The evolution of cancer genomic medicine in Japan and the role of the National Cancer Center Japan

The journey to implement cancer genomic medicine(CGM)in oncology practice began in the 1980s,which is considered the dawn of genetic and genomic cancer research.At the time,a variety of activating oncogenic alterations and their functional significance were unveiled in cancer cells,which led to the development of molecular targeted therapies in the 2000s and beyond.Although CGM is still a relatively new discipline and it is difficult to predict to what extent CGM will benefit the diverse pool of cancer patients,the National Cancer Center(NCC)of Japan has already contributed considerably to CGM advancement for the conquest of cancer.Looking back at these past achievements of the NCC,we predict that the future of CGM will involve the following:1)A biobank of paired cancerous and non-cancerous tissues and cells from various cancer types and stages will be developed.The quantity and quality of these samples will be compatible with omics analyses.All biobank samples will be linked to longitudinal clinical information.2)New technologies,such as whole-genome sequencing and artificial intelligence,will be introduced and new bioresources for functional and pharmacologic analyses(e.g.,a patient-derived xenograft library)will be systematically deployed.3)Fast and bidirectional translational research(bench-to-bedside and bedside-to-bench)performed by basic researchers and clinical investigators,preferably working alongside each other at the same institution,will be implemented;4)Close collaborations between academia,industry,regulatory bodies,and funding agencies will be established.5)There will be an investment in the other branch of CGM,personalized preventive medicine,based on the individual's genetic predisposition to cancer.

Mission of the National Cancer Center Hospital in Japan to promote clinical trials for precision medicine

Precision medicine is a growing field worldwide.Despite its potential benefit to many patients,several major obstacles must be overcome before precision medicine can be more widely used in clinical practice.The main obstacles are associated with the quality of samples used for genomic analysis。

Collagen matrix scaffolds:Future perspectives for the management of chronic liver diseases

Approximately 1.5 billion chronic liver disease(CLD)cases have been estimated worldwide,encompassing a wide range of liver damage severities.Moreover,liver disease causes approximately 1.75 million deaths per year.CLD is typically characterized by the silent and progressive deterioration of liver parenchyma due to an incessant inflammatory process,cell death,over deposition of extracellular matrix proteins,and dysregulated regeneration.Overall,these processes impair the correct function of this vital organ.Cirrhosis and liver cancer are the main complications of CLD,which accounts for 3.5%of all deaths worldwide.Liver transplantation is the optimal therapeutic option for advanced liver damage.The liver is one of the most common organs transplanted;however,only 10%of liver transplants are successful.In this context,regenerative medicine has made significant progress in the design of biomaterials,such as collagen matrix scaffolds,to address the limitations of organ transplantation(e.g.,low donation rates and biocompatibility).Thus,it remains crucial to continue with experimental and clinical studies to validate the use of collagen matrix scaffolds in liver disease.

Current and future trends in whole genome sequencing in cancer

Cancer remains a formidable global health challenge affecting millions of lives annually.For decades,conventional cancer treatments used a one-size-fits-all approach,overlooking the intricate genetic variations that drive tumors.The emergence of cancer genomics has ushered in a new era of personalized and targeted cancer therapies.The Human Genome Project,which was launched in 1990 and completed in 2003。

Genomic medicine in clinical practice:national genomic medicine program in Japan

Cancer statistics in Japan Cancer is the most common cause of death in Japan based on Statistics 2021~1.Since statistics were first gathered,infectious diseases,such as tuberculosis,and cerebrovascular disease have been the main causes of death in Japan.Cancer surpassed cerebrovascular disease as the main cause of death in 1981,and the number of cancer deaths has increased.Approximately 38,000 people died of cancer in 2021.The National Cancer Center(NCC)reported that the 5-year survival rate for patients with cancer was improving(62%for males and 66.9%for females)in a population-based cancer registry.

