Publications by authors named "Takeharu Yamanaka"

231 Publications

Japanese Lung Cancer Society Guidelines for Stage IV NSCLC With Mutations.

JTO Clin Res Rep 2021 Jan 12;2(1):100107. Epub 2020 Oct 12.

Division of Applied Pharmaceutical Education and Research, Hoshi University, Tokyo, Japan.

Patients with NSCLC in East Asia, including Japan, frequently contain mutations. In 2018, we published the latest full clinical practice guidelines on the basis of those provided by the Japanese Lung Cancer Society Guidelines Committee. The purpose of this study was to update those recommendations, especially for the treatment of metastatic or recurrent -mutated NSCLC. We conducted a literature search of systematic reviews of randomized controlled and nonrandomized trials published between 2018 and 2019 that multiple physicians had reviewed independently. On the basis of those studies and the advice from the Japanese Society of Lung Cancer Expert Panel, we developed updated guidelines according to the Grading of Recommendations, Assessment, Development, and Evaluation system. We also evaluated the benefits of overall and progression-free survival, end points, toxicities, and patients' reported outcomes. For patients with NSCLC harboring -activating mutations, the use of EGFR tyrosine kinase inhibitors (EGFR TKIs), especially osimertinib, had the best recommendation as to first-line treatment. We also recommended the combination of EGFR TKI with other agents (platinum-based chemotherapy or antiangiogenic agents); however, it can lead to toxicity. In the presence of uncommon mutations, except for an exon 20 insertion, we also recommended the EGFR TKI treatment. However, we could not provide recommendations for the treatment of mutations with immune checkpoint inhibitors, including monotherapy, and its combination with cytotoxic chemotherapy, because of the limited evidence present in the literature. The 2020 Japanese Lung Cancer Society Guidelines can help community-based physicians to determine the most appropriate treatments and adequately provide medical care to their patients.
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http://dx.doi.org/10.1016/j.jtocrr.2020.100107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474490PMC
January 2021

Effect of melatonin and melatonin agonists on postoperative sleep quality in adult patients: a protocol for systematic review and meta-analysis with trial sequential analysis.

BMJ Open 2021 09 6;11(9):e047858. Epub 2021 Sep 6.

Department of Biostatics, Yokohama City University, Yokohama, Kanagawa, Japan.

Introduction: The circadian rhythm of melatonin secretion is disturbed after general anaesthesia, leading to postoperative sleep disturbance. Small studies investigating the preventive effect of melatonin administration on postoperative sleep disturbance have not reached any conclusions. Therefore, we will conduct a systematic review and meta-analysis to obtain conclusive results.

Methods And Analysis: We prepared this protocol following the 2015 Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols guidelines. We will conduct a search for randomised controlled trials that evaluated the effect of melatonin and melatonin agonists on postoperative sleep quality in adult patients undergoing general anaesthesia or regional anaesthesia with sedation. We will exclude patients undergoing regional anaesthesia without sedation. Relevant studies will be searched in the following eight databases: MEDLINE, the Cochrane Central Register of Controlled Trials, Embase, Web of Science and four preregistration sites from inception to 1 January 2021. No language restrictions will be applied. Two authors will independently scan and select eligible studies and perform data extraction and assessment of the risk of bias. The Visual Analogue Scale scores for sleep quality will be combined as the mean difference with a 95% CI using a random-effect model; we will use I to assess heterogeneity. We will evaluate the quality of trials using the Cochrane methodology and assess the quality of evidence using the Grading of Recommendation Assessment, Development and Evaluation approach. If appropriate, trial sequential analysis will be performed.

Ethics And Dissemination: No ethical approval is required for this meta-analysis, as it does not include individual patient data. We will disseminate the results of this meta-analysis in a peer-reviewed journal.

Prospero Registration Number: CRD42020180167.
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http://dx.doi.org/10.1136/bmjopen-2020-047858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8422307PMC
September 2021

Rapid detection of neutralizing antibodies to SARS-CoV-2 variants in post-vaccination sera.

J Mol Cell Biol 2021 Aug 27. Epub 2021 Aug 27.

Department of Microbiology, Yokohama City University School of Medicine, Yokohama, Japan.

The uncontrolled spread of the COVID-19 pandemic has led to the emergence of different SARS-CoV-2 variants across the globe. The ongoing global vaccination strategy to curtail the COVID-19 juggernaut, is threatened by the rapidly spreading Variants of Concern (VOC) and other regional mutants, which are less responsive to neutralization by infection or vaccine derived antibodies. We have previously developed the hiVNT system which detects SARS-CoV-2 neutralizing antibodies in sera in less than three hours. In this study, we modify the hiVNT for rapid qualitative screening of neutralizing antibodies (nAb) to multiple VOC of SARS-CoV-2, and assess the neutralizing efficacy of the BNT162b2 mRNA vaccine on seven epidemiologically relevant SARS-CoV-2 variants. Here we show that the BNT162b2 mRNA vaccine can activate humoral immunity against the major SARS-CoV-2 mutants that are currently in circulation. Albeit a small sample size, we observed that one dose of vaccine was sufficient to elicit a protective humoral response in previously infected people. Using a panel of seven SARS-CoV-2 variants and a single prototype virus, our modified hiVNT would be useful for large-scale community wide testing to detect protective immunity that may confer vaccine/immune passport in the ongoing COVID-19 pandemic.
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http://dx.doi.org/10.1093/jmcb/mjab050DOI Listing
August 2021

Bevacizumab plus platinum-based chemotherapy in advanced non-squamous non-small-cell lung cancer: a randomized, open-label phase 2 study (CLEAR).

Transl Lung Cancer Res 2021 Jul;10(7):3059-3070

Department of Thoracic Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan.

Background: Atezolizumab combined with bevacizumab plus platinum-based chemotherapy is a standard treatment for advanced non-squamous non-small-cell lung cancer (nsNSCLC). We aimed to determine the most effective platinum-based combination, such that future studies with atezolizumab can be conducted to further improve patient outcomes.

Methods: This phase 2 study enrolled treatment-naïve patients with advanced or recurrent nsNSCLC who were randomly assigned to either cisplatin (75 mg/m) + pemetrexed (500 mg/m) + bevacizumab (15 mg/kg) (CisPemBev) followed by maintenance PemBev (N=132) or carboplatin (area under the concentration-time curve of 6 mg/mL/min) + paclitaxel (200 mg/m) + bevacizumab (15 mg/kg) (CarPacBev) followed by maintenance Bev (N=67). The primary endpoint was progression-free survival (PFS, by central review). Secondary endpoints included overall survival (OS) and overall response rate (ORR). Adverse events (AEs) were evaluated for safety. This study was designed with the point estimate of the hazard ratio (HR) for PFS calculated based on an expected HR <0.830 with a probability ≥80%.

Results: The HR for PFS (CisPemBev/CarPacBev) was 0.825 [95% confidence interval (CI), 0.600-1.134, median PFS, 7.6 . 7.0 months]. Because the observed point estimate of the HR for PFS was <0.830, the primary endpoint was met, and CisPem doublet therapy was deemed to be more effective than CarPac in terms of PFS. Median OS was 23.4 months for CisPemBev and 21.6 months for CarPacBev (HR 0.845; 95% CI, 0.583-1.242). The ORR was 57% for CisPemBev and 55% for CarPacBev. Both CisPemBev and CarPacBev were well tolerated; grade ≥3 AEs were reported in 67% and 82% of patients, respectively.

