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Abstract Elucidating exciton migration in polymer chains has been one of the major research goals in photophysics for over half a century. While great efforts have been made to understand picosecond phenomena by ultrafast spectroscopy, ambiguous molecular conformations and/or random polymer sequences have hindered the construction of an ideal exciton migration model. Here we present the creation of unique end-capped coordination nanochains and quantitative description of intrachain exciton migration therein. The nanochain features unique molecular architectures in discrete polynuclear complexes, with a linear and rigid structure, the defined number of metal nuclei, and charge neutrality. These features allow well-defined arrangement of emissive dye moieties, making the nanochain a sound platform for studying exciton dynamics. Readily accessible absorption spectroscopy, and photoluminescence lifetime and quantum yield measurements allow the construction of continuous-time Markov chains model, thereby estimating non-trivial exciton migration across the metal center.

ABSTRACT Background Borderline ovarian tumors (BOTs) differ from ovarian carcinomas in their clinical presentation and behavior, yet their molecular characteristics remain poorly understood. This study aims to address this gap by integrating whole‐exome sequencing (WES) and RNA sequencing (RNA‐seq) to compare BOTs with high‐grade serous carcinoma (HGSC), endometrioid carcinoma (EC), and clear‐cell carcinoma (CCC). Objective To elucidate the molecular features of BOTs and evaluate their similarities and differences in comparison to HGSC, EC, and CCC. Methods The study analyzed 44 ovarian tumor samples, employing WES to identify genomic alterations and RNA‐seq to examine transcriptomic profiles. Comparative analyses were conducted to investigate the molecular relationships among the tumor types. Results The genomic analysis revealed that BOTs share significant similarities with EC. Furthermore, the transcriptomic data highlighted a novel and substantial similarity between BOTs and EC, suggesting deeper biological linkages, including potentially shared oncogenic pathways or tumor microenvironmental factors. These findings challenge traditional classifications and suggest a closer molecular alignment of BOTs with EC than previously understood. Conclusions This study provides new insights into the molecular characteristics of BOTs, demonstrating their significant resemblance to EC at both the genomic and transcriptomic levels. These results underscore the potential need to reconsider the molecular classification of ovarian tumors and open new avenues for research into the pathogenesis and treatment strategies for BOTs.

Abstract Positive peritoneal washing cytology is an indicator of poor prognosis in patients with pancreatic ductal adenocarcinoma (PDAC); however, its sensitivity is relatively low. This study evaluated the performance of peptide nucleic acid (PNA)-directed PCR clamping as a molecular-based peritoneal washing cytology for sensitive detection of KRAS mutation in PDAC. Intraoperative peritoneal washing fluid (IPWF) obtained from patients with PDAC who underwent surgery was analyzed. PNA-directed PCR clamping was performed on DNA extracted from IPWF. Among 54 patients enrolled, threshold cycle (Ct) was significantly lower in patients with positive peritoneal washing cytology than in those with negative peritoneal washing cytology (P

Abstract Ionic polymers are intriguing materials whose functionality arises from the synergy between ionic polymer backbones and counterions. A key method for enhancing their functionality is the post-synthetic ion-exchange reaction, which is instrumental in improving the chemical and physical properties of polymer backbones and introducing of the functionalities of the counterions. Electronic interaction between host polymer backbone and guest ions plays pivotal roles in property modulation. The current study highlights the modulation of responses to external electric field in cationic bis(terpyridine)cobalt(II) polymer nanofilms through anion-exchange reactions. Initially, as-prepared chloride-containing polymers exhibited supercapacitor behaviour. Introducing anionic metalladithiolenes into the polymers altered the behaviour to either conductive or insulative, depending on the valence of the metalladithiolenes. This modulation was accomplished by fine tuning of charge-transfer interactions between the bis(terpyridine)cobalt(II) complex moieties and redox-active anions. Our findings open up new avenue for ionic polymers, showcasing their potential as versatile platform in materials science.

Abstract Background Hyalinizing trabecular tumor (HTT) is an uncommon follicular cell-derived thyroid tumor classified as a low-risk neoplasm by the World Health Organization Classification of Tumors of Endocrine Organs, 5th edition. The PAX8-GLIS3 gene fusion is reportedly a pathognomonic genetic alteration of HTT. Case presentation A 43-year-old Japanese female was incidentally discovered to have an 8-mm, well-defined, hypoechoic mass in the left lobe of the thyroid gland by ultrasound examination. Contrast-enhanced computed tomography scan revealed a solid mass exhibiting slight homogeneous enhancement in the lower pole of the thyroid gland. The mass was diagnosed as atypia of undetermined significance by fine-needle aspiration cytology. The patient underwent left hemithyroidectomy with routine central compartment dissection. Histologic findings revealed tumor cells with elongated nuclei and intranuclear pseudoinclusions arranged with trabeculae architecture or small nests in hyalinized stroma. Weak membranous and cytoplasmic staining was found by MIB1 (Ki-67) immunostaining. The final diagnosis was HTT of the thyroid gland. Next-generation sequencing genetic analysis of a surgical specimen revealed no pathologic mutations, including BRAF, H/K/NRAS, or RET-PTC fusions. The PAX8-GLIS3 fusion was detected by RT-PCR. Conclusions A rare case of HTT was demonstrated through imaging, cytologic, histologic and molecular investigations. PAX8-GLIS3 fusion detected by RT-PCR and Sanger sequencing was confirmed to be a genetic hallmark of HTT.