Multidisciplinary therapy for treatment of patients with peritoneal carcinomatosis from gastric cancer

There is no standard treatment for peritoneal carcinomatosis (PC) from gastric cancer.A novel multidisciplinary treatment combining bidirectional chemotherapy [neoadjuvant intraperitoneal-systemic chemotherapy protocol (NIPS)],peritonectomy,hyperthermic intraperitoneal chemoperfusion (HIPEC) and early postoperative intraperitoneal chemotherapy has been developed.In this article,we assess the indications,safety and eff icacy of this treatment,review the relevant studies and introduce our experiences.The aims of NIPS are stage reduction,the eradication of peritoneal free cancer cells,and an increased incidence of complete cytoreduction (CC-0) for PC.A complete response after NIPS was ob-tained in 15 (50%) out of 30 patients with PC.Thus,a signif icantly high incidence of CC-0 can be obtained in patients with a peritoneal cancer index (PCI) ≤ 6.Using a multivariate analysis to examine the survival benef it,CC-0 and NIPS are identified as significant indicators of a good outcome.However,the high morbidity and mortality rates associated with peritonectomy and perioperative chemotherapy make stringent patient selection important.The best indications for multidisciplinary therapy are localized PC (PCI≤6) from resectable gastric cancer that can be completely removed during a peritonectomy.NIPS and complete cytoreduction are essential treatment modalities for improving the survival of patients with PC from gastric cancer.

Activation of the PI3K/AKT pathway mediates FSH-stimulated VEGF expression in ovarian serous cystadenocarclnoma

There is evidence to suggest that follicle-stimulating hormone （FSH） can facilitate the neovascularization of ovarian cancers by increasing vascular endothelial growth factor （VEGF） expression in cancer cells, although the underlying molecular mechanism of this process is not well known. Therefore, we investigated the effect of FSH on VEGF expression in the ovarian cancer cell lines SKOV-3 and ES-2. Treatment with FSH significantly increased VEGF expression in a dose- and time-dependent manner. In addition, FSH treatment enhanced the expression of survivin and hypoxlainducible factor-1 （HIF-1α）. Knockdown of survivin or HIF-1α suppressed VEGF expression, but only knockdown of survivin inhibited FSH-stimulated VEGF expression. Pretreatment with LY294002, a phosphoinositide 3-kinase （PI3K）/AKT inhibitor, neutralized the enhanced expression of survivin induced by FSH, but treatment with U0126, a mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor, had no such effect. We further showed that ovarian serous cystadenocarcinoma samples had much higher incidence of positive AKT and phosphorylated AKT （pAKT） protein staining than did benign ovarian cystadenoma samples （p 〈 0.01）. The 5-year survival rate was only about 15% in patients with ovarian serous cystadenocarcinoma who had AKT and pAKT expression, whereas it was about 80% in those who did not have AKT or pAKT expression. Taken together, these results indicate that FSH increases the expression of VEGF by upregulating the expression of survivin, which is activated by the PI3K/AKT signaling pathway. Understanding the role of the PI3K/AKT pathway in FSH-stimulated expression of survivin and VEGF will be beneficial for evaluating the prognosis for patients with ovarian serous cystadenocarcinoma and for pursulug effective treatment against this disease.

The diverse heterogeneity of molecular alterations in prostate cancer identified through next-generation sequencing

Prostate cancer is a leading cause of global cancer-related death but attempts to improve diagnoses and develop novel therapies have been confounded by significant patient heterogeneity. In recent years, the application of next-generation sequencing to hundreds of prostate tumours has defined novel molecular subtypes and characterized extensive genomic aberration underlying disease initiation and progression. It is now clear that the heterogeneity observed in the clinic is underpinned by a molecular landscape rife with complexity, where genomic rearrangements and rare mutations combine to amplify transcriptomic diversity. This review dissects our current understanding of prostate cancer ＇omics＇, including the sentinel role of copy number variation, the growing spectrum of oncogenic fusion genes, the potential influence of chromothripsis, and breakthroughs in defining mutation-associated subtypes. Increasing evidence suggests that genomic lesions frequently converge on specific cellular functions and signalling pathways, yet recurrent gene aberration appears rare. Therefore, it is critical that we continue to define individual tumour genomes, especially in the context of their expressed transcriptome. Only through improved characterisation of tumour to tumour variability can we advance to an age of precision therapy and personalized oncology.

MicroRNA therapeutics:principles,expectations,and challenges

MicroRNAs(miRNAs) are a class of highly abundant non-coding RNA molecules that are involved in several biological processes.Many miRNAs are often deregulated in several diseases including cancer.There is substantial interest in exploiting miRNAs for therapeutic applications.In this editorial,we briefly review current advances in the use of miRNAs or antisense oligonucleotides(antagomirs) for such therapies.One of the key issues related to therapy using miRNAs is degradation of naked particles in vivo.To overcome this limitation,delivery systems for miRNA-based therapeutic agents have been developed,which hold tremendous potential for improving therapeutic outcome of cancer patients.