Conclusions: CisPem combined with Bev was more effective in improving PFS compared with CarPacBev in patients with advanced nsNSCLC. CisPemBev was also well tolerated by this patient population. A study to evaluate the efficacy of atezolizumab plus CisPemBev is warranted.

Trial Registration: University hospital Medical Information Network Clinical Trial Registry (ID: UMIN000013354).
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http://dx.doi.org/10.21037/tlcr-21-240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350093PMC
July 2021

Clinicopathological and Molecular Characteristics of Early-Onset Stage III Colon Adenocarcinoma: An Analysis of the ACCENT Database.

J Natl Cancer Inst 2021 Aug 18. Epub 2021 Aug 18.

Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.

Background: Colon cancer (CC) incidence in young adults (age 20-49 years), termed early-onset CC (EO-CC), is increasing.

Methods: Individual patient data on 35 713 subjects with stage III colon cancer from 25 randomized studies in the Adjuvant Colon Cancer ENdpoint database were pooled. The distributions of demographics, clinicopathological features, biomarker status, and outcome data were summarized by age group. Overall survival, disease-free survival, time to recurrence, and survival after recurrence were assessed by Kaplan-Meier curves and Cox models stratified by treatment arms within studies, adjusting for sex, race, body mass index, performance status, disease stage, grade, risk group, number of lymph nodes examined, disease sidedness, and molecular markers. All statistical tests were 2-sided.

Results: Using a 5% difference between age groups as the clinically meaningful cutoff, patients with stage III EO-CC had similar sex, race, performance status, risk group, tumor sidedness, and T stage compared with patients with late-onset CC (age 50 years and older). EO-CC patients were less likely to be overweight (30.2% vs 36.2%) and more commonly had 12 or more lymph nodes resected (69.5% vs 58.7%). EO-CC tumors were more frequently mismatch repair deficient (16.4% vs 11.5%) and less likely to have BRAFV600E (5.6% vs 14.0%), suggesting a higher rate of Lynch syndrome in EO-CC. Patients with EO-CC had statistically significantly better overall survival (hazard ratio [HR] = 0.81, 95% confidence interval [CI] = 0.74 to 0.89; P < .001), disease-free survival (HR = 0.91, 95% CI = 0.84 to 0.98; P = .01), and survival after recurrence (HR = 0.88, 95% CI = 0.80 to 0.97; P = .008) in the analysis without molecular markers; however, age at onset of CC lost its prognostic value when outcome was adjusted for molecular markers.

Conclusion: Tumor biology was found to be a more important prognostic factor than age of onset among stage III colon cancer patients in the Adjuvant Colon Cancer ENdpoint database.
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http://dx.doi.org/10.1093/jnci/djab123DOI Listing
August 2021

Prospective observational study of the efficacy of nivolumab in Japanese patients with advanced melanoma (CREATIVE study).

Jpn J Clin Oncol 2021 Aug;51(8):1232-1241

Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.

Background: Nivolumab, the anti-programmed cell death protein 1 antibody, has been approved for advanced melanoma, mainly based on evidence from Western countries. The profile of melanoma differs between Caucasian and Asian patients. This study was performed to obtain post-marketing data of nivolumab in Japanese patients with advanced melanoma.

Methods: This prospective, observational study involved patients with unresectable or metastatic melanoma treated with nivolumab at dosages of 2 mg/kg every 3 weeks or 3 mg/kg every 2 weeks. The primary endpoints were objective response rate and overall survival. The secondary endpoints were progression-free survival and the objective response rate according to immune-related Response Evaluation Criteria in Solid Tumours.

Result: Among 124 patients analysed, mucosal melanoma was the most common subtype, followed by acral lentiginous, nodular, superficial spreading and lentigo maligna melanoma. Response Evaluation Criteria in Solid Tumours evaluation showed an objective response rate of 17.7%. The median survival time was 15.93 months, and the 1-year overall survival rate was 66%. Outcomes were not significantly different among melanoma subtypes. Better overall survival and/or progression-free survival but not objective response rate were associated with performance status 0, lower levels of lactate dehydrogenase, C-reactive protein and neutrophil-to-lymphocyte ratio. Patients with immune-related adverse events showed a better objective response rate, 3-month landmark overall survival and progression-free survival than patients without immune-related adverse events.

Conclusion: The objective response rate and median survival time in Japanese patients treated with nivolumab were lower in daily practice than the >30% and >30 months, respectively, seen in global phase III trials. The occurrence of immune-related adverse events may be a predictor for survival and response to treatment with nivolumab.
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http://dx.doi.org/10.1093/jjco/hyab064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326387PMC
August 2021

REMARRY and PURSUIT trials: liquid biopsy-guided rechallenge with anti-epidermal growth factor receptor (EGFR) therapy with panitumumab plus irinotecan for patients with plasma RAS wild-type metastatic colorectal cancer.

BMC Cancer 2021 Jun 7;21(1):674. Epub 2021 Jun 7.

Department of Colorectal Surgery, Osaka General Medical Center, 3-1-56 Bandai-Higashi, Sumiyoshi-ku, Osaka, Japan.

Background: Previous clinical trials have demonstrated the potential efficacy of rechallenge with anti- epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) for patients with RAS/BRAF V600E wild-type metastatic colorectal cancer (mCRC). Moreover, post hoc biomarker analyses of clinical trials has suggested that RAS status in circulating tumor DNA (ctDNA) has a high probability to select patients who could benefit from anti-EGFR mAb rechallenge.

Methods: This trial is composed of 2 phases: a monitoring phase (REMARRY) and a trial phase (PURSUIT). A monitoring phase, the REMARRY study, aims to evaluate the dynamics of plasma RAS status during the subsequent treatments after refractory to anti-EGFR therapy in patients with mCRC with RAS/BRAF V600E wild-type tumors who have progressed after a response to previous anti-EGFR therapy, using a highly sensitive digital polymerase chain reaction OncoBEAM RAS CRC kit in a central laboratory (Sysmex, Japan). A trial phase, the PURSUIT trial, is a multicenter, single-arm phase II trial to assess the efficacy and safety of rechallenge therapy with panitumumab plus irinotecan in patients without RAS mutations in ctDNA (plasma RAS negative) in the REMARRY study. Key eligibility criteria of the PURSUIT trial include RAS/BRAF V600E wild-type mCRC in tumor tissue refractory or intolerant to fluoropyrimidine, oxaliplatin, and irinotecan; progression after complete or partial response to previous anti-EGFR therapy; plasma RAS negative (defined as plasma mutant allele frequencies [MAF] of all RAS ≤ 0.1%) within 28 days prior to enrollment; 4 months or more between the last administration of previous anti-EGFR mAb and the start of protocol treatment; and Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 1. The primary endpoint is the confirmed objective response rate (ORR). The target sample size of the PURSUIT trial is 50 patients. Biomarker analyses will be performed in parallel using the OncoBEAM RAS CRC kit and a next-generation sequencing-based ctDNA analysis (Guardant360).

Discussion: Our trial aims to confirm the clinical benefit of anti-EGFR mAb rechallenge therapy in patients with plasma RAS negative. Moreover, through biomarker analyses, our trial will shed light on which patients would benefit from rechallenge in addition to being plasma RAS negative.

