National Cancer Center, Japan
Recent publications
Hereditary leiomyomatosis and renal cell carcinoma caused by loss-of-function germline variants of the FH gene can develop into aggressive renal cell carcinoma (RCC). We report the case of a 27-year-old man who died of RCC. Genetic testing revealed a novel pathogenic variant of FH , NM_000143.3:c.1013_1014del (p.Ile338Serfs*3), that was also identified in healthy siblings. Identification of genetic causes in the proband helped us to provide relatives with precise genetic counseling and appropriate surveillance programs.
In the FUGA-BT trial (JCOG1113), gemcitabine plus S-1 (GS) showed non-inferiority to gemcitabine plus cisplatin (GC) in overall survival (OS) with good tolerance for patients with advanced biliary tract cancer (BTC). We performed a subgroup analysis focused on the elderly cohort of this trial. All 354 enrolled patients in JCOG1113 were classify into two groups; < 75 (non-elderly) and ≥ 75 years (elderly) group. We investigated the influence of age on the safety analysis, including the incidence of chemotherapeutic adverse events and the efficacy analysis, including OS. There were no remarkable differences in OS between the elderly ( n = 60) and the non-elderly groups ( n = 294). In the elderly group, median OS was 12.7 and 17.7 months for those who received GC ( n = 20) and GS ( n = 40), respectively. The prevalence of all-grade adverse events was similar between the elderly and the non-elderly groups. However, among the elderly group, Grade ≥ 3 hematological adverse events were more frequently observed in the GC arm than in the GS arm. The clinical outcomes of combination chemotherapy in elderly patients with advanced BTC were comparable to non-elderly patients. GS may be the more favorable treatment for elderly patients with advanced BTC.
Pevonedistat, the first small-molecule inhibitor of NEDD8-activating enzyme, has demonstrated clinical activity in Western patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). We report findings from a phase 1/1b study in East Asian patients with AML or MDS, conducted to evaluate the safety/tolerability and characterize the pharmacokinetics of pevonedistat, alone or in combination with azacitidine, in this population, and determine the recommended phase 2/3 dose for pevonedistat plus azacitidine. Twenty-three adult patients with very high/high/intermediate-risk AML or MDS were enrolled in Japan, South Korea and Taiwan. All 23 patients experienced at least one grade ≥ 3 treatment-emergent adverse event. One patient in the combination cohort reported a dose-limiting toxicity. Eighteen patients discontinued treatment; in nine patients, discontinuation was due to progressive disease. Three patients died on study of causes considered unrelated to study drugs. Pevonedistat exhibited linear pharmacokinetics over the dose range of 10–44 mg/m ² , with minimal accumulation following multiple-dose administration. An objective response was achieved by 5/11 (45%) response-evaluable patients in the pevonedistat plus azacitidine arm (all with AML), and 0 in the single-agent pevonedistat arm. This study showed that the pharmacokinetic and safety profiles of pevonedistat plus azacitidine in East Asian patients were similar to those observed in Western patients as previously reported. The recommended Phase 2/3 dose (RP2/3D) of pevonedistat was determined to be 20 mg/m ² for co-administration with azacitidine 75 mg/m ² in Phase 2/3 studies, which was identical to the RP2/3D established in Western patients. Trial registration : NCT02782468 25 May 2016.
For the last three decades, Japan has been using the population of 1985 for age standardisation to compare mortality rates over time. With the population of Japan declining and ageing rapidly every year, there is a need to update the standard population to make the comparison representative of the current scenario. This is particularly relevant owing to declining mortality rates among the super-ageing Japanese elderly population and more data availability for older age groups. The choice of one population as standard over another is arbitrary because it does not make much difference to the trends in rates. The proportion of elderly in Japan is increasing rapidly and is expected to be one-third of the total population by 2030, in contrast to the proportion of 10% in the 1980s. Using a standard population with a lower proportion of elderly may weight the rates disproportionately for this age group. It is typically suitable to change the standard population every 25 to 30 years. It is advisable to choose the population of 2015 as the new standard population as suggested by the working group of the Ministry of Health, Labour and Welfare of Japan for revising the standard population. However, it should be noted that the newly calculated age-standardised mortality rates will no longer be comparable to those calculated using the older standard populations. Updating the standard population will produce age-standardised rates for recent years closer to the crude rates and would thus reduce the extent of misinterpreting decreased mortality risks using age-standardised rates that do not closely resemble the crude rates.
