Publications by authors named "Hironobu Minami"

236 Publications

Did the Randomized Phase III KEYNOTE-181 Study of Pembrolizumab for Esophageal Cancer Yield Negative or Positive Results?

J Clin Oncol 2021 Apr 12:JCO2003262. Epub 2021 Apr 12.

Hironobu Minami, MD, DMedSci, Medical Oncology and Hematology, Kobe University Graduate School of Medicine, Kobe, Japan; Naomi Kiyota, MD, PhD, Cancer Center, Kobe University Hospital, Kobe, Japan and Takashi Omori, PhD, Biostatistics, Social/Community Medicine and Health Science, Kobe University School of Medicine, Kobe, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.20.03262DOI Listing
April 2021

Five-year survival with nivolumab in previously untreated Japanese patients with advanced or recurrent malignant melanoma.

J Dermatol 2021 Mar 14. Epub 2021 Mar 14.

Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan.

We report the 5-year follow-up results from a single-arm, open-label, multicenter phase II study (ONO-4538-08) conducted in Japan. Twenty-four patients with treatment-naïve, recurrent, or unresectable stage III/IV malignant melanoma received 3 mg/kg nivolumab every 2 weeks until progressive disease or unacceptable toxicity occurred. The 5-year overall survival (OS) rate was 26.1%. Five years after the start of nivolumab treatment, there were six survivors. The 5-year OS rate was 66.7% for patients with a superficial spreading type, 14.3% for acral lentiginous type, and 16.7% for mucosal type. The 5-year progression-free survival rate was 17.2%. No new cases of partial response or complete response were observed after 3 years, and overall response and disease control rates were similar to those reported at 3 years. The treatment-related adverse events reported between the 3- and 5-year follow-up periods were anemia (grade 2), white blood cell count decrease (grade 2), and psoriasiform dermatitis (grade 2) in one patient each. No new grade 3 or higher treatment-related adverse events occurred in this period. In conclusion, first-line treatment with nivolumab in Japanese patients with unresectable or metastatic melanoma resulted in confirmed long-term survival. No new safety signals were reported in the studied population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1346-8138.15804DOI Listing
March 2021

Secondary -rearranged sarcoma responsive to chemotherapy regimens for Ewing sarcoma: A case report.

Mol Clin Oncol 2021 Apr 8;14(4):68. Epub 2021 Feb 8.

Department of Medical Oncology/Hematology, Kobe University Hospital, Kobe, Hyogo 650-0017, Japan.

Capicua transcriptional repressor -rearranged sarcoma is an Ewing-like sarcoma with an aggressive clinical course and poor prognosis. No standard treatment has been established. The present study describes a case of -rearranged sarcoma with lung metastases developing in a 24-year-old woman as a therapy-associated malignancy following chemotherapy for anaplastic large cell lymphoma at nine years old. This was treated with palliative regimens used for Ewing sarcoma. The patient achieved disease control for one year. Of note, ifosfamide and etoposide (IE), which were used as a second line treatment lead to a partial response. The case described in the present study indicated that treatment with Ewing regimens is a reasonable option for patients with metastatic -rearranged sarcoma, including those with a second malignant case.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3892/mco.2021.2230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890439PMC
April 2021

Expression of a novel type of KMT2A/EPS15 fusion transcript in FLT3 mutation-positive B-lymphoblastic leukemia with t(1;11)(p32;q23).

Cancer Genet 2021 Jun 13;254-255:92-97. Epub 2021 Feb 13.

Division of Medical Oncology/Hematology, Department of Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.

The t(1;11)(p32;q23) translocation is a rare but recurrent cytogenetic aberration in acute myeloid leukemia (AML) and B-cell acute lymphoblastic leukemia (B-ALL). This translocation was initially shown to form a fusion gene between KMT2A exon 8 at 11q23 and EPS15 exon 2 at 1p32 in AML. Activating mutations of FLT3 are frequently found in AML but are very rare in ALL. Here, we describe a 75-year-old woman who was diagnosed with B-ALL since her bone marrow was made up of 98.2% lymphoblasts. These blasts were positive for CD19, CD22, CD79a, CD13, and CD33 but negative for CD10 and myeloperoxidase. The karyotype by G-banding and spectral karyotyping was 46,XX,t(1;11)(p32;q23). Expression of KMT2A/EPS15 and reciprocal EPS15/KMT2A fusion transcripts were shown: KMT2A exon 8 was in-frame fused to EPS15 exon 12, indicating that this fusion transcript was a novel type. Considering three reported B-ALL cases, EPS15 breakpoints were markedly different between AML (exon 2) and B-ALL (exons 10-12). Furthermore, an uncommon type of FLT3 mutation in the juxtamembrane domain was detected: in-frame 4-bp deletion and 10-bp insertion. Accordingly, our results indicate that the novel type of KMT2A/EPS15 fusion transcript and FLT3 mutation may cooperate in the pathogenesis of adult B-ALL as class II and class I mutations, respectively.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cancergen.2021.02.006DOI Listing
June 2021

A phase I, dose-escalation study of oral PIM447 in Japanese patients with relapsed and/or refractory multiple myeloma.