Trial Registration: The REMARRY study: UMIN, UMIN000036424 . Registered date: April 5, 2019. The PURSUIT trial: jRCT, jRCTs031190096 . Registered date: October 1, 2019.
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http://dx.doi.org/10.1186/s12885-021-08395-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186219PMC
June 2021

Sustained Neutralizing Antibodies 6 Months Following Infection in 376 Japanese COVID-19 Survivors.

Front Microbiol 2021 7;12:661187. Epub 2021 May 7.

Department of Health Data Science, Yokohama City University Graduate School of Data Science, Yokohama, Japan.

There is scarce evidence regarding the long-term persistence of neutralizing antibodies among coronavirus disease 2019 (COVID-19) survivors. This study determined neutralizing antibody titers (NT) and antibodies against spike protein (SP) or nucleocapsid protein (NP) antigens approximately 6 months after the diagnosis of COVID-19. COVID-19 survivors in Japan were recruited. Serum samples and data related to patients' characteristics and COVID-19 history were collected. NT and titers of antibodies against NP and SP antigens were measured at 20-32 weeks after the first positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test results. Factors associated with NT were identified using the multivariable linear regression and the correlations among NT and titers of immunoglobulin G (IgG) and total immunoglobulins (Igs) against NP and SP were assessed by Spearman's correlation. Among 376 participants (median [range] days after testing positive for SARS-CoV-2, 180 (147-224); median [range] years of age, 50 (20-78); 188 [50%] male), most tested positive for NT ( = 367, 98%), SP-IgG ( = 344, 91%), SP-total Ig ( = 369, 98%), NP-IgG ( = 314, 84%), and NP-total Ig ( = 365, 97%). Regression analysis indicated that higher BMI, fever, and the requirement of mechanical ventilation or extracorporeal membrane oxygenation were significantly associated with higher NT. Anti-SP antibodies correlated moderately with NT (Spearman's correlation: 0.63 for SP IgG; 0.57 for SP-total Ig), while the correlation was weak for anti-NP antibodies (0.37 for NP IgG; 0.32 for NP-total Ig). Most COVID-19 survivors had sustained neutralizing antibodies and tested positive for SP-total Ig and NP-total Ig approximately 6 months after infection.
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http://dx.doi.org/10.3389/fmicb.2021.661187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137897PMC
May 2021

Corticosteroids for hospitalized patients with mild to critically-ill COVID-19: a multicenter, retrospective, propensity score-matched study.

Sci Rep 2021 05 21;11(1):10727. Epub 2021 May 21.

Department of Emergency and Critical Care Medicine, Tokyo Bay Urayasu-Ichikawa Medical Center, 3-4-32 Todaijima, Urayasu-city, Chiba, 279-0001, Japan.

Corticosteroids use in coronavirus disease 2019 (COVID-19) is controversial, especially in mild to severe patients who do not require invasive/noninvasive ventilation. Moreover, many factors remain unclear regarding the appropriate use of corticosteroids for COVID-19. In this context, this multicenter, retrospective, propensity score-matched study was launched to evaluate the efficacy of systemic corticosteroid administration for hospitalized patients with COVID-19 ranging in the degree of severity from mild to critically-ill disease. This multicenter, retrospective study enrolled consecutive hospitalized COVID-19 patients diagnosed January-April 2020 across 30 institutions in Japan. Clinical outcomes were compared for COVID-19 patients who received or did not receive corticosteroids, after adjusting for propensity scores. The primary endpoint was the odds ratio (OR) for improvement on a 7-point ordinal score on Day 15. Of 1092 COVID-19 patients analyzed, 118 patients were assigned to either the corticosteroid and non-corticosteroid group, after propensity score matching. At baseline, most patients did not require invasive/noninvasive ventilation (85.6% corticosteroid group vs. 89.8% non-corticosteroid group). The odds of improvement in a 7-point ordinal score on Day 15 was significantly lower for the corticosteroid versus non-corticosteroid group (OR, 0.611; 95% confidence interval [CI], 0.388-0.962; p = 0.034). The time to improvement in radiological findings was significantly shorter in the corticosteroid versus non-corticosteroid group (hazard ratio [HR], 1.758; 95% CI, 1.323-2.337; p < 0.001), regardless of baseline clinical status. The duration of invasive mechanical ventilation was shorter in corticosteroid versus non-corticosteroid group (HR, 1.466; 95% CI, 0.841-2.554; p = 0.177). Of the 106 patients who received methylprednisolone, the duration of invasive mechanical ventilation was significantly shorter in the pulse/semi-pulse versus standard dose group (HR, 2.831; 95% CI, 1.347-5.950; p = 0.006). In conclusion, corticosteroids for hospitalized patients with COVID-19 did not improve clinical status on Day 15, but reduced the time to improvement in radiological findings for all patients regardless of disease severity and also reduced the duration of invasive mechanical ventilation in patients who required intubation.Trial registration: This study was registered in the University hospital Medical Information Network Clinical Trials Registry on April 21, 2020 (ID: UMIN000040211).
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http://dx.doi.org/10.1038/s41598-021-90246-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140087PMC
May 2021

Combination therapy of capecitabine, irinotecan, oxaliplatin, and bevacizumab as a first-line treatment for metastatic colorectal cancer: Safety lead-in results from the QUATTRO-II study.

Invest New Drugs 2021 May 21. Epub 2021 May 21.

Department of Medical Oncology, Kagawa University Hospital, 1750-1 Ikenobe, Kita District, Miki, Kagawa, 761-0793, Japan.

Background FOLFOXIRI plus bevacizumab is the first-line treatment for metastatic colorectal cancer (mCRC) but demonstrates high neutropenia incidence among Asian patients. Hence, we conducted the randomized phase II QUATTRO-II study (ClinicalTrials.gov identifier: NCT04097444; Japan Registry of Clinical Trials identifier: jRTCs041190072) to evaluate the safety and efficacy of capecitabine, oxaliplatin, and irinotecan (CAPOXIRI) combination plus bevacizumab versus FOLFOXIRI plus bevacizumab, expecting a lower incidence of neutropenia without compromising the efficacy. Methods We investigated the recommended doses (RD) of oxaliplatin and irinotecan as a safety lead-in portion of Step 1 before initiating the randomized portion as Step 2. Four dose levels of CAPOXIRI (fixed dose of capecitabine, 1600 mg/m; escalated/de-escalated doses of oxaliplatin and irinotecan) plus bevacizumab (7.5 mg/kg) were investigated in a 3 + 3 manner. A dose level of ≤ 2/6 of dose-limiting toxicity (DLT) cases was expected as the RD. Results In Step 1, we included nine patients (three and six in levels 0 and + 1, respectively). Level 0 (irinotecan, 200 mg/m; oxaliplatin, 100 mg/m) did not demonstrate DLTs. In level + 1 (irinotecan, 200 mg/m; oxaliplatin, 130 mg/m), although one patient experienced grade 4 febrile neutropenia, no further safety concerns were observed. As a preliminary efficacy result, the objective response rate in all nine patients was 89 % (100 and 83 % in levels 0 and + 1, respectively). Conclusions The RD of CAPOXIRI plus bevacizumab was 200, 130, and 1600 mg/m for irinotecan, oxaliplatin, and capecitabine, respectively, and 7.5 mg/kg for bevacizumab. The randomized portion is still ongoing.
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http://dx.doi.org/10.1007/s10637-021-01125-2DOI Listing
May 2021

Validation of tissue factor pathway inhibitor 2 as a specific biomarker for preoperative prediction of clear cell carcinoma of the ovary.