Abstract Tumor structure is heterogeneous and complex, and it is difficult to obtain complete characteristics by two‐dimensional analysis. The aim of this study was to visualize and characterize volumetric vascular information of clear cell renal cell carcinoma (ccRCC) tumors using whole tissue phenotyping and three‐dimensional light‐sheet microscopy. Here, we used the diagnosing immunolabeled paraffin‐embedded cleared organs pipeline for tissue clearing, immunolabeling, and three‐dimensional imaging. The spatial distributions of CD34, which targets blood vessels, and LYVE‐1, which targets lymphatic vessels, were examined by calculating three‐dimensional density, vessel length, vessel radius, and density curves, such as skewness, kurtosis, and variance of the expression. We then examined those associations with ccRCC outcomes and genetic alteration state. Formalin‐fixed paraffin‐embedded tumor samples from 46 ccRCC patients were included in the study. Receiver operating characteristic curve analyses revealed the associations between blood vessel and lymphatic vessel distributions and pathological factors such as a high nuclear grade, large tumor size, and the presence of venous invasion. Furthermore, three‐dimensional imaging parameters stratified ccRCC patients regarding survival outcomes. An analysis of genomic alterations based on volumetric vascular information parameters revealed that PI3K‐mTOR pathway mutations related to the blood vessel radius were significantly different. Collectively, we have shown that the spatial elucidation of volumetric vasculature information could be prognostic and may serve as a new biomarker for genomic alterations. High‐end tissue clearing techniques and volumetric immunohistochemistry enable three‐dimensional analysis of tumors, leading to a better understanding of the microvascular structure in the tumor space.

Abstract Background PIK3CA mutations are implicated in various cancers, but the implications of multiple concurrent mutations and their orientations within the gene have not been fully explored. Methods In this study, we analyzed multi‐PIK3CA mutations across a diverse pan‐cancer cohort comprising 3564 tumors. Results Multi‐PIK3CA mutations were present in 10.3% of all PIK3CA‐mutant tumors, predominantly occurring in breast and gynecological cancers. Notably, mutations within the helical domain (E542:E545) exclusively occurred in the trans‐orientation, contrasting with mutations in the kinase ABD and C2 domains, which mainly appeared in the cis orientation. Conclusions The distinct pattern of mutation orientations in PIK3CA suggests variable oncogenic potential, with helical domain mutations in the trans‐orientation potentially being less oncogenic. These findings highlight the importance of mutation orientation in the PIK3CA gene as potential biomarkers for targeted therapy. This understanding is crucial for designing clinical trials that leverage PI3K inhibitors, aiming for more effective and precise cancer treatment.

Abstract Choline kinase (CK) is reportedly overexpressed in various malignancies. Among its isoforms, CKα overexpression is presumably related to oncogenic change. Choline positron emission tomography (PET) is reportedly useful for detecting and evaluating therapy outcomes in malignancies. In this study, we investigated the correlation between CKα expression and 11C-choline accumulation in breast cancer cells. We also compared the CKα expression level with other pathological findings for investigating tumour activity. Fifty-six patients with breast cancer (mean age: 51 years) who underwent their first medical examination between May 2007 and December 2008 were enrolled. All the patients underwent 11C-choline PET/computed tomography imaging prior to surgery. The maximum standardised uptake value was recorded for evaluating 11C-choline accumulation. The intensity of CKα expression was classified using immunostaining. A significant correlation was observed between CKα expression and 11C-choline accumulation (P

Abstract Background Companion diagnostic tests play a crucial role in guiding treatment decisions for patients with non‐small cell lung cancer (NSCLC). The Oncomine Dx Target Test (ODxTT) Multi‐CDx System has emerged as a prominent companion diagnostic method. However, its efficacy in detecting driver gene mutations, particularly rare mutations, warrants investigation. Aims This study aimed to assess the performance of the ODxTT in detecting driver gene mutations in NSCLC patients. Specifically, we aimed to evaluate its sensitivity in detecting epidermal growth factor receptor (EGFR) mutations, a key determinant of treatment selection in NSCLC. Materials and Methods We conducted a retrospective analysis of NSCLC patients who underwent testing with the ODxTT at Keio University Hospital between May 2020 and March 2022. Patient samples were subjected to both DNA and RNA tests. Driver gene mutation status was assessed, and instances of missed mutations were meticulously examined. Results Of the 90 patients, five had nucleic acid quality problems, while 85 underwent both DNA and RNA tests. Driver gene mutations were detected in 56/90 (62.2%) patients. Of the 34 patient specimens, driver mutations were not detected using the ODxTT; however, epidermal growth factor receptor (EGFR) mutations were detected using polymerase chain reaction‐based testing in two patients, and a KRAS mutation was detected by careful examination of the sequence data obtained using the ODxTT in one patient. For the above three cases, carefully examining the gene sequence information obtained using the ODxTT could identify driver mutations that were not mentioned in the returned test results. Additionally, we confirmed comparable instances of overlook results for EGFR mutations in the dataset from South Korea, implying that this type of oversight could occur in other countries using the ODxTT. EGFR mutation was missed in ODxTT in Japan (6.3%, 2/32), South Korea (2.0%, 1/49), and overall (3.7%, 3/81). Conclusion Even if sufficient tumor samples are obtained, rare EGFR mutations (which are excluded from the ODxTT's genetic mutation list) might not be detected using the current ODxTT system due to the program used for sequence analysis. However, such rare EGFR mutations can still be accurately detected on ODxTT's sequence data using next‐generation sequencing.