Int J Hematol 2021 Feb 27. Epub 2021 Feb 27.

Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.

PIM447, a pan-proviral integration site for Moloney leukemia (PIM) kinase inhibitor, has shown preclinical activity in multiple myeloma (MM). This phase I, open-label, multicenter, dose-escalation study aimed to determine the maximum tolerated dose (MTD) and recommended dose for expansion (RDE) of PIM447 in Japanese patients with relapsed and/or refractory (R/R) MM. The study included 13 patients (250 mg once daily (QD), [n = 7]; 300 mg QD, [n = 6]). The sole dose-limiting toxicity observed was grade 3 QTc prolongation in one patient from the 300 mg group, and the MTD and RDE was not determined. The most common suspected PIM447-related adverse events (AEs) included thrombocytopenia (76.9%), anemia (53.8%), and leukopenia (53.8%). All patients experienced at least one grade 3 or 4 AE, most frequently thrombocytopenia or leukopenia (61.5% each). The overall response rate was 15.4%, disease control rate 69.2%, clinical benefit rate 23.1%, and two patients had a partial response (one in each dose group). Two patients treated with 250 mg QD had a progression-free survival > 6 months. PIM447 250 mg or 300 mg QD was tolerated in Japanese patients with R/R MM. Further studies are required to evaluate clinical outcomes of PIM447 in combination with other drugs for the treatment of MM.Trial registration: clinicaltrials.gov: (NCT02160951).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-021-03096-9DOI Listing
February 2021

Serum Soluble Interleukin-2 Receptor as a Potential Biomarker for Immune-related Adverse Events.

Anticancer Res 2021 Feb;41(2):1021-1026

Division of Medical Oncology/Hematology, Department of Medicine, Kobe University Hospital and Graduate School of Medicine, Kobe, Japan.

Background/aim: Biomarkers for immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs) are required. We encountered a patient whose skin irAE fluctuated in parallel with serum soluble interleukin-2 receptor (sIL-2R).

Patients And Methods: We examined 15 patients with cancer who received ICIs. Serum sIL-2R levels before and during ICI treatment were measured. The sIL-2R levels of preserved serum samples from another five patients who developed grade 3 irAEs were measured.

Results: Twelve patients showed no significant changes in sIL-2R levels during ICI treatment. Baseline serum sIL-2R levels in three patients increased beyond the normal range before the second cycle. These three patients had grade ≥2 irAEs at the second cycle treatment visit, supporting our hypothesis. Furthermore, at diagnosis of irAEs, the sIL-2R levels of all preserved samples from patients with grade 3 irAEs were significantly elevated.

Conclusion: Serum sIL-2R is a promising biomarker for the diagnosis of irAEs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21873/anticanres.14857DOI Listing
February 2021

Regorafenib-induced exacerbation of chronic immune thrombocytopenic purpura in remission: A case report.

Mol Clin Oncol 2021 Feb 16;14(2):30. Epub 2020 Dec 16.

Department of Medical Oncology/Hematology, Kobe University Hospital, Kobe, Hyogo 650-0017, Japan.

Regorafenib is an oral multi-kinase inhibitor which targets tumor angiogenesis, the tumor microenvironment and oncogenesis. Based on this mode of action, regorafenib has a broad spectrum of toxicities. However, at present, few reports have focused on autoimmune adverse events. We report a first case of regorafenib-induced exacerbation of chronic immune thrombocytopenic purpura in remission during treatment for the patients with heavily treated advanced colorectal cancer. This case report highlights the need for caution with regard to regorafenib treatment in patients with cancer with concomitant immune thrombocytopenic purpura.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3892/mco.2020.2192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783712PMC
February 2021

Relationship between PDGFR expression and the response to pazopanib in intimal sarcoma of the pulmonary artery: A case report.

Mol Clin Oncol 2021 Jan 9;14(1). Epub 2020 Nov 9.

Department of Medical Oncology/Hematology, Kobe University Hospital and Graduate School of Medicine, Kobe City, Hyogo 650-0017, Japan.