Int J Clin Oncol 2021 Jul 19;26(7):1336-1344. Epub 2021 May 19.

Department of Obstetrics and Gynecology, Nara Medical University, Nara, Japan.

Background: Tissue factor pathway inhibitor 2 (TFPI2) is a novel serum biomarker that discriminates ovarian clear cell carcinoma (CCC) from borderline ovarian tumors (BOTs) and non-clear cell epithelial ovarian cancers (EOCs). Here, we examined the performance of TFPI2 for preoperative diagnosis of CCC.

Methods: Serum samples were obtained preoperatively from patients with ovarian masses, who needed surgical treatment at five hospitals in Japan. The diagnostic powers of TFPI2 and cancer antigen 125 (CA125) serum levels to discriminate CCC from BOTs, other EOCs, and benign lesions were compared.

Results: A total of 351 patients including 69 CCCs were analyzed. Serum TFPI2 levels were significantly higher in CCC patients (mean ± SD, 508.2 ± 812.0 pg/mL) than in patients with benign lesions (154.7 ± 46.5), BOTs (181 ± 95.5) and other EOCs (265.4 ± 289.1). TFPI2 had a high diagnostic specificity for CCC (79.5%). In patients with benign ovarian endometriosis, no patient was positive for TFPI2, but 71.4% (15/21) were CA125 positive. TFPI2 showed good performance in discriminating stage II-IV CCC from BOTs and other EOCs (AUC 0.815 for TFPI2 versus 0.505 for CA125) or endometriosis (AUC 0.957 for TFPI2 versus 0.748 for CA125). The diagnostic sensitivity of TFPI2 to discriminate CCC from BOTs and other EOCs was improved from 43.5 to 71.0% when combined with CA125.

Conclusions: High specificity of TFPI2 for preoperative detection of CCC was verified with the defined cutoff level of TFPI2 in clinical practice. TFPI2 and CA125 may contribute substantially to precise prediction of intractable CCC.
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http://dx.doi.org/10.1007/s10147-021-01914-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213588PMC
July 2021

CIRCULATE-Japan: Circulating tumor DNA-guided adaptive platform trials to refine adjuvant therapy for colorectal cancer.

Cancer Sci 2021 Jul 7;112(7):2915-2920. Epub 2021 Jun 7.

Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.

Adjuvant chemotherapy has reduced the risk of tumor recurrence and improved survival in patients with resected colorectal cancer. Potential utility of circulating tumor DNA (ctDNA) prior to and post surgery has been reported across various solid tumors. We initiated a new type of adaptive platform trials to evaluate the clinical benefits of ctDNA analysis and refine precision adjuvant therapy for resectable colorectal cancer, named CIRCULATE-Japan including three clinical trials. The GALAXY study is a prospectively conducted large-scale registry designed to monitor ctDNA for patients with clinical stage II to IV or recurrent colorectal cancer who can undergo complete surgical resection. The VEGA trial is a randomized phase III study designed to test whether postoperative surgery alone is noninferior to the standard therapy with capecitabine plus oxaliplatin for 3 months in patients with high-risk stage II or low-risk stage III colon cancer if ctDNA status is negative at week 4 after curative surgery in the GALAXY study. The ALTAIR trial is a double-blind, phase III study designed to establish the superiority of trifluridine/tipiracil as compared with placebo in patients with resected colorectal cancer who show circulating tumor-positive status in the GALAXY study. Therefore, CIRCULATE-Japan encompasses both "de-escalation" and "escalation" trials for ctDNA-negative and -positive patients, respectively, and helps to answer whether measuring ctDNA postoperatively has prognostic and/or predictive value. Our ctDNA-guided adaptive platform trials will accelerate clinical development toward further precision oncology in the field of adjuvant therapy. Analysis of ctDNA status could be utilized as a predictor of risk stratification for recurrence and to monitor the effectiveness of adjuvant chemotherapy. ctDNA is a promising, noninvasive tumor biomarker that can aid in tumor monitoring throughout disease management.
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http://dx.doi.org/10.1111/cas.14926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253296PMC
July 2021

Real-World Evidence on Second-Line Treatment of Metastatic Colorectal Cancer Using Fluoropyrimidine, Irinotecan, and Angiogenesis Inhibitor.

Clin Colorectal Cancer 2021 09 8;20(3):e173-e184. Epub 2021 Mar 8.

Department of Biostatistics, Yokohama City University School of Medicine, Yokohama, Japan.

Background: Combination therapy comprised of fluoropyrimidine plus irinotecan with an angiogenesis inhibitor is widely used as a second-line treatment for metastatic colorectal cancer (mCRC).

Patients And Methods: This retrospective study evaluated the efficacy and safety of fluorouracil and irinotecan (FOLFIRI) plus ramucirumab (RAM); FOLFIRI plus aflibercept (AFL); irinotecan and S-1 (IRIS) plus bevacizumab (BEV); and capecitabine and irinotecan (CAPIRI) plus BEV, with FOLFIRI plus BEV serving as the control among mCRC patients who failed treatment with fluoropyrimidine and oxaliplatin plus BEV. Data were collected from a medical claim database provided by Medical Data Vision Co., Ltd. (Tokyo, Japan). The primary outcome was time to treatment failure (TTF). Secondary outcomes were time to first subsequent therapy (TFST), overall survival (OS), and safety.

Results: Among 3,136 patients assessed, TTF was significantly shorter with FOLFIRI plus RAM (adjusted hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.26-1.56; P < .001) and FOLFIRI plus AFL (HR, 1.34; 95% CI, 1.09-1.66; P = .002), and significantly longer with IRIS plus BEV (HR, 0.80; 95% CI, 0.70-0.92; P = .002). TFST was significantly shorter with FOLFIRI plus RAM (HR, 1.32; 95% CI, 1.17-1.49; P < .001); no significant difference in OS was observed. The incidences of neutropenia requiring granulocyte colony-stimulating factor were significantly lower with IRIS plus BEV and CAPIRI plus BEV.

Conclusion: Regarding TTF, BEV seemed to be a favorable option compared with RAM and AFL when combined with FOLFIRI, and IRIS might be preferable compared to FOLFIRI when combined with BEV for patients who failed to respond to fluoropyrimidine, oxaliplatin, and BEV.
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http://dx.doi.org/10.1016/j.clcc.2021.03.001DOI Listing
September 2021

Sofosbuvir-based therapies associated with regression of liver fibrosis in patients with hepatitis C virus infection: A prospective observational study.

Medicine (Baltimore) 2021 Mar;100(12):e25110

Department of Gastroenterology, Yokohama City University Graduate School of Medicine.

