo, Eisai, Kissei Pharmaceutical, Lilly, Merck & Co., Kenilworth, NJ, Novartis, Pfizer, and the healthcare business of Merck KGaA, Darmstadt, Germany. Dr. Okamoto has received honoraria from AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Johnson & Johnson, Merck & Co., Kenilworth, NJ, Boehringer Ingelheim, Nippon Kayaku, Novartis, Ono Pharmaceutical, and Taiho Pharmaceutical; and has received institutional research funding from AnHeart Therapeutics, AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Covidien Japan, Daiichi Sankyo, Lilly, KM Biologics, the healthcare business of Merck KGaA, Darmstadt, Germany, Merck & Co., Kenilworth, NJ, Boehringer Ingelheim, Nippon Kayaku, Novartis, Pfizer, and Taiho Pharmaceutical. Dr. Zhang is an employee of Pfizer and owns stock and has other ownership interests in Pfizer. Dr. Martini is an employee of Pfizer and owns stock and has other ownership interests in Pfizer. Dr. Wang was an employee of Pfizer at the time this study was conducted. Dr. De Beukelaer was an employee of Pfizer at the time this study was conducted and owns stock and has other ownership interests in Pfizer. Dr. Bauer reports providing a consulting or advisory role for AstraZeneca, Bayer, Lilly, and Pfizer; has provided speaker services for Bayer, Bristol Myers Squibb, Lilly, and Pfizer; and has received institutional research funding from AstraZeneca, Bayer, Bristol Myers Squibb, Lilly, and Pfizer., (© 2024 by the International Association for the Study of Lung Cancer.)

Epidermal keratinocytes, forming the outermost layer of the human body, serve as a crucial barrier against diverse external stressors such as ultraviolet radiation. Proper keratinocyte differentiation and effective responses to external stimuli are pivotal for maintaining barrier integrity. Heat is one such stimulus that triggers the synthesis of heat shock proteins (HSPs) when cells are exposed to temperatures above 42 °C. Additionally, activation of the transient receptor potential cation channel subfamily V member 1 (TRPV1) occurs at 42 °C. Here, we explore the interplay between TRPV1 signaling and HSP induction in human keratinocytes. Both heat and capsaicin, a TRPV1 agonist, induce expression of HSP27, HSP70, and HSP90 in keratinocytes. Interestingly, pharmacological inhibition of TRPV1 attenuates heat-induced HSP27 expression, but not that of HSP70 or HSP90. Furthermore, both heat and capsaicin stimulation result in distinct phosphorylation patterns of heat shock factor 1 (HSF1), with phosphorylation at serine 326 being a common feature. Notably, genetic manipulation to mimic dephosphorylation of HSF1 at serine 326 reduces HSP27 levels. Additionally, ΔNp63, a key regulator of epidermal differentiation, negatively modulates HSP27 expression independently of HSF1 phosphorylation status. While heat stimulation has no effect on ΔNp63 expression, capsaicin reduces its levels. The precise role of TRPV1 signaling in keratinocytes warrants further investigation for a comprehensive understanding of its impact on barrier function., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Paratesticular cellular angiofibroma is a rare benign mesenchymal tumor. The optimal management is surgical resection due to the difficulty of preoperative accurate diagnosis., Case Presentation: A 51-year-old Japanese male visited our hospital complaining of asymptomatic left scrotal swelling. Physical examination revealed a nontender elastic paratesticular mass (5.5 cm in diameter). Although testicular germ cell tumor was ruled out clinically, the possibility of malignant potential remained for the tumor. Since the patient consented to complete resection, a transinguinal radical orchiectomy was performed. The pathological diagnosis revealed cellular angiofibroma. The patient recovered without perioperative complications, and no apparent recurrence was observed at 5 years after surgery., Conclusion: The pathological findings were compatible for cellular angiofibroma. The tumor was successfully resected, and no apparent recurrence was observed at 5 years after surgery., (© 2024. The Author(s).)

The efficacy of combination therapy with an immune checkpoint inhibitor (ICI) and cytotoxic chemotherapeutic agents has been investigated in cancer, including melanoma. Before ICIs were introduced, dacarbazine or temozolomide (TMZ) were used to treat melanoma. Several studies using glioma or colorectal cancer cells showed that TMZ can increase the tumor mutation burden (TMB) and induce mismatch repair (MMR) deficiency associated with microsatellite instability (MSI). These could increase immunoreactivity to an ICI, but this has not been evaluated in melanoma cells. We investigated the effects of TMZ on MSI status and TMB in melanoma cells. To evaluate the TMB, we performed whole-exome sequencing using genomic DNA from the human melanoma cell lines Mel18, A375, WM266-4, G361, and TXM18 before and after TMZ treatment. Polymerase chain reaction amplification of five mononucleotide repeat markers, BAT25, BAT26, NR21, NR24, and MONO27, was performed, and we analyzed changes in the MSI status. In all cell lines, the TMB was increased after TMZ treatment (the change amount of TMB with ≤ 5% variant allele frequency [VAF] was 18.0-38.3 mutations per megabase) even in the condition without obvious cytological damage. MSI after TMZ treatment was not observed in any cells. TMZ increased TMB but did not change MSI status in melanoma cells., (© 2023 Japanese Dermatological Association.)