Intimal sarcoma of the pulmonary artery (PAIS) is a rare disease with a poor prognosis. Pazopanib, which has been indicated in metastatic non-adipocytic soft-tissue sarcomas and is expected to be active in PAIS, is a multi-kinase inhibitor that targets the tyrosine kinase activity of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and stem cell factor receptor. The present study reports findings related to two cases of PAIS with PDGF and VEGF expression following treatment with pazopanib. A case with a moderate to strong expression of PDGFR-α and -β presented a long-term stable disease when treated with pazopanib (progression-free survival, 5.8 months). In a second case with a weak expression of PDGFR-α and -β, the disease progressed rapidly on pazopanib (progression-free survival, 1.1 months). VEGFR-2 was not expressed in the tumors of both cases. The level of PDGFR expression in the tumor tissue may therefore be predictive of pazopanib efficacy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3892/mco.2020.2168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690247PMC
January 2021

Phase 1 study of Gemcitabine/Nab-paclitaxel/S-1 in patients with unresectable pancreatic cancer (GeNeS1S trial).

Cancer Chemother Pharmacol 2021 Jan 24;87(1):65-71. Epub 2020 Oct 24.

Department of Medical Oncology/Hematology, Kobe University Hospital and Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan.

Purpose: We conducted a phase 1 study to determine the maximum tolerated dose and the recommended dose of gemcitabine/nab-paclitaxel/S-1 combination chemotherapy in patients with unresectable pancreatic cancer.

Methods: We enrolled patients aged 20 years or older with unresectable pancreatic cancer and who had not been treated with chemotherapy or radiation therapy. Gemcitabine and nab-paclitaxel were administered on days 1 and 8, and S-1 was administered orally twice daily for 2 weeks, repeated every 3 weeks. The starting dose was level 0 [gemcitabine 700 mg/m, nab-paclitaxel 90 mg/m, S-1 60/80/100 mg/day (< 1.25 m/1.25-1.50 m/ > 1.5 m)]. Dose-limiting toxicities were determined during the first course, and a classical 3 + 3 dose finding design was planned.

Results: From March 2018 to October 2019, 20 patients were enrolled. At dose level 0, three of six patients experienced dose-limiting toxicities; one grade 3 skin rash on day 8, and two grade 3 or 4 neutropenia on day 8. At dose level-1 (gemcitabine 600 mg/m, nab-paclitaxel 90 mg/m, and S-1 50/70/80 mg/day), two of twelve patients experienced dose-limiting toxicities, all of which were grade 3 neutropenia on day 8. The most frequently observed toxicity during eight courses was neutropenia. Other treatment-related adverse events were mild. Eleven out of 19 (58%) patients achieved partial response.

Conclusion: We defined the maximum tolerated dose and the recommended dose for combination therapy with gemcitabine/nab-paclitaxel/S-1 as dose level-1. Considering the observed response rate, further studies are warranted in order to determine the efficacy of this regimen (UMIN-CTR 000030007).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00280-020-04174-1DOI Listing
January 2021

Site-Specific and Targeted Therapy Based on Molecular Profiling by Next-Generation Sequencing for Cancer of Unknown Primary Site: A Nonrandomized Phase 2 Clinical Trial.

JAMA Oncol 2020 Oct 15. Epub 2020 Oct 15.

Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.

Importance: Although profiling of gene expression and gene alterations by next-generation sequencing (NGS) to predict the primary tumor site and guide molecularly targeted therapy might be expected to improve clinical outcomes for cancer of unknown primary site (CUP), to our knowledge, no clinical trial has previously evaluated this approach.

Objective: To assess the clinical use of site-specific treatment, including molecularly targeted therapy based on NGS results, for patients with CUP.

Design, Setting, And Participants: This phase 2 clinical trial was conducted at 19 institutions in Japan and enrolled 111 previously untreated patients with the unfavorable subset of CUP between March 2015 and January 2018, with 97 patients being included in the efficacy analysis. Eligibility criteria included a diagnosis of unfavorable CUP after mandatory examinations, including pathological evaluation by immunohistochemistry, chest-abdomen-pelvis computed tomography scans, and a positron emission tomography scan.

Interventions: RNA and DNA sequencing for selected genes was performed simultaneously to evaluate gene expression and gene alterations, respectively. A newly established algorithm was applied to predict tumor origin based on these data. Patients received site-specific therapy, including molecularly targeted therapy, according to the predicted site and detected gene alterations.

Main Outcomes And Measures: The primary end point was 1-year survival probability. Secondary end points included progression-free survival (PFS), overall survival (OS), objective response rate, safety, efficacy according to predicted site, and frequency of gene alterations.