Abstract Advanced cutaneous squamous cell carcinoma (cSCC) is treated with chemotherapy and/or radiotherapy, but these typically fail to achieve satisfactory clinical outcomes. There have been no preclinical studies to evaluate the effectiveness of eribulin against cSCC. Here, we examine the effects of eribulin using cSCC cell lines and a novel cSCC patient-derived xenograft (PDX) model. In the cSCC cell lines (A431 and DJM-1 cells), eribulin was found to inhibit tumor cell proliferation in vitro as assessed by cell ATP levels. DNA content analysis by fluorescence-activated cell sorting (FACS) showed that eribulin induced G2/M cell cycle arrest and apoptosis. In xenograft models of cSCC cell lines, the administration of eribulin suppressed tumor growth in vivo. We also developed a cSCC patient-derived xenograft (PDX) which reproduces the histological and genetic characteristics of a primary tumor. Pathogenic mutations in TP53 and ARID2 were detected in the patient’s metastatic tumor and in the PDX tumor. The cSCC-PDX responded well to the administration of eribulin and cisplatin. In conclusion, the present study shows the promising antineoplastic effects of eribulin in cSCC. Also, we established a novel cSCC-PDX model that preserves the patient’s tumor. This PDX could assist researchers who are exploring innovative therapies for cSCC.

Abstract Background Genomic profile analysis using next‐generation sequencing can potentially elucidate the pathogenesis of rare cancers. Ductal adenocarcinoma, a rare subtype of prostate cancer, has an aggressive nature. This is the first study to analyze the genomic profile of ductal adenocarcinoma in an Asian population. Methods We identified 12 patients newly diagnosed with ductal adenocarcinoma of the prostate at two hospitals, and nine patients (75.0%) had the pure type. Genomic assessment was performed using either the PleSSision testing platform or FoundationOne CDx. Results At least one genomic alteration occurred in 11 patients (91.7%), and the most frequently mutated gene was tumor suppressor protein p53 (TP53), which was found in six cases (50.0%). Alterations characteristic of this cohort were found in four cases (33.3%) of retinoblastoma transcriptional corepressor 1 (RB1), which was only observed in the pure type. Compared to previous study results, the frequency of genetic alterations in the phosphoinositide 3‐kinase (PI3K) pathway (n = 3; 25.0%) and Wnt‐β‐catenin pathway (n = 5; 41.7%) was comparable, but no alterations in the DNA damage repair (DDR) pathway were observed. None of the patients presented high tumor mutation burden or microsatellite instability. Conclusions We found that the Asian cohort with ductal adenocarcinoma had actionable alterations, and a high frequency of alterations in TP53 and RB1 reflected the aggressive nature of the tumor. Genetic analysis using next‐generation sequencing is expected to help elucidate the pathogenesis of ductal adenocarcinoma.

Introduction Squamous cell carcinoma of the prostate is very rare. Due to difficulty in diagnosis, it is often detected in advanced stages. Effective treatment of squamous cell carcinoma and the genetic profiling has not yet been established. Case presentation We experienced the case of a 79‐year‐old man who was diagnosed with primary squamous cell carcinoma of the prostate. He had multiple lymph node metastases, liver metastases, and lung metastases, and he was treated with gemcitabine and carboplatin. However, he had poor patient status: it became difficult to continue after one course, and best supportive care was provided. We also performed targeted next‐generation sequencing of 160 cancer‐related genes and detected SMARCA4 mutation. Conclusion This is the first study reporting the genomic profiling of squamous cell carcinoma of prostate in Japan.

Abstract Background Abnormalities in homologous recombination contribute to the aggressive nature of castration-resistant prostate cancer. Retinoblastoma transcriptional corepressor 1 (RB1) and breast cancer 2 (BRCA2) exist close to each other in the same chromosome, and the significance of their concurrent loss has become a hot topic in the field of cancer research. Case presentation A 61-year-old man presented with a chief complaint of a mass on his head and was diagnosed as multiple bone metastases from prostate cancer. He was treated with standard medication, but he died 2 years 6 months after being diagnosed with prostate cancer. Simultaneous biallelic loss of RB1 and BRCA2 as well as a truncating mutation of tumor protein p53 (TP53) were revealed by genomic analysis. Conclusion To our knowledge, this is the first report of castration-resistant prostate cancer (CRPC) with BRCA2 and RB1 co-loss and TP53 mutation. To establish a treatment strategy for highly malignant cases with such multiple genetic features is important.

Abstract Background Prostate cancer (PC) is mainly known to metastasize to bone, lung and liver, but isolated metastases of prostate cancer, including ductal carcinoma, in the urinary tract are very rare. We describe two patients with nodular masses in the urinary tract (the anterior urethra or the urinary bladder) that were found on cystoscopy during treatment of castration-resistant prostate cancer. Case presentation In both cases, the pathological diagnosis from transurethral tumor resection showed that they were androgen indifferent prostate cancer (AIPC), including aggressive variant prostate cancer (AVPC) in Case 1 and treatment-induced neuroendocrine differentiation prostate cancer (NEPC) in Case 2. In Case 1, Loss of genetic heterozygosity (LOH) of BRCA2 and gene amplification of KRAS was identified from the urethra polyps. In Case 2, homozygous deletion was observed in PTEN, and LOH without mutation was observed in RB1. Conclusion These are the first reports of two cases of urinary tract metastasis of AIPC.