Purpose ²¹¹ At, a promising alpha-particle-emitting radionuclide, can easily volatilize and contaminate the environment. To safely manage this unique alpha-particle-emitting radionuclide, we investigated the permeability of four types of plastic films and two types of rubber gloves against ²¹¹ At and identified suitable materials that prevent contamination by ²¹¹ At. Methods Four types of plastic films, polyethylene, polyvinylidene chloride, polyvinyl chloride, and a laminated film, and two types of rubber gloves, latex and nitrile, were examined. Small pieces of filter paper were covered with these materials, and a drop containing 100 kBq of ²¹¹ At was placed on them. The radioactivity of the pieces of filter paper under the materials was evaluated by measuring counts using a gamma counter and obtaining autoradiograms 3.5 h later. These experiments were also performed using ²²⁵ Ac, ¹²⁵ I, ¹¹¹ In, ²⁰¹ Tl, and 99m Tc. Results ²¹¹ At solution easily penetrated polyethylene, polyvinyl chloride, and latex rubber. Similar results were obtained for ¹²⁵ I, while other radionuclides did not penetrate films or gloves. These results suggest that halogenic radionuclides under anionic conditions are likely to penetrate plastic films and rubber gloves. Conclusion Our evaluation revealed that, when ²¹¹ At solution is used, the protection by polyvinylidene chloride, a laminated film, or nitrile rubber would be more effective than that by polyethylene, polyvinyl chloride, or latex rubber.
Background The high rate of aseptic loosening of cemented stems has led to their frequent use in endoprosthetic reconstruction. However, problems, such as stem breakage and stress shielding at the insertion site, remain. The Japanese Musculoskeletal Oncology Group (JMOG) has developed Kyocera Modular Limb Salvage System (KMLS) cementless stems with a unique tapered press-fit and short fixation design. This study aimed to clarify the short-term postoperative outcomes of this prosthesis and validate the stem design. Methods One hundred cases of KMLS cementless stems (51 male patients; median age, 49 years; mean follow-up period, 35 months), with a minimum follow-up of 2 years, for the proximal femur (PF), distal femur (DF), and proximal tibia were prospectively registered for use. Prosthesis survival, complication rates, postoperative functional, and radiographical evaluation were analyzed. Complications or failures after insertion of the KMLS endoprostheses were classified into five types and functional results were analyzed according to the MSTS scoring system at postoperative 1 year. The diaphyseal interface and anchorage were graded by the ISOLS system at postoperative 2 years. Results The overall prosthesis survival rates at 2 and 4 years were 88.2 and 79.6%, respectively. The prosthesis-specific survival rate excluding infection and tumor recurrence was 90.2 and 87.9%, respectively. Younger age ( p = 0.045) and primary tumor ( p = 0.057) were associated with poor prognosis of prosthesis-specific survival excluding infection and tumor recurrence. Complications were observed in 31 patients, 13 patients underwent revision surgery. The mean MSTS functional score at 1 year postoperatively was 68%. Early implant loosening was significantly more common in the DF ( p = 0.006) and PF/DF straight stem ( p = 0.038). The ISOLS radiographic evaluation at 2 years after surgery revealed good bone remodeling and anchorage in most cases (bone remodeling: 90% / excellent and good, anchorage: 97% / excellent and good). Conclusions Tumor endoprosthesis long-term fixation to the diaphysis of the lower extremity remains challenging. The KMLS cementless stem with a unique tapered press fit design showed good short-term results in maintaining bone stock. To prevent early loosening, a curved stem should be used in PF and DF, but long-term follow-up is necessary.