Abstract: Oral direct-acting antiviral (DAA) treatment leads to >95% sustained virological response (SVR) and could be clinically useful in regression of liver fibrosis in chronic hepatitis C virus (HCV) infection. We evaluated if ledipasvir/sofosbuvir or sofosbuvir + ribavirin is associated with regression of fibrosis in HCV patients who achieved SVR.In this prospective cohort study performed at 3 sites in Japan, patients with genotype 1 and genotype 2 were given standard treatment of ledipasvir 90 mg/sofosbuvir 400 mg and sofosbuvir 400 mg + 200-1000 mg/day ribavirin, respectively, for 12 weeks. Liver fibrosis was assessed using Mac-2-binding protein glycosylation isomer (M2BPGi) and other fibrosis markers (platelet count, Fib-4 index, liver stiffness measurement [LSM]) in patients who achieved SVR.A total of 98.1% of (n = 101/103) patients in genotype 1 cohort and 100% (n = 16/16) in the genotype 2 cohort achieved SVR12. Based on per-protocol analysis, M2BPGi levels showed a significant decrease (-2.2  cut-off index [COI], P < .0001) at week 48 after treatment initiation. Forty-three patients showed a significant decrease in Fib-4 index (-1.2, P < .0001), and 44 patients showed improvement in LSM (-5.9 kPa, P < .0001).Achievement of SVR after antiviral therapy was associated with fibrosis regression. M2BPGi correlated well with LSM at week 48 after treatment initiation, supporting the sustainable benefit of HCV therapy.
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http://dx.doi.org/10.1097/MD.0000000000025110DOI Listing
March 2021

Combined Analysis of Concordance between Liquid and Tumor Tissue Biopsies for Mutations in Colorectal Cancer with a Single Metastasis Site: The METABEAM Study.

Clin Cancer Res 2021 May 18;27(9):2515-2522. Epub 2021 Feb 18.

Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.

Purpose: OncoBEAM™ is a circulating tumor DNA (ctDNA) test that uses the BEAMing digital PCR technology. We clarified the association between the baseline tumor burden and discordance in the status by metastatic sites in patients with a single metastatic site.

Experimental Design: Data from previous Spanish and Japanese studies investigating the concordance of the status between OncoBEAM™ and tissue biopsy in 221 patients with metastatic colorectal cancer (mCRC) were used. We collected data from patients with liver, peritoneal, or lung metastases and evaluated the concordance rates according to the metastatic site and the association between the concordance rate and tumor burden.

Results: Patients had metastases in the liver ( = 151), peritoneum ( = 25), or lung ( = 45) with concordance rates of 91% (95% confidence interval, 85%-95%), 88% (68%-97%), and 64% (49%-78%), respectively. Factors associated with concordance included the baseline longest diameter and lesion number ( = 0.004), and sample collection interval ( = 0.036). Concordance rates ≥90% were observed in the following groups: liver metastases alone, regardless of the baseline longest diameter and lesion number; peritoneal metastases alone in patients with a baseline longest diameter ≥20 mm; and lung metastases alone in patients with a baseline longest diameter ≥20 mm and/or number of lesions ≥10.

Conclusions: Plasma ctDNA-based liquid biopsy in patients with mCRC may be useful depending on the metastatic site. The maximum diameter and lesion number should be carefully considered when determining patients' status with only peritoneal or lung metastases.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3677DOI Listing
May 2021

Comparing the effects of tofogliflozin and pioglitazone in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus (ToPiND study): a randomized prospective open-label controlled trial.

BMJ Open Diabetes Res Care 2021 02;9(1)

Department of Gastroenterology and Hepatology, Yokohama City University, Yokohama, Japan.

Introduction: The treatment of diabetes has a significant impact on the pathogenesis of non-alcoholic fatty liver disease (NAFLD). We compared the effectiveness of tofogliflozin, a selective sodium-glucose cotransporter 2 inhibitor, and pioglitazone for the treatment of NAFLD patients with type 2 diabetes mellitus.

Research Design And Methods: This open-label, prospective, single-center, randomized clinical trial recruited NAFLD patients with type 2 diabetes mellitus and a hepatic fat fraction of at least 10% as assessed based on the MRI-proton density fat fraction (MRI-PDFF). Eligible patients were stratified according to hemoglobin A1c (HbA1c), alanine transaminase, and MRI-PDFF levels and randomly assigned (1:1) to receive either 20 mg tofogliflozin or 15-30 mg pioglitazone, orally, once daily for 24 weeks. The primary endpoint was an absolute change in MRI-PDFF at 24 weeks. Efficacy and safety was assessed in all treated patients. This trial was registered in the Japan Registry of Clinical Trials.

Results: Overall, 40 eligible patients were randomly assigned to receive tofogliflozin (n=21) or pioglitazone (n=19). Changes in hepatic steatosis after 24 weeks of treatment were evaluated by MRI-PDFF, which showed a significant decrease in both groups (-7.54% (p<0.0001) and -4.12% (p=0.0042) in the pioglitazone and tofogliflozin groups, respectively). Compared with baseline, the body weight decreased by 2.83±2.86 kg (-3.6%, p=0.0443) in the tofogliflozin group and increased by 1.39±2.62 kg (1.7%, p=0.0002) in the pioglitazone group after 24 weeks. No life-threatening events or treatment-related deaths occurred.

Conclusions: Tofogliflozin was well tolerated, and it reduced the MRI-PDFF levels in NAFLD patients with type 2 diabetes mellitus.

Trial Registration Number: jRCTs031180159.
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http://dx.doi.org/10.1136/bmjdrc-2020-001990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888333PMC
February 2021

Short-Term Outcomes from a Randomized Screening Phase II Non-inferiority Trial Comparing Omentectomy and Omentum Preservation for Locally Advanced Gastric Cancer: the TOP-G Trial.

World J Surg 2021 06 10;45(6):1803-1811. Epub 2021 Feb 10.

Department of Surgery, Fujisawa Shonandai Hospital, Fujisawa, Japan.

Background: Omentectomy is considered an essential part of curative gastrectomy for locally advanced gastric cancer (GC), albeit without solid evidence. We conducted a randomized phase II trial (the TOP-G trial) comparing omentectomy and omentum preservation for gastric cancer. This report describes the short-term findings regarding the trial's secondary endpoints.

Methods: The trial protocol was submitted to the University Hospital Medical Information Network Clinical Trials Registry ( http://www.umin.ac.jp/ctr/ : UMIN000005421). The key eligibility criteria were histologically confirmed cT2-4a and N0-2 gastric adenocarcinoma. Short-term surgical outcomes, including morbidity and mortality, were compared between the omentectomy group (group A, control arm) and the omentum-preserving surgery group (group B, test arm). All procedures were performed via an open approach. Based on a non-inferiority margin of 7%, statistical power of 0.7, and type I error of 0.2, the sample size was set to 250 patients.

Results: A total of 251 patients were eligible and randomized (group A: 125 patients, group B: 126 patients) between April 2011 and October 2018. After excluding patients who had peritoneal metastasis or laparotomy history, safety outcomes were analyzed for 247 patients. Group A had a significantly longer median operation time (225 min vs. 204 min, p = 0.022) and tended to have greater median blood loss (260 mL vs. 210 mL p = 0.073). The incidences of morbidity were similar and < 10% in both groups (8% vs. 9%, p = 1.000). There was no mortality in either group.

Conclusions: Operative risk was generally similar between omentectomy and omentum-preserving surgery for locally advanced gastric cancer.
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http://dx.doi.org/10.1007/s00268-021-05988-7DOI Listing
June 2021

Development of an Automated Chemiluminescence Assay System for Quantitative Measurement of Multiple Anti-SARS-CoV-2 Antibodies.

Front Microbiol 2020 15;11:628281. Epub 2021 Jan 15.

Department of Microbiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Objectives: Serological tests for COVID-19 have been instrumental in studying the epidemiology of the disease. However, the performance of the currently available tests is plagued by the problem of variability. We have developed a high-throughput serological test capable of simultaneously detecting total immunoglobulins (Ig) and immunoglobulin G (IgG) against nucleocapsid protein (NP) and spike protein (SP) and report its performance in detecting COVID-19 in clinical samples.