Abstract Background The use of whole-genome sequencing in clinical practice has revealed variable genomic characteristics across cancer types, one of which is whole-genome doubling (WGD), which describes the duplication of a complete set of chromosomes. Yet it is relatively rare in prostate cancer and no such case has ever been reported in Japanese patients. Case presentation A 54-year-old patient with prostatic adenocarcinoma with bone and lymph node metastases was started on androgen-deprivation therapy. As the prostate cancer turned castration-resistant, multimodal therapies including taxane- and platinum-based chemotherapy, androgen-receptor antagonist inhibitors, radiotherapy and radium-233 were introduced. Good controls of serum prostate-specific antigen (PSA) level and bone metastases were achieved for more than 13 years since after the initial treatment. During the treatment, a metastatic lymph node biopsy was performed to confirm the tumor histology, and spinal decompression surgery were performed for spinal compression due to lumber vertebral metastases. The immunohistochemical analysis identified PSA and androgen receptor positive tumor cells in both metastatic lesions, while no variable cancer cells were detected in the prostate on second biopsy. Whole-genome sequencing was performed on the biopsied metastatic lymph node in search for another possible treatment and it revealed that the tumor had WGD and CDK12 mutation. The WGD-positive tumor cells contained large and polymorphic nucleus, presumably reflecting on the ploidy abnormality of the chromosomes. Conclusions This report is the first case of a Japanese patient presenting with WGD, who survived more than 13 years with multimodal chemotherapies and radiotherapies.

Abstract To implement precision oncology, analytical validity as well as clinical validity and utility are important. However, proficiency testing (PT) to assess validity has not yet been systematically performed in Japan. To investigate the quality of next-generation sequencing (NGS) platforms and cancer genome testing prevalent in laboratories, we performed pilot PT using patient samples. We prepared genomic DNA from the cancer tissue and peripheral blood of 5 cancer patients and distributed these to 15 laboratories. Most participating laboratories successfully identified the pathogenic variants, except for two closely located KRAS variants and 25 bp delins in EGFR. Conversely, the EGFR L858R variant was successfully identified, and the allele frequency was similar for all the laboratories. A high DNA integrity number led to excellent depth and reliable NGS results. By conducting this pilot study using patient samples, we were able to obtain a glimpse of the current status of cancer genome testing at participating laboratories. To enhance domestic cancer genome testing, it is important to conduct local PT and to involve the parties concerned as organizers and participants.

Introduction Deoxyribonucleic acid repair gene mutations are now being studied in a variety of solid tumors, with the hope of predicting prognosis, pathogenesis, and treatment outcomes. Case presentation We report the case of a Japanese patient with advanced castration‐resistant prostate cancer who exhibited a prominent response to platinum therapy and had coexisting BRCA2 and PTEN mutations according to retrospective multigene panel analysis. Conclusion Through a review of clinical outcomes and genetic/pathologic profiling, the presented case provides insights into future management strategies based on the tumor genetic status.

Abstract Various malignancies exhibit high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR). The MSI-IVD kit, a polymerase chain reaction (PCR)-based method, was the first tumor-agnostic companion diagnostic to detect MSI status in MSI-H solid tumors. Recently, next-generation sequencing (NGS), which can also detect MSI-H/dMMR, has been made clinically available; however, its real-world concordance with PCR-based testing of MSI-H/dMMR remains to be investigated. The co-primary end points included the positive and negative predictive values of MSI-H/dMMR. A retrospective analysis of 80 patients who had undergone both MSI testing and NGS between July 2015 and March 2021 was conducted. Five patients were confirmed to have MSI-H in both examinations. Among the 75 patients diagnosed as microsatellite stable (MSS) by PCR-based testing, one with pancreatic cancer was diagnosed as having MSI-H after NGS. One patient with pancreatic cancer was diagnosed as having MSS in both tests was found to have a mutation in MLH1 by NGS, which was confirmed as dMMR by IHC staining. NGS had positive and negative predictive values of 100% (5/5) and 98.7% (74/75), respectively, for MSI-H. The concordance between NGS and PCR-based testing was 98.8% (79/80). Thus, NGS can be useful for evaluating MSI/MMR status in clinical practice and can be an important alternative method for detecting MSI-H/dMMR in the future.

Abstract Background Ductal adenocarcinoma and neuroendocrine cancer are rare subtypes of prostate cancer with poor prognosis and limited therapeutic options. We present the first case of ductal adenocarcinoma having a neuroendocrine phenotype. Case presentation A 63-year-old man presented with gross hematuria and urinary retention, and his serum prostate-specific antigen level was 4.58 ng/mL. We performed transurethral resection of the prostate, and the diagnosis was ductal adenocarcinoma with a Gleason score of 5 + 4 for acinar adenocarcinoma. Magnetic resonance imaging showed local invasion of left lobe of the prostate and bone metastasis of the left trochanteric section of the femur. Multidisciplinary treatments such as androgen deprivation therapy, chemoradiation therapy, and surgery for metastatic lesions have led to long-term survival. Since next-generation sequencing revealed PTEN and RB1 co-loss and TP53 mutations, we re-evaluated the immunohistochemistry and he was found to be positive for synaptophysin. Conclusions This is the first Japanese case of ductal adenocarcinoma with a neuroendocrine phenotype. Genetic analysis may help not only guide the therapeutic strategies, but also sometimes with the diagnosis.