Results: Of 97 participants, 49 (50.5%) were women and the median (range) age was 64 (21-81) years. The cancer types most commonly predicted were lung (21 [21%]), liver (15 [15%]), kidney (15 [15%]), and colorectal (12 [12%]) cancer. The most frequent gene alterations were in TP53 (45 [46.4%]), KRAS (19 [19.6%]), and CDKN2A (18 [18.6%]). The 1-year survival probability, median OS, and median PFS were 53.1% (95% CI, 42.6%-62.5%), 13.7 months (95% CI, 9.3-19.7 months), and 5.2 months (95% CI, 3.3-7.1 months), respectively. Targetable EGFR mutations in tumor specimens were detected in 5 patients with predicted non-small-cell lung cancer (5.2%), 4 of whom were treated with afatinib; 2 of these patients achieved a durable PFS of longer than 6 months.

Conclusions And Relevance: This study's findings suggest that site-specific treatment, including molecularly targeted therapy based on profiling gene expression and gene alterations by NGS, can contribute to treating patients with the unfavorable subset of CUP.

Trial Registration: UMIN Identifier: UMIN000016794.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaoncol.2020.4643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563669PMC
October 2020

Phase I study of the antiprogrammed cell death-1 Ab spartalizumab (PDR001) in Japanese patients with advanced malignancies.

Cancer Sci 2021 Feb 22;112(2):725-733. Epub 2020 Dec 22.

Nagoya University Hospital, Nagoya, Japan.

Spartalizumab is a humanized IgG4/κ mAb directed against human programmed cell death-1 (PD-1). In this phase I study, we investigated safety, pharmacokinetics, preliminary antitumor activity, and toxicity of spartalizumab in patients with advanced malignancies. Patients (n = 18) with a range of tumor types received spartalizumab i.v. at doses of 1, 3, and 10 mg/kg every 2 weeks until disease progression, unacceptable toxicity, or discontinuation at the discretion of the investigator or patient. Most patients (61%) had received five or more prior lines of therapy. No dose-limiting toxicities were reported and, hence, the maximum tolerated dose was 10 mg/kg or more. Pharmacokinetics in Japanese patients aligned with those reported in a global dose-escalation study. The safety profile was consistent with other approved anti-PD-1 mAbs; the most common drug-related adverse events were maculopapular rash (22%), followed by malaise and increased blood alkaline phosphatase (11% each). Partial responses were reported in two patients (11%), one with transitional cell carcinoma and the other with hepatocellular carcinoma. In conclusion, this study confirmed the safety of spartalizumab given at a dose of up to 10 mg/kg every 2 weeks in Japanese patients with cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cas.14678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893979PMC
February 2021

Upregulation of S100A10 in metastasized breast cancer stem cells.

Cancer Sci 2020 Dec 11;111(12):4359-4370. Epub 2020 Oct 11.

Department of Biochemistry, Fujita Health University School of Medicine, Toyoake, Japan.

Metastatic progression remains the major cause of death in human breast cancer. Cancer cells with cancer stem cell (CSC) properties drive initiation and growth of metastases at distant sites. We have previously established the breast cancer patient-derived tumor xenograft (PDX) mouse model in which CSC marker CD44 cancer cells formed spontaneous microscopic metastases in the liver. In this PDX mouse, the expression levels of S100A10 and its family proteins were much higher in the CD44 cancer cells metastasized to the liver than those at the primary site. Knockdown of S100A10 in breast cancer cells suppressed and overexpression of S100A10 in breast cancer PDX cells enhanced their invasion abilities and 3D organoid formation capacities in vitro. Mechanistically, S100A10 regulated the matrix metalloproteinase activity and the expression levels of stem cell-related genes. Finally, constitutive knockdown of S100A10 significantly reduced their metastatic ability to the liver in vivo. These findings suggest that S100A10 functions as a metastasis promoter of breast CSCs by conferring both invasion ability and CSC properties in breast cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cas.14659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734155PMC
December 2020

Population pharmacokinetics and renal toxicity of cisplatin in cancer patients with renal dysfunction.

Cancer Chemother Pharmacol 2020 Oct 19;86(4):559-566. Epub 2020 Sep 19.

Department of Pharmacometrics and Pharmacokinetics, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo, 204-8588, Japan.

Purpose: The pharmacokinetics (PKs) of cisplatin have not been investigated in patients with renal dysfunction, characterized by creatinine clearance (Ccr) < 60 mL/min. In this study, we performed a population pharmacokinetic (PPK) analysis of unchanged cisplatin in patients with renal dysfunction. We investigated the effects of renal dysfunction on the PKs and nephrotoxicity of unchanged cisplatin.