Principles of microRNA involvement in human cancers

Naturally occurring microRNAs (miRNAs), small non-coding RNAs of 19 to 24 nucleotides (nt), are encoded in the genomes of invertebrates, vertebrates, and plants. miRNAs act as regulators of gene expression during development and differentiation at the transcriptional, posttranscriptional, and/or translational levels, although most target genes are still elusive. Many miRNAs are conserved in sequence between distantly related organisms, suggesting that these molecules participate in essential processes. In this review, we present principles related to the basic and translational research that has emerged in the last decade, a period that can be truly considered the "miRNA revolution" in molecular oncology. These principles include the regulation mechanism of miRNA expression, functions of miRNAs in cancers, diagnostic values and therapeutic potentials of miRNAs. Furthermore, we present a compendium of information about the main miRNAs that have been identified in the last several years as playing important roles in cancers. Also, we orient the reader to several additional reviews that may provide a deeper understanding of this new and exciting field of research.

The role of mRNA splicing in prostate cancer

Alternative splicing （AS） is a crucial step in gene expression. It is subject to intricate regulation, and its deregulation in cancer can lead to a wide array of neoplastic phenotypes. A large body of evidence implicates splice isoforms in most if not all hallmarks of cancer, including growth, apoptosis, invasion and metastasis, angiogenesis, and metabolism. AS has important clinical implications since it can be manipulated therapeutically to treat cancer and represents a mechanism of resistance to therapy. In prostate cancer （PCa） AS also plays a prominent role and this review will summarize the current knowledge of alternatively spliced genes with important functional consequences. We will highlight accumulating evidence on AS of the components of the two critical pathways in PCa： androgen receptor （AR） and phosphoinositide 3-kinase （PI3K）. These observations together with data on dysregulation of splice factors in PCa suggest that AR and PI3K pathways may be interconnected with previously unappreciated splicing regulatory networks. In addition, we will discuss several lines of evidence implicating splicing regulation in the development of the castration resistance.

Redox regulation of mast cell histamine release in thioredoxin-1 （TRX） transgenic mice

Thioredoxin-1 （TRX） is a stress-inducible redox-regulatory protein with antioxidative and anti-inflammatory effects. Here we show that the release of histamine from mast cells elicited by cross-linking of high-affinity receptor for IgE （FcεRI） was significantly suppressed in TRX transgenic （TRX-tg） mice compared to wild type （WT） mice. Intracellular reactive oxygen species （ROS） of mast cells stimulated by IgE and antigen was also reduced in TRX-tg mice compared to WT mice. Whereas there was no difference in the production ofcytokines （IL-6 and TNF-α） from mast cells in response to 2,4-dinitrophenylated bovine serum albumin （DNP-BSA） stimulation in TRX-tg and WT mice. Immunological status of TRX-tg mice inclined to T helper （Th） 2 dominant in primary immune response, although there was no difference in the population of dendritic cells （DCs） and regulatory T cells. We conclude that the histamine release from mast cells in TRX-tg mice is suppressed by inhibition of ROS generation. As ROS are involved in mast cell activation and facilitate mediator release, TRX may be a key signaling molecule regulating the early events in the IgE signaling in mast cells and the allergic inflammation.

Immune phenotypes of prostate cancer cells: Evidence of epithelial immune cell-like transition?

Prostate cancers(PCa)have been reported to actively suppress antitumor immune responses by creating an immune-suppressive microenvironment.There is mounting evidence that PCas may undergo an‘‘Epithelial Immune Cell-like Transition’’(EIT)by expressing molecules conventionally associated with immune cells(e.g.,a variety of cytokines/receptors,immune transcription factors,Ig motifs,and immune checkpoint molecules),which subsequently results in the suppression of anti-cancer immune activity within the tumor microenvironment.Recent progress within the field of immune therapy has underscored the importance of immune checkpoint molecules in cancer development,thus leading to the development of novel immunotherapeutic approaches.Here,we review the expression of select immune checkpoint molecules in PCa epithelial and associated immune cells,with particular emphasis on clinical data supporting the concept of an EIT-mediated phenotype in PCa.Furthermore,we summarize current advances in anti-immune checkpoint therapies,and provide perspectives on their potential applicability.