Targeting the inhibitory receptors (IRs) LAG-3, TIM-3 and TIGIT is a promising immune-oncology approach and the identification of biomarkers of response is crucial. Here, the authors apply automated single-cell count for these IRs in human renal cell carcinoma and investigate the immunogenomic landscape of the disease.

Introduction Genomic profiling provides useful information for diagnosis, treatment, and prognosis, and detection of certain defects, such as DNA repair gene aberrations or microsatellite instability, can possibly lead to optimal treatment, but this testing has not been widely used to inform prostate cancer treatment. Case presentation A 55‐year‐old man sequentially treated for prostate cancer was diagnosed as neuroendocrine prostate cancer from prostate specimens resected because of urinary retention. Subsequently, he received five cycles of platinum‐based chemotherapy in total and responded well. We also performed next‐generation sequencing of a sample from the prostate specimen and identified a breast cancer susceptibility gene mutation with Murine Double Minute 2 amplification and loss of heterozygosity in retinoblastoma 1. Conclusion We report a neuroendocrine prostate cancer patient with Murine Double Minute 2 amplification who experienced an aggressive course and for whom platinum‐based chemotherapy was effective, and one of the reasons for the good response might be the breast cancer susceptibility gene mutation.

Introduction Ductal adenocarcinoma of the prostate is a rare prostate cancer variant and associated with higher stage and greater risk of mortality. Optimal systemic therapy for metastatic ductal adenocarcinoma is not known. Case presentation A 67‐year‐old man presented with ductal adenocarcinoma of the prostate accompanied by multiple lung metastases and advanced bone metastases. We performed channel transurethral resection of the prostate and confirmed the diagnosis of ductal adenocarcinoma of the prostate. DNA sequencing identified a TP53 somatic point mutation (p.Gly245Ser) as the pathogenic variant. Furthermore, a homozygous deletion was observed in mitogen‐activated protein kinase kinase kinase 1. The patient received enzalutamide but deceased 5 months after presenting to our institution. Conclusion To our knowledge, this is the first report of ductal adenocarcinoma of the prostate with a mitogen‐activated protein kinase kinase kinase 1 homozygous deletion. Accumulation of whole‐exome sequencing data is expected to inform future advances in therapy development.

Abstract Objectives In lung cancer, surgery remains the most curative treatment and limited resection is beneficial for patients with low cardiopulmonary function and low malignancy tumors. However, there are no biomarkers of low malignancy to select candidates for limited resection without compromising the outcome of treatments. Recently we identified biglycan (BGN) as a tumor endothelial cell (TEC) marker that is associated with tumor progression in various cancers. In this study, we analyzed the association between BGN expression in TECs in lung cancer and cancer progression in patients. Materials and Methods First, we performed immunohistochemistry of BGN with resected lung tumor tissues of 155 patients who had undergone thoracic surgery and analyzed the correlation between BGN‐positive vessel density in primary lung tumors and clinicopathological factors. Second, we measured the BGN levels in preoperative serum of other 46 patients with lung cancer by ELISA, and analyzed the correlation between BGN expression in tumor tissues and blood BGN levels. Results High BGN expression in the TECs was significantly associated with T factor, and was a significant negative predictor. BGN levels in preoperative serum of 46 patients with lung cancer was significantly correlated with BGN expression in the TECs. Preoperative serum BGN level was significantly lower in healthy volunteers and less invasive adenocarcinoma than in invasive adenocarcinoma and other lung carcinomas. These results suggest that low BGN level in preoperative serum in patients with lung cancer might indicate low malignancy. Conclusions BGN can be a potential biomarker for lung cancer.

Abstract 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.

Abstract Precision medicine based on cancer genomics is being applied in clinical practice. However, patients do not always derive benefits from genomic testing. Here, we performed targeted amplicon exome sequencing‐based panel tests, including 160 cancer‐related genes (PleSSision‐160), on 88 malignant ovarian tumors (high‐grade serous carcinoma, 27; endometrioid carcinoma, 15; clear cell carcinoma, 30; mucinous carcinoma, 6; undifferentiated carcinoma, 4; and others, 6 (immature teratoma, 1; carcinosarcoma, 3; squamous cell carcinoma, 1; and mixed, 1)), to assess treatment strategies and useful biomarkers for malignant ovarian tumors. Overall, actionable gene variants were found in 90.9%, and druggable gene variants were found in 40.9% of the cases. Actionable BRCA1 and BRCA2 variants were found in 4.5% of each of the cases. ERBB2 amplification was found in 33.3% of mucinous carcinoma cases. Druggable hypermutation/ultramutation (tumor mutation burden ≥ 10 SNVs/Mbp) was found in 7.4% of high‐grade serous carcinoma, 46.7% of endometrioid carcinoma, 10% of clear cell carcinoma, 0% of mucinous carcinoma, 25% of undifferentiated carcinoma, and 33.3% of the other cancer cases. Copy number alterations were significantly higher in high‐grade serous carcinoma (P

Abstract Background Ductal carcinoma of the prostate is a histological subtype with a higher mortality than acinar adenocarcinoma. The number of cases is small and there are no treatment guidelines. We believe that this is the first report of ductal carcinoma of the prostate with an adenomatosis polyposis coli (APC) gene mutation in Japan. Case presentation An 85-year-old man presented with gross hematuria, and a papillary tumor in the prostatic urethra that was diagnosed as ductal carcinoma of the prostate following transurethral resection. Genetic analysis found an APC mutation with loss of heterozygosity. Immunostaining revealed focal nuclear translocation of β-catenin. APC mutations associated with loss of β-catenin degradation in the Wnt signaling pathway and result in over accumulation of β-catenin are thought to increase mortality. In this patient, β-catenin migrated into tumor cell nuclei. Conclusion To the best of our knowledge, this is the first report of ductal carcinoma of the prostate with an APC mutation in Japan. The development of a therapeutic Wnt inhibitor is discussed.