Background Some cancer survivors develop second primary cancers. However, differences in prognosis between patients who have and have not had prior cancer have not been established. We examined and compared the prognoses of such patients. Methods Using the record-linked database of the population-based Cancer Registry of Osaka Prefecture and Vital Statistics in Japan, we identified patients aged ≥ 40 years who were diagnosed with stomach (n = 70,946), colorectal (n = 60,582), or lung (n = 58,016) cancers during 1995–2009. We defined these cancers as index cancers. Patients were classified into three groups according to history of prior cancer and interval between diagnosis of index and prior cancer: single (no prior cancer or interval of ≥10 years), synchronous (interval ≤3 months), and metachronous (interval 3 months to 10 years). The 5-year prognosis from index cancer diagnosis was investigated using the Kaplan–Meier method and log-rank test. Results 5-year prognoses of patients with synchronous stomach and colorectal cancers were significantly worse than that of patients with single primary, about 60 % of these patients’ deaths being attributable to the prior cancer. In contrast, 5-year prognoses of patients with metachronous primaries were not significantly worse, except for men with colorectal cancer. The percentages of index cancer deaths were 1.7–4.3 times those for non-index cancer deaths. Conclusion A prior cancer contributed to an inferior prognosis in patients with synchronous stomach and colorectal cancers. The prognoses of patients with metachronous primaries were more affected by the index than by the prior cancer, whereas most of them had similar or better prognoses than did patients with a single primary. This finding would help to relieve cancer survivors’ anxiety about their development and prognosis of metachronous second primary cancer.
Background Movement towards Universal Health Coverage (UHC) can improve health services, risk factor management, and inequality in non-communicable diseases (NCD); conversely, prioritizing and monitoring NCD management can support pathways to UHC in resource-limited settings. We aimed to estimate trends in NCD management indicators in Vietnam from 2010, and projections to 2030 at national and sub-national levels; compute the probability of reaching UHC targets; and measure inequalities in NCD management indicators at demographic, geographic, and socio-economic levels. Methods We included data of 37,595 households from four nationally representative surveys from 2010. We selected and estimated the coverage of NCD health service and risk management indicators nationally and by six sub-national groups. Using Bayesian models, we provided trends and projections and calculated the probability of reaching UHC targets of 80% coverage by 2030. We estimated multiple inequality indices including the relative index of inequality, slope index of inequality, and concentration index of inequality, and provided an assessment of improvement in inequalities over the study period. Findings Nationally, all indicators showed a low probability of achieving 2030 targets except sufficient use of fruit and vegetables (SUFV) and non-use of tobacco (NUT). We observed declining trends in national coverage of non-harmful use of alcohol (NHUA), sufficient physical activity (SPA), non-overweight (NOW), and treatment of diabetes (TOD). Except for SPA, no indicator showed the likelihood of achieving 2030 targets at any regional level. Our model suggested a non-achievement of 2030 targets for all indicators in any wealth quintile and educational level, except for SUFV and NUT. There were diversities in tendency and magnitude of inequalities with widening gaps between genders (SPA, TOD), ethnic groups (SUFV), urban-rural areas (TOH), wealth quintiles, and educational levels (TOD, NUT, NHUA). Interpretation Our study suggested slow progress in NCD management at the national level and among key sub-populations in Vietnam, together with existing and increasing inequalities between genders, ethnicities, geographic areas, and socioeconomic groups. We emphasised the necessity of continuously improving the healthcare system and facilities, distributing resources between geographic areas, and simultaneously integrating economic, education, and gender intervention and programs. Funding None.
Immunophenotyping of tumor-infiltrating lymphocytes (TILs) by flow cytometry can predict clinical efficacy of immunotherapy. However, several obstacles need to be overcome for developing a flow cytometry assay starting from solid tumor specimens. Here, we show a detailed enzyme-based protocol to isolate TILs from human tumor tissues. The protocol was optimized to obtain enough viable TILs from a biopsy tissue specimen for flow cytometry-based TIL immunophenotyping. Additionally, tissue samples could be preserved for up to 72 h for subsequent characterization. For complete details on the use and execution of this protocol, please refer to Kumagai et al. (2020, 2022).