Sapacitabine,the prodrug of CNDAC,is a nucleoside analog with a unique action mechanism of inducing DNA strand breaks

Sapacitabine is an orally bioavailable prodrug of the nucleoside analog 2'-C-cyano-2'-deoxy-1-β-D-arabino-pentofuranosylcytosine(CNDAC).Both the prodrug and active metabolite are in clinical trials for hematologic malignancies and/or solid tumors.CNDAC has a unique mechanism of action:after incorporation into DNA,it induces single-strand breaks(SSBs) that are converted into double-strand breaks(DSBs) when cells go through a second S phase.In our previous studies,we demonstrated that CNDAC-induced SSBs can be repaired by the transcription-coupled nucleotide excision repair pathway,whereas lethal DSBs are mainly repaired through homologous recombination.In the current work,we used clonogenic assays to compare the DNA damage repair mechanism of CNDAC with two other deoxycytidine analogs:cytarabine,which is used in hematologic malignacies,and gemcitabine,which shows activity in solid tumors.Deficiency in two Rad51 paralogs,Rad51D and XRCC3,greatly sensitized cells to CNDAC,but not to cytarabine or gemcitabine,indicating that homologous recombination is not a major mechanism for repairing damage caused by the latter two analogs.This study further suggests clinical activity and application of sapacitabine that is distinct from that of cytarabine or gemcitabine.

Prevention of H2O2 Induced Oxidative Damages of Rat Testis by Thymus algeriensis

Objective We evaluate the effects of Thymus algeriensis （TEO） against hydrogen peroxide （H202） toxicity on body and testis weight, testis sperm count, testis lipid peroxidation, and antioxidant enzyme activities in rats. Methods Rats were treated with low （LD） and high dose （HD） of H202 （0.1 and 1 mmol/L） in the presence or absence of TEO （150 mg/kg）. Results The results exhibited a significant decrease in body weight and testis weight, in total sperm number decrease （P〈0.05）, sperm motility and percentage of sperm viability, leading to complete arrest, in sperm flagellar beat frequency by the gavage of 1 mmol/L H202 compared to controls. The administration of H2O2 resulted in a significant reduction in testis GSH, GPx, CAT, SOD, and GST activity and significant increase （P〈0.05） in MDA concentration compared with the untreated control animals. TEO pre-treatment protected testis from the H2O2 generated oxidative stress. These results were confirmed by histological architecture examinations. Conclusion H2O2 has the ability to alter the sperm function, characteristics and development of testis. However, TEO is an efficient natural agent, which can prevent the testis from H2O2-induced oxidative damage in rats.

Psychological Distress and Resilience among Partners of Cancer Patients Receiving Outpatient Chemotherapy

Background: Partners of cancer patients are at elevated risk of experiencing psychological distress. Psychological distress is known to be countered by the protective factor, resilience. The relationship between psychological distress and resilience among partners of cancer patients remains to be examined by quantitative studies. We aimed to investigate the association between psychological distress, and resilience and cancer-related psychological experience among partners of cancer patients receiving outpatient chemotherapy. Methods: Spouses and significant others of cancer patients were consecutively recruited into our cross-sectional study. The primary outcome was psychological distress, as assessed by the Hospital Anxiety and Depression Scale. The primary explanatory variables were resilience, as assessed by the short Japanese version of the Resilience Scale, and cancer-related psychological experience. Traumatic stress was assessed by the Japanese-language version of the Impact of Event Scale-Revised, while perception of caregiving burden and patients’ symptoms, and psychological support needs were assessed by single-item questions. To examine the association between psychological distress, and resilience and partners’ psychological experience, hierarchical multiple regression analysis was applied. Results: Psychological distress was evident in 33 of 109 partners, (30.3%, 95% confidence interval, 21.5 - 39.1). After adjusting for potential confounders, hierarchical multiple regression analysis showed the main effect of resilience. In the final step, while resilience was not found to be significant, psychological distress was observed to be positively associated with traumatic stress and perceived caregiving burden (β = 0.64, p β = 0.22, p Conclusions: The protective effect of resilience on partners’ psychological distress is moderated by traumatic stress and perceived caregiving burden during patients’ chemotherapy. The findings of this study suggest that a systematic way of providing appropriate psychological service to appropriate partners of cancer patients is required.