Abstract Two-dimensional coordination nanosheets (CONASHs) are grown at the spherical liquid–liquid interface of a dichloromethane droplet in water to form zero-dimensional nano- and micro-capsules using a simple dropping method, a syringe-pump method, and an emulsion method. Reaction of 1,3,5-tris[4-(4′-2,2′:6′,2″-terpyridyl)phenyl]benzene (1) with Fe(BF4)2 affords electrochromic Fe(tpy)2 CONASH capsules and that of ligand 1 with ZnSO4 does photoluminescent Zn2(μ-O2SO2)2(tpy)2 CONASH capsules. Fe(tpy)2 CONASH capsules containing magnetite particles were produced by the syringe-pump method by adding magnetite to the aqueous phase, with the assembly and dispersion of the magnetite-containing CONASH capsules being easily controlled with a magnet. This indicates that physicochemically functional CONASH capsules are suitable for incorporating other functional materials to develop hybrid systems.

Abstract Background Bartholin gland carcinomas (BGCs) are rare tumor types, for which no molecular analyses including genomic sequencing have been reported to date. Adenoid cystic carcinomas (ACCs) of the Bartholin’s glands are an atypical histological type of BGC, and currently nothing is known regarding their genetic profiles or similarity to ACC carcinogenesis in other organs including the salivary glands, thereby limiting possible therapeutic options using precision medicine. Case presentation We used targeted gene sequencing to analyze the occurrence of 160 cancer-related genes in two patients with BG-ACC. KRAS and KDM6A mutations were detected in tumor samples collected from each patient. No KRAS mutations have been previously reported in salivary gland ACCs, indicating that the carcinogenesis of BG-ACC differs from that of the salivary gland ACCs. KDM6A mutations are often reported in salivary gland ACCs and facilitate novel gene-targeted therapy, including the use of BET and HDAC inhibitors. Conclusions A better understanding of the underlying genetic mechanisms will help to clarify the carcinogenesis of BG-ACC. In turn, this will enable treatment with novel targeting agents, as well as the initial exploration of gene-based precision oncological therapies, which aim to improve treatment outcomes for patients with this disease.

Background The aims of this study were (1) to clarify the impact of tertiary lymphoid structure (TLS) status on the outcome and immunogenomic profile of human clear cell renal cell carcinoma (ccRCC) and (2) to determine phenotypic differences in TLSs between different types of genitourinary cancer, that is, urinary ccRCC and bladder cancer.Methods We performed a quantitative immunohistological analysis of ccRCC tissue microarrays and conducted integrated genome mutation analysis by next-generation sequencing and methylation array analysis. Since the tumor immune microenvironment of ccRCC often differs from that of other cancer types, we analyzed the phenotypic differences in TLSs between ccRCC and in-house bladder cancer specimens.Results Varying distribution patterns of TLSs were observed throughout ccRCC tumors, revealing that the presence of TLSs was related to poor prognosis. An analysis of genomic alterations based on TLS status in ccRCC revealed that alterations in the PI3K-mTOR pathway were highly prevalent in TLS-positive tumors. DNA methylation profiling also revealed distinct differences in methylation signatures among ccRCC samples with different TLS statuses. However, the TLS characteristics of ccRCC and bladder cancer markedly differed: TLSs had the exact opposite prognostic impact on bladder cancer as on ccRCC. The maturity and spatial distribution of TLSs were significantly different between the two cancer types; TLSs were more mature with follicle-like germinal center organization and likely to be observed inside the tumor in bladder cancer. Labeling for CD8, FOXP3, PD-1, and PD-L1 showed marked differences in the diversity of the immune microenvironment surrounding TLSs. The proportions of CD8-, FOXP3-, and PD-L1-positive cells were significantly higher in TLSs in bladder cancer than in TLSs in ccRCC; rather the proportion of PD-1-positive cells was significantly higher in TLSs in ccRCC than in TLSs in bladder cancer.Conclusion The immunobiology of ccRCC is unique, and various cancerous phenomena conflict with that seen in other cancer types; therefore, comparing the TLS characteristics between ccRCC and bladder cancer may help reveal differences in the prognostic impact, maturity and spatial distribution of TLSs and in the immune environment surrounding TLSs between the two cancers.