Purpose Anaplastic thyroid cancer (ATC) is a rare and highly aggressive cancer for which effective systemic therapy has long been sought. Here, we assessed the efficacy and safety of lenvatinib in patients with unresectable ATC. Patients and methods The study was investigator-initiated and conducted under a multicenter, open-label, nonrandomized, phase II design. Eligibility criteria included pathologically proven ATC; unresectable measurable lesion as defined by RECIST 1.1; age 20 years or older; ECOG PS 0–2; and adequate organ function. The primary end-point was overall survival. Secondary end-points were progression-free survival, objective response rate, disease control rate, clinical benefit rate, and safety. Results Of 52 patients enrolled from 17 institutions, 42 patients who were confirmed to have ATC were included for efficacy analysis, and 50 patients were included for safety analysis. The estimated 1-year overall survival rate was 11.9% (95% CI, 4.4%–23.6%). One patient (2.4%) achieved complete response, four patients (9.5%) partial response, and 26 patients (61.9%) stable disease, including nine patients (21.4%) who demonstrated durable stable disease, giving an objective response rate of 11.9%, disease control rate of 73.8%, and clinical benefit rate of 33.3%. Adverse events of any grade were observed in 45 patients (90.0%), the most common of which of any grade included loss of appetite (48.0%), fatigue (48.0%), hypertension (44.0%), and palmar-plantar erythrodysesthesia syndrome (26.0%). Conclusion Lenvatinib treatment resulted in disappointing survival for unresectable ATC patients. Although the number of responders was small, responses were durable, indicating that lenvatinib may be beneficial for selected patients. Further investigation to identify suitable candidates for lenvatinib monotherapy is needed.
Selpercatinib, a first-in-class, highly selective and potent central nervous system-active RET kinase inhibitor demonstrated clinically meaningful activity with manageable toxicity in pretreated and treatment-naive advanced/metastatic RET fusion-positive non-small-cell lung cancer (NSCLC). LIBRETTO-432 is a global, randomized, double-blind, phase III trial evaluating selpercatinib versus placebo in stage IB-IIIA, RET fusion-positive NSCLC, previously treated with definitive surgery or radiation; participants must have undergone available anti-cancer therapy (including chemotherapy or durvalumab) or not be suitable for it, per investigator's discretion. The primary end point is investigator-assessed event-free survival (EFS) in the primary analysis population (stage II-IIIA RET fusion-positive NSCLC). Key secondary end points include EFS in the overall population, overall survival, and time to distant disease recurrence in the central nervous system.
Extracellular vesicles (EVs) have emerged as immunomodulatory regulators during tumor progression. These small vesicles encapsulate a variety of molecules, including DNA, RNA, and proteins. When EVs come in contact with recipient cells, the EVs transmit various physiological characteristics; for example, proteins on the surface of EVs act as ligands. Immune checkpoint blockade targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) has shown promise in a subset of cancer patients. PD-L1 on EVs acts as a key immunomodulator. Suppression of EV secretion enhances the efficacy of immunotherapy using immune checkpoint blockade antibodies. In addition to immune checkpoint blockade therapy, chimeric antigen receptor T (CAR-T) cell therapy has also been used to successfully eliminate cancer cells. Interestingly, CAR-T-cell-derived EVs express CAR on their surface. Compared with CAR-T cells, CAR-expressing EVs do not express PD1, so their antitumor effect cannot be weakened. In this review, we describe the current understanding of EVs in cancer immunity and summarize their crucial roles in immunomodulation.
Background & Aims Endoscopic techniques are rapidly emerging for resection of subepithelial tumors (SETs). Submucosal tunneling for endoscopic resection (STER), endoscopic full-thickness resection (EFTR) and laparoscopic endoscopic cooperative surgery (LECS) are current alternatives to open surgery. In this study, we aim to compare the three endoscopic techniques. Methods Consecutive patients who underwent resection of a submucosal esophageal or gastric lesion from several tertiary care centers were included in a dedicated registry over three years. Demographics, size and location of resected lesion, histology of specimen, length of procedure, adverse events, duration of hospital stay and follow up data were collected. Results 96 patients were included (47.7% M, mean age 62): STER n=34, EFTR n=34, LECS n=280. The lesions included leiomyoma, GIST and other. The mean lesion size was 28mm (STD 16, range 20-72mm). The majority of lesions in the EFTR and laparoscopic assisted resection group were GISTs. There was no significant difference in clear resection margins, post procedure complication rates, recurrence rate and total follow up duration between the groups. However, the LECS group had a procedure time at least 30 minutes longer than STER or EFTR (p<0.01). Total hospital stay for the laparoscopic assisted resection group was also longer when compared to STER (1.5) and EFTR (1.8) (p value<0.01). Conclusion STER, EFTR, and laparoscopic assisted resection are efficacious approaches for resection of SETs with similar R0 resection rates, complication rates, and adverse event rates. Laparoscopic assisted resection appears more time consuming and is associated with a longer hospital stay.