Methods: We designed and prepared reagents for measuring NP-IgG, NP-Total Ig, SP-IgG, and SP-Total Ig (using N-terminally truncated NP (ΔN-NP) or receptor-binding domain (RBD) antigen) dedicated automated chemiluminescent enzyme immunoassay analyzer AIA-CL1200. After determining the basal thresholds based on 17 sera obtained from confirmed COVID-19 patients and 600 negative sera, the clinical validity of the assay was evaluated using independent 202 positive samples and 1,000 negative samples from healthy donors.

Results: All of the four test parameters showed 100% specificity individually (1,000/1,000; 95%CI, 99.63-100). The sensitivity of the assay increased proportionally to the elapsed time from symptoms onset, and all the tests achieved 100% sensitivity (153/153; 95%CI, 97.63-100) after 13 days from symptoms onset. NP-Total Ig was the earliest to attain maximal sensitivity among the other antibodies tested.

Conclusion: Our newly developed serological testing exhibited 100% sensitivity and specificity after 13 days from symptoms onset. Hence, it could be used as a reliable method for accurate detection of COVID-19 patients and to evaluate seroprevalence and possibly for surrogate assessment of herd immunity.
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http://dx.doi.org/10.3389/fmicb.2020.628281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843449PMC
January 2021

Sequential therapy of crizotinib followed by alectinib for non-small cell lung cancer harbouring anaplastic lymphoma kinase rearrangement (WJOG9516L): A multicenter retrospective cohort study.

Eur J Cancer 2021 03 22;145:183-193. Epub 2021 Jan 22.

Respiratory Division, Department of Internal Medicine, Itami City Hospital, 1-100 Koyaike, Itami City, Hyogo, 664-8540, Japan.

Background: The data of sequential therapy of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) in clinical practice have been limited.

Methods: We reviewed the clinical data of patients with ALK-rearranged non-small cell lung cancer who received crizotinib (CRZ) or alectinib (ALEC) between May 2012 and December 2016. Patients were divided into two groups based on the first-administered ALK-TKI, the CRZ or ALEC group. The combined time-to-treatment failure (TTF) was defined as the sum of the 'TTF of CRZ' plus the 'TTF of ALEC' if patients were treated with CRZ followed by ALEC in the CRZ group. The primary end-point is the comparison between the combined TTF and the TTF of ALEC in the ALEC group.

Results: Of 864 patients enrolled from 61 institutions, 840 patients were analysed. There were 535 of 305 patients in the CRZ/ALEC groups. The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group (median, 34.4 versus 27.2 months; hazard ratio [HR], 0.709; P = 0.0044). However, there was no significant difference in overall survival (OS) between the patients who received ALEC after CRZ in the CRZ group and the patients in the ALEC group (median, 88.4 months versus. not reached; HR, 1.048; P = 0.7770). In the whole population, the CRZ group had a significantly shorter OS than the ALEC group (median, 53.6 months versus not reached; HR, 1.821, P < 0.0001).

Conclusion: The combined TTF in the CRZ group was significantly longer than the TTF in the ALEC group; however, OS benefit of sequential therapy against ALEC as the first ALK-TKI was not shown.
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http://dx.doi.org/10.1016/j.ejca.2020.12.026DOI Listing
March 2021

Relationship between basal sodium intake and the effects of dapagliflozin in albuminuric diabetic kidney disease.

Sci Rep 2021 01 13;11(1):951. Epub 2021 Jan 13.

Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.

We investigated the impact of basal dietary sodium intake on the dapagliflozin-induced changes in albuminuria and blood pressure (BP) measured at home in patients with diabetic kidney disease (DKD).This was a secondary analysis of the Y-AIDA Study, in which DKD patients with estimated glomerular filtration rate (eGFR) ≥ 45 ml/min/1.73 m and urinary albumin-to-creatinine ratio (UACR) ≥ 30 mg/g creatinine were administered dapagliflozin for 24 weeks, and dapagliflozin significantly improved albuminuria levels and home BP profiles. The effects on UACR, home-measured BP, and eGFR were compared between high- and low-sodium intake groups (HS and LS groups), which were created using baseline urinary sodium-to-creatinine ratio of 84 participants with available basal sodium-to-creatinine ratios. At baseline, clinic-/home-measured BPs, UACR, and eGFR, were comparable in the two groups. After 24 weeks, the reductions from baseline in ln-UACR were comparable in the two groups. In contrast, the reductions in evening home systolic BP and eGFR from baseline were larger in HS than in LS (BP: - 13 ± 2.08 vs. - 6 ± 1.88, P = 0.020; eGFR: - 3.33 ± 1.32 vs. 0.37 ± 1.29, P = 0.049). The home BP-lowering effects of dapagliflozin are larger in HS than LS, concomitant with a larger reduction in eGFR, suggesting a dapagliflozin-induced improvement in glomerular relative hyperfiltration in HS.
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http://dx.doi.org/10.1038/s41598-020-79687-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806956PMC
January 2021

Duration of Adjuvant Doublet Chemotherapy (3 or 6 months) in Patients With High-Risk Stage II Colorectal Cancer.

J Clin Oncol 2021 02 13;39(6):631-641. Epub 2021 Jan 13.

University of Glasgow, Institute of Cancer Sciences, Scotland, United Kingdom.

Purpose: As oxaliplatin results in cumulative neurotoxicity, reducing treatment duration without loss of efficacy would benefit patients and healthcare providers.

Patients And Methods: Four of the six studies in the International Duration of Adjuvant Chemotherapy (IDEA) collaboration included patients with high-risk stage II colon and rectal cancers. Patients were treated (clinician and/or patient choice) with either fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPOX) and randomly assigned to receive 3- or 6-month treatment. The primary end point is disease-free survival (DFS), and noninferiority of 3-month treatment was defined as a hazard ratio (HR) of < 1.2- 6-month arm. To detect this with 80% power at a one-sided type one error rate of 0.10, a total of 542 DFS events were required.

Results: 3,273 eligible patients were randomly assigned to either 3- or 6-month treatment with 62% receiving CAPOX and 38% FOLFOX. There were 553 DFS events. Five-year DFS was 80.7% and 83.9% for 3-month and 6-month treatment, respectively (HR, 1.17; 80% CI, 1.05 to 1.31; [for noninferiority] .39). This crossed the noninferiority limit of 1.2. As in the IDEA stage III analysis, the duration effect appeared dependent on the chemotherapy regimen although a test of interaction was negative. HR for CAPOX was 1.02 (80% CI, 0.88 to 1.17), and HR for FOLFOX was 1.41 (80% CI, 1.18 to 1.68).

Conclusion: Although noninferiority has not been demonstrated in the overall population, the convenience, reduced toxicity, and cost of 3-month adjuvant CAPOX suggest it as a potential option for high-risk stage II colon cancer if oxaliplatin-based chemotherapy is suitable. The relative contribution of the factors used to define high-risk stage II disease needs better understanding.
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http://dx.doi.org/10.1200/JCO.20.01330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078416PMC
February 2021

Randomized Phase II Study of Gemcitabine Monotherapy vs. Gemcitabine with an EPA-Enriched Oral Supplement in Advanced Pancreatic Cancer.

Nutr Cancer 2021 Jan 13:1-10. Epub 2021 Jan 13.