From the beginning of the COVID-19 pandemic, the demand for diagnostic and screening tests has exceeded supply. Although the proportion of vaccinated people has increased in wealthier countries, breakthrough infections have occurred amid the emergence of new variants. Pooled-sample COVID-19 testing using saliva has been proposed as an efficient, inexpensive, and non-invasive method to allow larger-scale testing, especially in a screening setting. In this study, we aimed to evaluate pooled RT-qPCR saliva testing and to compare the results with individual tests. Employees of Philips Japan, Ltd. were recruited to participate in COVID-19 screening from October to December 2020. Asymptomatic individuals (n = 824) submitted self-collected saliva samples. Samples were tested for the presence of SARS-CoV-2 by RT-qPCR in both 10-sample pools and individual tests. We also surveyed participants regarding their thoughts and behaviors after the PCR screening project. Two of the 824 individuals were positive by RT-qPCR. In the pooled testing, one of these two had no measurable Ct value, but showed an amplification trend at the end of the PCR cycle. Both positive individuals developed cold-like symptoms, but neither required hospitalization. Of the 824 participants, 471 responded to our online questionnaire. Overall, while respondents agreed that PCR screening should be performed regularly, the majority were willing to undergo PCR testing only when it was provided for free or at low cost. In conclusion, pooled testing of saliva samples can support frequent large-scale screening that is rapid, efficient, and inexpensive.

Abstract Background Precision medicine based on genomic analysis of germline or tumor tissue is attracting attention. However, there is no consensus on how to apply the results of genomic analysis to treatment. Case presentation A 59-year-old man diagnosed with metastatic prostate cancer was diagnosed with castration-resistant prostate cancer. Although he was sequentially treated with enzalutamide and abiraterone, bone metastasis progression was identified by skeletal scintigraphy. Therefore, we sequentially performed docetaxel therapy followed by cabazitaxel. After the third cycle of cabazitaxel, his prostate-specific antigen level was stable at

Abstract Organometallic two‐dimensional (2D) nanosheets with tailorable components have recently fascinated the optoelectronic communities due to their solution‐processable nature. However, the poor stability of organic molecules may hinder their practical application in photovoltaic devices. Instead of conventional organometallic 2D nanosheets with low weatherability, an air‐stable π‐conjugated 2D bis(dithiolene)iron(II) (FeBHT) coordination nanosheet (CONASH) is synthesized via bottom‐up liquid/liquid interfacial polymerization using benzenehexathiol (BHT) and iron(II) ammonium sulfate [Fe(NH4)2(SO4)2] as precursors. The uncoordinated thiol groups in FeBHT are easily oxidized, but the Fe(NH4)2(SO4)2 dissociation rate is slow, which facilitates the protection of sulfur groups by iron(II) ions. The density functional theory calculates that the resultant FeBHT network gains the oxygen‐repelling function for oxidation suppression. In air, the FeBHT CONASH exhibits self‐powered photoresponses with short response times (

OX40 (CD134) is a co-stimulatory molecule mostly expressed on activated T lymphocytes. Previous reports have shown that OX40 can be an immuno-oncology target and a clinical biomarker for cancers of various organs. In this study, we collected formalin-fixed paraffin-embedded tumor samples from 124 patients with small-cell lung cancer (SCLC) who had undergone surgery. We analyzed the expression profiles of OX40 and other relevant molecules, such as CD4, CD8, and Foxp3, in tumor stroma and cancer nest using immunohistochemistry and investigated their association with survival. High infiltration of OX40+ lymphocytes (OX40high) in tumor stroma was positively associated with relapse-free survival (RFS) and overall survival (OS) compared with low infiltration of OX40+ lymphocytes (OX40low) (RFS, median, 26.0 months [95% confidence interval (CI), not reached (NR)–NR] vs 13.2 months [9.1–17.2], p = .024; OS, NR [95% CI, NR–NR] vs 29.8 months [21.3–38.2], p = .049). Multivariate analysis revealed that OX40high in tumor stroma was an independent indicator of prolonged RFS. Moreover, RFS of patients with OX40high/CD4high in tumor stroma was significantly longer than that of patients with OX40low/CD4low. The RFS of patients with tumor stroma with OX40high/CD8high was significantly longer than that of patients with tumor stroma with OX40low/CD8high, OX40high/CD8low, or OX40low/CD8low. These findings suggest that OX40+ lymphocytes in tumor stroma play a complementary role in regulating the relapse of early-stage SCLC. Reinforcing immunity by coordinating the recruitment of OX40+ lymphocytes with CD4+ and CD8+ T cells in tumor stroma may constitute a potential immunotherapeutic strategy for patients with SCLC.

Objectives: Few reports have explored clinical biomarkers, including those identified by targeted exome sequencing (TES) of surgically resected small-cell lung cancer (SCLC) and correlation with patient survival. Patients and methods: We collected formalin-fixed paraffin-embedded tumor samples from 127 patients with SCLC who had undergone surgery and analysed nonsynonymous somatic gene mutation profiles by TES of 26 cancer-related genes using next-generation sequencing (NGS) and web databases (UMIN Registration No. 000010117). Results: We detected 38 nonsynonymous somatic tumor protein p53 (TP53) mutations in 43 (54.4%) patients. Among these TP53 lesions, we identified clinically relevant mutations including those encoding Y220C, R248W, R249M, M237I, and R273L substitutions in the p53 protein. These mutations have been reported to be associated with certain clinical outcomes or biology in other types of malignancies but not in SCLC. Moreover, nonsynonymous somatic mutations of TP53 were positively associated with relapse-free survival (RFS) (median, 17.33 months [95% confidence interval (CI), 3.86–30.79] in a mutation-positive group vs 10.39 months (6.96–13.82) in a mutation-negative group, p = 0.042). Multivariate analysis revealed that nonsynonymous somatic TP53 mutation was an independent factor of prolongation of RFS (hazard ratio: 0.51, 95% CI: 0.29–0.89, p = 0.019) but not overall survival (OS). Conclusion: These data suggested that TES may play a critical role for promoting reverse-translational studies, including investigations of the biology of TP53 mutations in different stages of SCLC. Accumulation of the data using cancer panels with a broader range of genes, including TP53, is expected to be useful for future clinical applications for patients with SCLC.