Background: Homeobox ( HOX ) family genes have been identified as regulators of cancer development. No research exists concerning the mechanisms underlying homeobox B8 ( HOXB8 ) activity in non-small cell lung cancer (NSCLC). In this study, we investigated expression and biological function in NSCLC to determine whether it is an important marker of patient prognosis., Methods: HOXB8 expression in NSCLC tissues was investigated using immunohistochemistry (IHC) and Western blot assays. In addition, HOXB8 was knocked down in NSCLC cells to assess its biological functions in this context. The invasive and migratory potential of cells was evaluated by using Transwell (BD, Franklin Lakes, NJ, USA) inserts with 8-µm pores. Furthermore, Western blotting was used to explore whether HOXB8 can influence epithelial-mesenchymal transition (EMT)., Results: HOXB8 was expressed at high levels in NSCLC tissues and cell lines compared with adjacent normal tissues. Patients with high HOXB8 expression had shorter survival time and worse prognosis. HOXB8 expression was associated with pathological grading, tumor size, and lymph node metastasis. HOXB8 was prognostic in patients with NSCLC. After knockdown of HOXB8 via small interfering RNA, the proliferation, migration and invasion ability of the cells were significantly reduced compared with the control group. Moreover, EMT was inhibited by the downregulation of HOXB8 expression, as the expressions of E-cadherin was upregulated and that of the N-cadherin, vimentin, matrix metalloproteinase 2 ( MMP2 ), and twist were downregulated. HOXB8 is a member of the ANTP homeobox family and encodes a nuclear protein with a homeobox DNA-binding domain. It is included in a cluster of homeobox B genes located on chromosome 17. The encoded protein functions as a sequence-specific transcription factor that is involved in development., Conclusions: HOXB8 is highly expressed in NSCLC and may predict prognosis of patients with this type of cancer. Furthermore, HOXB8 may promote NSCLC progression through the regulation of the EMT process., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-2344/coif). The authors have no conflicts of interest to declare., (2024 Translational Cancer Research. All rights reserved.)

To study the inhibitory effects on microphthalmia-associated transcription factor (MITF)-related biological aspects in malignant melanomas (MMs) in the presence or absence of the low-molecular MITF specific inhibitor ML329, cell viability, cellular metabolic functions, and three-dimensional (3D) spheroid formation efficacy were compared among MM cell lines including SK-mel-24, A375, dabrafenib- and trametinib-resistant A375 (A375DT), and WM266-4. Upon exposure to 2 or 10 μM of ML329, cell viability was significantly decreased in WM266-4, SK-mel-24, and A375DT cells, but not A375 cells, in a dose-dependent manner, and these toxic effects of ML329 were most evident in WM266-4 cells. Extracellular flux assays conducted using a Seahorse bioanalyzer revealed that treatment with ML329 increased basal respiration, ATP-linked respiration, proton leakage, and non-mitochondrial respiration in WM266-4 cells and decreased glycolytic function in SK-mel-24 cells, whereas there were no marked effects of ML329 on A375 and A375DT cells. A glycolytic stress assay under conditions of high glucose concentrations also demonstrated that the inhibitory effect of ML329 on the glycolytic function of WM266-4 cells was dose-dependent. In addition, ML329 significantly decreased 3D-spheroid-forming ability, though the effects of ML329 were variable among the MM cell lines. Furthermore, the mRNA expression levels of selected genes, including STAT3 as a possible regulator of 3D spheroid formation, KRAS and SOX2 as oncogenic-signaling-related factors, PCG1a as the main regulator of mitochondrial biogenesis, and HIF1a as a major hypoxia transcriptional regulator, fluctuated among the MM cell lines, possibly supporting the diverse ML329 effects mentioned above. The findings of diverse ML329 effects on various MM cell lines suggest that MITF-associated biological activities are different among various types of MM.

Purpose: Dynamic chest radiography (DCR) is a novel imaging technique used to noninvasively evaluate pulmonary perfusion. However, the standard DCR protocol, which is roughly adapted to the patient's body size, occasionally causes over- or underexposure, which could influence clinical evaluation. Therefore, we proposed a refined protocol by increasing the number of patient body mass index (BMI) categories from three to seven groups and verified its usefulness by comparing the image sensitivity indicators (S-values) and entrance surface doses (ESDs) of the conventional protocol with those of our refined protocol., Methods: This retrospective observational study included 388 datasets (standing position, 224; supine position, 164) for the conventional protocol (December 2019-April 2021) and 336 datasets (standing position, 233; supine position, 103) for the refined protocol (June-November 2021). The conventional protocol (BMI-3 protocol) divided the patients into three BMI groups (BMI < 17, 17≤BMI < 25, and BMI ≥ 25 kg/m 2 ), whereas the refined protocol (BMI-7 protocol) divided the patients into seven BMI groups (BMI < 17, 17 ≤ BMI < 20, 20 ≤ BMI < 23, 23 ≤ BMI < 26, 26 ≤ BMI < 29, 29 ≤ BMI < 32, and BMI ≥ 32 kg/m 2 ). The coefficients of variation (CVs) for the S-values and ESDs acquired using the two protocols were compared., Results: The CVs of the S-values in the BMI-7 protocol group were significantly lower than those in the BMI-3 protocol group for the standing (28.8% vs. 16.7%; p < 0.01) and supine (24.5% vs. 17.7%; p < 0.01) positions. The ESDs of patients scanned using the BMI-7 protocol were significantly lower than those scanned using the BMI-3 protocol in the standing (1.3 vs. 1.1 mGy; p < 0.01) and supine positions (2.5 vs. 1.6 mGy; p < 0.01), although the mean BMI of the two groups were similar., Conclusion: We introduced the BMI-7 protocol and demonstrated its standardized image quality and reduced radiation exposure in patients undergoing DCR., (© 2023 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)