A Retrospective Analysis for Different Routes of Administration in Mice-Percutaneous Retro-Orbital, Jugular Catheter, Tail Vein and Femoral Cut Down Injections

Liposomes effectively transport fatty proteins to targeted tissues. Laboratory experiments use multiple methods to administer liposomes, but comparison of these methods is not available. In this retrospective study, we characterized and compared four intravenous administration routes (tail vein, jugular catheter, femoral vein and percutaneous retro-orbital injections) in murine models. ApoE-/- mice were used to compare administration routes. Results indicate that the jugular catheter route delivered the highest amount of liposomes to tissues due to longer period of injections compared to other routes;however, this route failed to remain patent for 8/10 animals. Delivery via tail vein, femoral vein and percutaneous retro-orbital injections resulted in similar accumulation in the organs. When including technical difficulty and expense, percutaneous retro-orbital injections of liposomes are the most convenient and efficacious approach.

A pilot double-blind, randomized, placebo-controlled trial of curcumin/bioperine for lung cancer chemoprevention in patients with chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease is an inflammatory condition with increased risk of lung cancer. We hypothesized that curcumin/ bioperine (CB), which has anti-inflammatory effects, may reduce cytological abnormalities in the sputum of patients with COPD. We conducted a 3-month, three-to-one randomized, doubleblind, pilot trial of escalating doses of CB in patients with moderate or worse COPD who were capable of producing sputum. The primary efficacy endpoint was changed in sputum cytology. We also explored changes in fluorescence in situ hybridization (FISH). We obtained sputum samples for cytology and chromosome abnormalities at baseline and each monthly follow-up visit. We enrolled 57 participants, with 35 completing the study. The participants’ mean age (standard deviation [SD]) was 66.6 (8.2) years, and they were mainly male (91.2%), with an average of 63.8 pack-years of smoking history. Also, 42.1% of participants were active smokers and the mean (SD) FEV1 was 37% (13%). At baseline, 13 subjects had moderate or worse dysplasia (22.8%). Subjects with moderate to severe sputum dysplasia had more chromosome abnormalities in epithelial cells and neutrophils, as measured by deletion and aneuploidy in 10q22.3. The changes in sputum cytology and chromosome abnormalities did not differ between the active and placebo arms. CB was well tolerated at the bid doses of 1, 1.5, and 2 gm of curcumin and 5 mg of bioperine, with minor side effects related to the gastrointestinal tract. In this short pilot trial, CB compared to placebo did not alter cytological and chromosomal abnormalities seen in sputum of patients with COPD.

华蟾素治疗肝癌、肺癌、胰腺癌的Ⅰ期临床研究:初步报道

背景与目的:华蟾素目前广泛应用于肿瘤的治疗中,由于在80年代上市,未进行临床Ⅰ期研究,无法确定其最大耐受剂量。因此本文旨在观察华蟾素治疗肝细胞癌、肺癌和胰腺癌的最大耐受剂量和不良反应,同时评价治疗疗效。方法:Ⅲ、Ⅳ期肝细胞癌、非小细胞肺癌和胰腺癌接受华蟾素治疗,采用静脉滴注,连续14 d,21 d为一疗程。如果没有出现剂量限制性毒性,治疗将持续2个疗程。剂量递增的方案为:10、20、40、60、90和120 m l/(m2.d)。结果:入组15例患者(每个剂量组为3例)中,11例为肝癌,2例胰腺癌和2例肺癌。第五剂量组结束时没有发现剂量限制性毒性(DLT)。其中14例患者可评价疗效,6例(42.9%)为SD,8例(57.1%)为PD。在第一剂量组中,1例肝癌患者肿瘤缩小20%并维持11个月。结论:本研究最高剂量达到常规剂量的8倍,尚未出现剂量限制性毒性。部分患者获得了肿瘤缩小或稳定的疗效。

Discovering genetic biomarkers for targeted cancer therapeutics with eXplainable Artificial Intelligence

High-Grade Serous Ovarian Cancer(HGSC)is the most prevalent and lethal form of gynecologic malignancies[1],accounting for 70%-80%of ovarian cancer fatalities.Despite decades of research,the overall survival rate for HGSC has remained largely unchanged[2],and patients with advanced stages of the disease have only a 41%chance of surviving beyond five years[3].