Bis(diimino)metal complex nanosheets composed of metal ions and hexaaminobenzene ligands (MHABs) are fascinating two-dimensional materials which have been gaining significant attention as electrode materials and electrocatalysts owing to their electrical conductivities, redox properties, and porous structures obtained by the π-conjugated system and regular metal complex arrangement. Although electrochemical oxidation enables the simple and direct formation of MHABs on electrodes within a couple of minutes only, the obtained MHABs are relatively rough and of low crystallinity. This study investigated the effects of the applied potential during the synthesis, the type of base, and the concentrations of bases and building blocks on the synthesis of NiHAB nanosheets. Optical microscopy (OM), atomic force microscopy (AFM), Raman spectroscopy, X-ray photoelectron spectroscopy (XPS), and grazing-incidence X-ray scattering (GIXS) results revealed that a low oxidation potential, high concentration of the ammonia solution, and low concentration of the building blocks in the reaction solution provided a nanometre-thick NiHAB layer. Under the optimal reaction conditions, NiHAB nanosheets were successfully synthesized in a face-on orientation manner on gold electrodes using electrochemical oxidation methods. Furthermore, the anisotropic electrochemical synthesis of CuHAB was achieved under the optimised conditions. The mechanism of the MHAB growth process with an anisotropic orientation and nanometre thickness was proposed and attributed to the flat adsorption of p-conjugated oligomers composed of bis(diamino)metal moieties in a solution onto an electrode surface and the electrochemical oxidation and deprotonation of the adsorbates on the electrode. [ABSTRACT FROM AUTHOR]

Abstract Several cellular signaling pathways, including insulin/IGF signaling, are known to be activated in hepatocellular carcinoma (HCC). Here, we investigated the roles of insulin receptor substrate (Irs) 1 and Irs2, both of which are the major molecules to be responsible for transducing insulin/IGF signaling in the liver, in the development of HCC by inducing chemical carcinogenesis using diethylnitrosamine (DEN) in mice. The Irs1 mRNA and protein expressions were upregulated in the tumors, along with enhanced insulin signaling. Liver-specific Irs1-knockout (LIrs1KO) mice exhibited suppression of DEN-induced HCC development, accompanied by reduced cancer cell proliferative activity and reduced activation of Akt. Gene expression analyses revealed that the tumors in the DEN-treated LIrs1KO mice showed modest metabolic alterations during hepatocarcinogenesis as well as decreased inflammation and invasion potentials. On the other hand, liver-specific Irs2-knockout (LIrs2KO) mice showed a similar pattern of HCC development to the DEN-treated control wild-type mice. Based on the knowledge that Wnt/β-catenin signaling is activated in HCC, we focused on Wnt/β-catenin signaling and demonstrated that Irs1 expression was induced by Wnt3a stimulation in the primary hepatocytes, associated with insulin-stimulated Akt activation. These data suggest that upregulated Irs1 by Wnt/β-catenin signaling plays a crucial role in the progression of HCC.

We developed an efficient and convenient electrochemical method to synthesize π-conjugated redox metal-complex linear polymer wires composed of azobenzene-bridged bis(terpyridine)metal (2-M, M = Fe, Ru) units covalently immobilized on glassy carbon (GC). Polymerization proceeds by electrochemical oxidation of bis(4′-(4-anilino)-2,2′:6′,2″-terpyridine)metal (1-M) in a water–acetonitrile–HClO4 solution, affording ultralong wires up to 7400 mers (corresponding to ca. 15 μm). Both 2-Fe and 2-Ru undergo reversible redox reactions, and their redox behaviors indicate remarkably fast redox conduction. Anisotropic hetero-metal-complex polymer wires with Fe and Ru centers are constructed via stepwise electropolymerization. The cyclic voltammograms of two hetero-metal-complex polymer wires, GC/[2-Fe]–[2-Ru] (3) and GC/[2-Ru]–[2-Fe] (4), show irreversible redox reactions with opposite electron transfer characteristics, indicating redox diodelike behavior. In short, the present electrochemical method is useful to synthesize polymer wire arrays and to integrate functional molecules on carbon.

Background/Aim: A genomic analysis based on next-generation sequencing is important for deciding cancer treatment strategies. Cancer tissue sometimes displays intratumor heterogeneity and a pathologic specimen may contain more than two tumor grades. Although tumor grades are very important for the cancer prognosis, the impact of higher tumor grade distribution in a specimen used for a genomic analysis is unknown. Patients and Methods: We retrospectively analyzed the data of 61 clear cell carcinoma and 46 prostate cancer patients that were diagnosed between December 2018 and August 2022 using the GeneRead Human Comprehensive Cancer Panel or SureSelect PrePool custom Tier2. Genome annotation and curation were performed using the GenomeJack software. Results: Tumor mutation burden (TMB) was increased in proportion to the higher tumor grade distribution in grade 2 clear cell renal cell carcinoma (ccRCC). In PC, Grade Group 3/4 specimens that included an increased distribution of Gleason pattern 4 had more frequent gene mutations. Conclusion: Our results suggest the importance of selecting the maximum distribution of higher tumor grade areas to obtain results on the precise gene alterations for genomics-focused treatments. [ABSTRACT FROM AUTHOR]