The first magnetic resonance (MR)-guided radiotherapy system in Japan was installed in May 2017. Implementation of online MR-guided adaptive radiotherapy (MRgART) began in February 2018. Online MRgART offers greater treatment accuracy owing to the high soft-tissue contrast in MR-images (MRI), compared to that in X-ray imaging. The Japanese Society for Magnetic Resonance in Medicine (JSMRM), Japan Society of Medical Physics (JSMP), Japan Radiological Society (JRS), Japanese Society of Radiological Technology (JSRT), and Japanese Society for Radiation Oncology (JASTRO) jointly established the comprehensive practical guidelines for online MRgART. These guidelines propose the essential requirements for clinical implementation of online MRgART with respect to equipment, personnel, institutional environment, practice guidance, and quality assurance/quality control (QA/QC). The minimum requirements for related equipment and QA/QC tools, recommendations for safe operation of MRI system, and the implementation system are described. The accuracy of monitor chamber and detector in dose measurements should be confirmed because of the presence of magnetic field. The ionization chamber should be MR-compatible. Non-MR-compatible devices should be used in an area that is not affected by the static magnetic field (outside the five Gauss line), and their operation should be checked to ensure that they do not affect the MR image quality. Dose verification should be performed using an independent dose verification system that has been confirmed to be reliable through commissioning. This guideline proposes the checklists to ensure the safety of online MRgART. Successful clinical implementation of online MRgART requires close collaboration between physician, radiological technologist, nurse, and medical physicist.
Background Gemcitabine plus nab-paclitaxel (GnP) has been a standard treatment for unresectable pancreatic cancer (uPC); however, the current treatment status and usefulness in older adults with uPC remain unclear. Therefore, we aimed to investigate the patient background and compare the efficacy and safety of GnP versus other treatments in older adults with uPC. Patients and Methods In this prospective observational study, we enrolled 233 eligible patients aged ≥76 years with pathologically proven, clinically uPC, and no history of chemotherapy from 55 Japanese centers during September 2018-September 2019. The main endpoints were overall survival (OS), progression-free survival (PFS), and safety. Geriatric assessments were performed upon registration and after 3 months. To adjust for confounders, we conducted propensity score-matched analyses. Results GnP, gemcitabine alone (Gem), best supportive care, and other therapies were administered to 116, 72, 16, and 29 patients, respectively. In the propensity score-matched analysis, 42 patients each were selected from the GnP and Gem groups. The median OS was longer in the GnP group than in the Gem group (12.2 vs. 9.4 months; hazard ratio [HR], 0.65; 95% CI, 0.37-1.13). The median PFS was significantly longer in the GnP group than in the Gem group (9.2 vs. 3.7 months; HR, 0.38; 95% CI, 0.23-0.64). The incidence of severe adverse events was higher with GnP than with Gem; however, the difference was not significant. Conclusion GnP is more efficacious than Gem in patients aged ≥76 years with uPC despite demonstrating a higher incidence of severe adverse events.
MOnocytic leukemia Zinc finger protein (MOZ, MYST3, or KAT6A) is a MYST-type acetyltransferase involved in chromosomal translocation in acute myelogenous leukemia (AML) and myelodysplastic syndrome. MOZ is established as essential for hematopoiesis; however, the role of MOZ in AML has not been addressed. We propose that MOZ is critical for AML development induced by MLL-AF9, MLL-AF10, or MOZ-TIF2 fusions. Moz-deficient hematopoietic stem/progenitor cells (HSPCs) transduced with an MLL-AF10 fusion gene neither formed colonies in methylcellulose nor induced AML in mice, and Moz-deficient HSPCs bearing MLL-AF9 also generated significantly reduced colony and cell numbers. Moz-deficient HSPCs expressing MOZ-TIF2 could form colonies in vitro but could not induce AML in mice. By contrast, Moz was dispensable for colony formation by HOXA9-transduced cells and AML development caused by HOXA9 and MEIS1, suggesting a specific requirement for MOZ in AML induced by MOZ/MLL-fusions. Expression of the Hoxa9 and Meis1 genes was decreased in Moz-deficient MLL-fusion expressing cells, while expression of Meis1, but not Hoxa9, was reduced in Moz-deficient MOZ-TIF2 AML cells. AML development induced by MOZ-TIF2 was rescued by introducing Meis1 into Moz-deficient cells carrying MOZ-TIF2. Meis1 deletion impaired MOZ-TIF2¬-mediated AML development. MOZ-TIF2 and endogenous Moz binding and active histone modifications were also severely reduced at the Meis1 locus in Moz-deficient MOZ-TIF2 and MLL-AF9 AML cells. These results suggest that endogenous MOZ is critical for MOZ/MLL-fusion-induced AML development and maintains fusion binding and active chromatin signatures at target gene loci.