Department of Biostatistics and Epidemiology, Yokohama City University Medical Center, Yokohama, Japan.

Background: Pancreatic cancer is often associated with cachexia. It had been reported that eicosapentaenoic acid (EPA) improve cachexia. This study aimed to evaluate the efficacy and safety of gemcitabine with an EPA-enriched oral supplement in patients with advanced pancreatic cancer.

Methods: This open-label phase II study consisted of patients (pts) who were randomly categorized into the EPA group (1,000 mg/m gemcitabine was administered on day 1, 8, and 15, every 4 weeks while an EPA-enriched oral supplement (prosure®, EPA 1.056 mg per pack) was taken daily at the maximum of two packs or the gemcitabine monotherapy group with an allocation ratio of 2:1. The primary endpoint was the evaluation of the 1-year survival estimating 10% addition.

Results: Randomized 68 pts were examined (EPA: 45, gemcitabine: 23). The 1-year survival probability of the EPA group was 35% while the gemcitabine group was 19%. The median survival times were 8.2 and 9.7 mo, respectively. The hazard ratio for EPA group was 0.79 [95% CI 0.46-1.37]; ( = 0.40). The toxicities were mild and insignificant in both groups. More beneficial effects of EPA in survival were observed in men, pancreatic body-tail and low C-reactive protein patients.

Conclusion: An EPA-enriched oral supplement may be effective in advanced pancreatic cancer.
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http://dx.doi.org/10.1080/01635581.2020.1871495DOI Listing
January 2021

Factors Predicting Rubella Vaccination among Pregnant Women in Japan: an Interim Report from the Pregnant Women Health Initiative.

Jpn J Infect Dis 2021 Jul 25;74(4):337-343. Epub 2020 Dec 25.

Yokohama City University School of Medicine Graduate School of Medicine, Japan.

Following the 2018 rubella outbreak in Japan, this study aimed to assess rubella prevention measures based on the vaccination and immunization status of pregnant women in Japan. Our cohort study involved 3 local core hospitals in Yokohama City, and a total of 666 pregnant women were recruited between June 2018 and September 2019 and answered an online questionnaire. In total, 67.5% of the pregnant women had received rubella vaccination. The rate of rubella vaccination among pregnant women in the present survey was lower than that among age-matched female participants in a nationwide survey conducted in 2018. Overall, the study results showed that pregnant women in their 20s had a higher vaccination rate than those in their 40s, women who were nonsmokers before pregnancy had a higher vaccination rate than those who were smokers, and pregnant women who were aware that rubella may affect their fetuses had a higher vaccination rate than those who were unaware of this. This survey elucidated multiple predictive factors for rubella vaccination among pregnant women in Japan. Our results confirm the recommendation that women considering pregnancy should be vaccinated against rubella.
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http://dx.doi.org/10.7883/yoken.JJID.2020.762DOI Listing
July 2021

Randomized phase II trial of S-1 plus cisplatin or docetaxel plus cisplatin with concurrent thoracic radiotherapy for inoperable stage III non-small cell lung cancer.

Cancer Med 2021 01 14;10(2):626-633. Epub 2020 Dec 14.

Department of Respiratory Medicine, Yokohama Municipal Citizen's Hospital, Kanagawa, Japan.

Cisplatin-based chemoradiotherapy is considered standard treatment for unresectable locally advanced non-small-cell lung cancer (LA-NSCLC). This study examined two regimens of chemotherapy in concurrent chemoradiation. Eligible patients with unresectable, radically irradible LA-NSCLC were randomized to either the SP (S-1 and cisplatin) or DP (docetaxel and cisplatin) arms with concurrent thoracic radiotherapy of 60 Gy, comprising 2 Gy per daily fraction. The primary endpoint was the overall survival (OS) rate at 2 years (the 2-year OS rate). From May 2011 to August 2014, 110 patients were enrolled. Of 106 eligible patients, the 2-year OS rates were 79% (95% CI: 66%-88%) and 69% (95% CI: 55%-80%) the SP and DP arms, respectively. The median progression-free survival was 11.6 months for the SP arm and 19.9 months for the DP arm, while the median survival time was 55.2 months for the SP arm and 50.8 months for the DP arm. Grade 3/4 leukopenia were more frequent in DP arm. The incidences of febrile neutropenia and pneumonitis tended to be higher in DP arm. There were no treatment-related deaths in either arm. The primary endpoint was met in both arms. The SP arm as a future reference regimen will be chosen due to fewer toxicities and better OS.
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http://dx.doi.org/10.1002/cam4.3641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877366PMC
January 2021

Effect of duration of adjuvant chemotherapy for patients with stage III colon cancer (IDEA collaboration): final results from a prospective, pooled analysis of six randomised, phase 3 trials.

Lancet Oncol 2020 12;21(12):1620-1629

Department of Health Science Research, Mayo Clinic, Rochester, MN, USA. Electronic address:

Background: A prospective, pooled analysis of six randomised phase 3 trials was done to investigate disease-free survival regarding non-inferiority of 3 months versus 6 months of adjuvant chemotherapy for patients with stage III colon cancer; non-inferiority was not shown. Here, we report the final overall survival results.

Methods: In this prospective, pooled analysis of six randomised phase 3 trials, we included patients with stage III colon cancer aged at least 18 years with an Eastern Cooperative Oncology Group performance status of 0-1 recruited between June 20, 2007, and Dec 31, 2015, across 12 countries in the CALGB/SWOG 80702, IDEA France, SCOT, ACHIEVE, TOSCA, and HORG trials, who started any treatment (modified intention-to-treat). Patients in all trials were randomly assigned to 3 months or 6 months of adjuvant fluorouracil, leucovorin, and oxaliplatin (FOLFOX) every 2 weeks or capecitabine and oxaliplatin (CAPOX) in different doses and methods every 3 weeks, at the treating physician's discretion. The primary endpoint was disease-free survival (time to relapse, secondary colorectal primary tumour, or death due to all causes), and overall survival (time to death due to all causes) was the prespecified secondary endpoint. The non-inferiority margin for overall survival was set as a hazard ratio (HR) of 1·11. Pre-planned subgroup analyses included regimen and risk group. Non-inferiority was declared if the one-sided false discovery rate adjusted (FDRadj) p value was less than 0·025.

Findings: With median follow-up of 72·3 months (IQR 72·2-72·5), 2584 deaths among 12 835 patients were observed. 5064 (39·5%) patients received CAPOX and 7771 (60·5%) received FOLFOX. 5-year overall survival was 82·4% (95% CI 81·4-83·3) with 3 months of therapy and 82·8% (81·8-83·8) with 6 months of therapy (HR 1·02 [95% CI 0·95-1·11]; non-inferiority FDRadj p=0·058). For patients treated with CAPOX, 5-year overall survival was 82·1% (80·5-83·6) versus 81·2% (79·2-82·9; HR 0·96 [0·85-1·08]); non-inferiority FDRadj p=0·033), and for patients treated with FOLFOX 5-year overall survival was 82·6% (81·3-83·8) and 83·8% (82·6-85·0; HR 1·07 [0·97-1·18]; non-inferiority FDRadj p=0·34). Updated disease-free survival results confirmed previous findings (HR 1·08 [95% CI 1·02-1·15]; non-inferiority FDRadj p=0·25). Data on adverse events were not further recorded.