Impact of venous thromboembolism in Japanese colorectal cancer patients has not been elucidated. This pre-specified sub-analysis of the Cancer-VTE Registry aimed to report venous thromboembolism and event data after 1 year of follow-up in 2477 patients with colorectal cancer and investigate risk factors of venous thromboembolism. Of 2477 patients, 158 (6.4%) had venous thromboembolism in venous thromboembolism screening at enrollment. Asymptomatic distal deep vein thrombosis accounted for 123/158 (77.8%) of venous thromboembolism cases. During the follow-up period, symptomatic, incidental events requiring treatment and composite venous thromboembolism incidences were 0.3%, 0.8%, and 1.0%, respectively. The incidence of bleeding events, cerebral infarction/transient ischemic attack/systemic embolic event, and all-cause death were 1.0%, 0.3%, and 4.8%, respectively. These results were consistent with the main study results. In multivariable analysis, venous thromboembolism at baseline was a risk factor of composite venous thromboembolism during the follow-up period. Japanese patients with colorectal cancer and advancing cancer stage before treatment had more frequent venous thromboembolism complications at baseline, higher incidence of venous thromboembolism events during cancer treatment, and higher mortality.
Background Aberrant fibroblast growth factor receptor (FGFR) signaling can substantially influence oncogenicity. Despite that FGFR gene abnormality is often detected by cancer genome profiling tests, there is no tumor-agnostic approval yet for these aberrations. E7090 (tasurgratinib) is an orally available selective tyrosine kinase inhibitor of FGFR1-3. Specific FGFR alterations were previously reported to be highly sensitive to E7090 based on a high-throughput functional evaluation method, called mixed-all-nominated-mutants-in-one (MANO) method, narrowing down the most promising targets. This trial was focused on the alterations identified by the MANO method and was performed under the nationwide large registry network for rare cancers in Japan (MASTER KEY Project). Methods/Design This single-arm Phase 2 trial was designed to evaluate the safety and efficacy of E7090 in patients with advanced or recurrent solid tumors harboring FGFR alterations. Three cohorts were set based on the type of FGFR alterations and the results of MANO method. A maximum of 45 patients will be enrolled from 5 institutions over 2.5 years. E7090 will be administered once daily as an oral single agent in 28-day cycles. The primary endpoint is the objective overall response rate; whereas, the secondary endpoints include progression-free survival, overall survival, disease control rate, safety, duration of response, and time to response. Ethics approval was granted by the National Cancer Center Hospital Certified Review Board. Patient enrollment began in June 2021. Discussion A unique investigator-initiated multicenter Phase 2 trial was designed based on the results of preclinical investigation aiming to acquire the approval of E7090 for solid tumors harboring FGFR gene alterations. The findings may serve as a novel model for the development of tumor-agnostic molecular targeted therapies against rare genetic abnormalities. Trial registration Japan Registry of Clinical Trial: jRCT2031210043 (registered April 20, 2021) NCT04962867 (registered July 15, 2021).
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467 members
Shimpei Miyamoto
  • Plastic and Reconstructive Surgery
Tomonori Yano
  • Department of Gastroenterology and GI Oncology
Hiroaki Ikematsu
  • Department of Gastroenterology and Endoscopy
Miyuki Sone
  • National Cancer Center Hospital
Taisuke Mori
  • Pathology
5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Tokyo, Japan