Interpretation: Non-inferiority of 3 months versus 6 months of adjuvant chemotherapy for patients with stage III colon cancer was not confirmed in terms of overall survival, but the absolute 0·4% difference in 5-year overall survival should be placed in clinical context. Overall survival results support the use of 3 months of adjuvant CAPOX for most patients with stage III colon cancer. This conclusion is strengthened by the substantial reduction of toxicities, inconveniencies, and cost associated with a shorter treatment duration.

Funding: US National Cancer Institute.
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http://dx.doi.org/10.1016/S1470-2045(20)30527-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786835PMC
December 2020

[Using Real World Data in Cancer Clinical Studies].

Gan To Kagaku Ryoho 2020 Nov;47(11):1531-1536

Dept. of Biostatistics, Yokohama City University School of Medicine.

There is a growing expectation for real world data(RWD)in the development of drugs and medical devices in oncology area. Current RWD in Japan consists of electronic medical record(EMR)and DPC data from hospital information systems, claims data for reimbursement, disease registry data by academia, and so on. The DPC database is now widely used as a commercial RWD, but our research has revealed that it has a limited number of data items available, which may pose a disadvantage in evaluating patient background and the efficacy and safety of drugs, although they are essential for cancer clinical research. On the other hand, Flatiron Health Inc.'s database in the US, which is RWD derived from EMR, allows for collecting essential information in oncology by installing a cancer-specific EMR system into participating hospitals as well as by deploying certified cancer experts who engage in building structured clinical data. In the use of cancer RWD, it is important to select databases based on the purpose of analysis and understand that the quality of databases varies.
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November 2020

Long-Term Clinical Outcomes After Filter Protection During Percutaneous Coronary Intervention in Patients With Attenuated Plaque - 1-Year Follow up of the VAMPIRE 3 (Vacuum Aspiration Thrombus Reemoval 3) Trial.

Circ J 2020 12 1;85(1):44-49. Epub 2020 Dec 1.

Ageo Central General Hospital.

Background: Selective use of distal filter protection during percutaneous coronary intervention (PCI) for acute coronary syndromes (ACS) decreased the incidence of no-reflow phenomena and in-hospital serious adverse cardiac events compared with conventional PCI in patients with attenuated plaque ≥5 mm; however, its long-term clinical outcome remains unknown.Methods and Results:Patients who had ACS with attenuated plaque ≥5 mm were assigned to receive distal protection (DP) (n=98) or conventional treatment (CT) (n=96). The rate of major adverse cardiovascular events (MACE), a composite of death from any cause, non-fatal myocardial infarction, or target vessel revascularization (TVR) at 1 year, was the pre-specified secondary endpoint of the trial. MACE at 1 year occurred in 12 patients (12.2%) in the DP group and 3 patients (3.1%) in the CT group (P=0.029), which was driven by a higher risk of TVR (11 [11.2%] vs. 2 [2.1%], P=0.018). In patients treated with bare-metal stents (n=42), MACE occurred in 25.0% of the patients in the DP group and in none of the patients in the CT group (P=0.029), whereas in patients treated with drug-eluting stents (n=151), rates of MACE were similar in the groups (8.1% vs. 3.9%, P=0.32).

Conclusions: In ACS patients with attenuated plaque ≥5 mm, the 1-year rates of MACE were higher in the DP group than in the CT group. This effect might be mitigated by the use of drug-eluting stents.
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http://dx.doi.org/10.1253/circj.CJ-20-0449DOI Listing
December 2020

Multicenter Phase I/II Study of Nivolumab Combined with Paclitaxel Plus Ramucirumab as Second-line Treatment in Patients with Advanced Gastric Cancer.

Clin Cancer Res 2021 02 1;27(4):1029-1036. Epub 2020 Dec 1.

Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku, Tokyo, Japan.

Purpose: We conducted a phase I/II study to investigate the safety and efficacy of nivolumab with paclitaxel plus ramucirumab.

Patients And Methods: Patients with advanced gastric cancer (AGC) refractory to first-line chemotherapy were included. Patients received nivolumab (3 mg/kg on days 1 and 15) combined with paclitaxel (80 mg/m on days 1, 8, and 15) and ramucirumab (8 mg/kg on days 1 and 15) every 4 weeks. After feasibility evaluation in six patients (phase I), 37 additional patients were enrolled in the phase II part with the primary endpoint of 6-month progression-free survival (PFS) rate with two-sided 80% confidence interval (CI). The combined positive score (CPS) was defined as the number of programmed death-ligand 1-positive cells divided by the total number of viable tumor cells multiplied by 100.

Results: Forty-three patients were enrolled. Of these, 60.5% had CPS ≥ 1. Dose-limiting toxicities were observed in two patients, and the recommended dose was determined as level 1. Thirty-nine (90.7%) patients experienced treatment-related adverse events (AEs) grade ≥3 and 14 (32.6%) patients experienced immune-related AEs grade ≥3. The overall response rate was 37.2% (95% CI, 23.0%-53.5%) and the 6-month PFS rate was 46.5% (80% CI, 36.4%-55.8%; = 0.067). Median survival time was 13.1 months (95% CI, 8.0-16.6 months): 13.8 months (95% CI, 8.0-19.5 months) in patients with CPS ≥ 1 and 8.0 months (95% CI, 4.8-24.1 months) in patients with CPS < 1.

Conclusions: Nivolumab with paclitaxel plus ramucirumab demonstrated promising antitumor activity with manageable toxicities as second-line treatment for AGC.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3559DOI Listing
February 2021

Tumor mutation burden as a biomarker for lung cancer patients treated with pemetrexed and cisplatin (the JIPANG-TR).

Cancer Sci 2021 Jan 30;112(1):388-396. Epub 2020 Nov 30.

Department of Genome Biology, Kindai University Faculty of Medicine, Osaka-sayama, Japan.

The JIPANG study is a randomized phase III study of pemetrexed/cisplatin (Pem/Cis) versus vinorelbine/cisplatin (Vnr/Cis) for completely resected stage II-IIIA non-squamous non-small cell lung cancer (Ns-NSCLC). This study did not meet the primary endpoint (recurrence-free survival, RFS) but Pem/Cis had a similar efficacy to Vnr/Cis with a better tolerability. Tumor mutation burden (TMB) is thought to have a predictive value of immune checkpoint inhibitors. However, the relevance of TMB to cytotoxic chemotherapy remains unknown. This exploratory study investigates the relationship between tumor mutation profiles and clinical outcome of Pem/Cis. Formalin-fixed, paraffin-embedded tumor tissues (n = 389) were obtained from the patients. Mutation status of tissue DNA was analyzed by targeted deep sequencing. Epidermal growth factor receptor (EGFR) mutations were detected frequently in Ns-NSCLC (139/374). Patients without any EGFR mutations experienced longer RFS in the Pem/Cis arm versus Vnr/Cis arms. Pem/Cis in patients with high TMB (≥12-16 mut/Mb) tended to have improved survival. In patients with wild-type EGFR, TMB ≥ 12 mut/Mb was significantly associated with improved RFS with Pem/Cis versus Vnr/Cis (not reached vs 52.5 months; hazard ratio (HR) 0.477). It could be proposed that TMB was predictive of RFS benefit with Pem/Cis versus Vnr/Cis in Ns-NSCLC. Further investigation is required to determine whether TMB combined with EGFR mutation status could be used as a predictive biomarker.
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http://dx.doi.org/10.1111/cas.14730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780021PMC
January 2021
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