Methods: We enrolled 23 patients with moderate renal dysfunction (Ccr calculated to be 30-60 mL/min using the Cockcroft-Gault formula) treated with cisplatin. PPK analysis was performed by nonlinear mixed effect modeling using NONMEM (Version 7.2). We evaluated gender, age, body surface area (BSA), weight, baseline Ccr, baseline serum creatinine (Scr), and baseline urea nitrogen as potential covariates. The final model was evaluated using bootstrap analysis. Renal toxicity was evaluated using Common Terminology Criteria for Adverse Events ver. 4.0. The frequency of severe renal dysfunction (Grade 3/4 Scr elevation) was measured in the population.

Results: A one-compartment model adequately described the unchanged cisplatin data. The population mean values for clearance (CLtot) and volume of distribution (Vd) were 19.1 L/h [coefficient of variation (CV) 19.4%] and 13.8 L (CV 41.0%), respectively. The final model identified BSA as a significant covariate for CLtot. There were no significant covariates for Vd. No patients suffered from severe nephrotoxicity to the point that hemodialysis was required.

Conclusion: Moderate renal dysfunction does not affect the PKs of unchanged cisplatin. The increased serum concentration of cisplatin may not lead to increased toxicity in patients with renal dysfunction.

Trial Registration Number And Date Of Registration: UMIN000007091 (January 17, 2012).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00280-020-04147-4DOI Listing
October 2020

Phase I Study of LFA102 in Patients With Advanced Breast Cancer or Castration-resistant Prostate Cancer.

Anticancer Res 2020 Sep;40(9):5229-5235

Novartis Pharmaceuticals Corporation, East Hanover, NJ, U.S.A.

Background/aim: The prolactin receptor (PRLR) is implicated in the tumorigenesis of breast and prostate cancers where it drives cell proliferation, survival, and migration. LFA102 is a humanized monoclonal antibody against PRLR with promising preclinical antitumor activity. To determine the maximum tolerated dose or a recommended dose, and to delineate the pharmacokinetic profile of LFA102 in Japanese patients, we conducted a phase I study.

Patients And Methods: LFA102 was intravenously infused every 4 weeks to patients with advanced breast or castration-resistant prostate cancer, and the dose increased from 3 to 40 mg/kg.

Results: Fourteen patients were treated, and toxicities were reported in 9 (64%) patients. They were all grade 1 or 2, and the most frequently observed toxicity was nausea (3 patients, 21%). No dose-limiting toxicities were observed. LFA102 did not show antitumor activity as a single agent.

Conclusion: Treatment with LFA102 was well tolerated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21873/anticanres.14526DOI Listing
September 2020

Association between clinical risk factors and left ventricular function in patients with breast cancer following chemotherapy.

Int J Cardiovasc Imaging 2021 Jan 28;37(1):197-205. Epub 2020 Aug 28.

Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.

The sequential or concurrent use of two different types of agents such as anthracyclines and trastuzumab may increase myocardial injury and cancer therapeutics-related cardiac dysfunction (CTRCD), which is often the result of the combined detrimental effect of the two therapies for breast cancer patients. However, the association between clinical risk factors and left ventricular (LV) function in such patients is currently unclear. We studied 86 breast cancer patients with preserved LV ejection fraction (LVEF) and treated with anthracyclines, trastuzumab, or both. Echocardiography was performed before and 16 days after chemotherapy. In accordance with the current position paper, clinical risk factors for CTRCD were defined as: cumulative dose of doxorubicin > 240 mg/m, age > 65-year-old, body mass index > 30 kg/m, previous radiation therapy, B-type natriuretic peptide > 100 pg/mL, previous history of cardiovascular disease, atrial fibrillation, hypertension, diabetes, and smoking. The relative decrease in LVEF after chemotherapy for patients with more than four risk factors was significantly greater than that for patients without (- 9.3 ± 10.8% vs. - 2.2 ± 10.2%; p = 0.02). However, this finding did not apply to patients with more than one, two or three risk factors. Patients with more than four risk factors also tended to show a higher prevalence of CTRCD than those without (14.3% vs. 2.8%; p = 0.12). Moreover, the relative decrease in LVEF became greater as the number of risk factors increased. This study found multiple risk factors were associated with LV dysfunction following chemotherapy. Our findings can thus be expected to have clinical implications for better management of patients with breast cancer referred for chemotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10554-020-01976-5DOI Listing
January 2021

Final analysis of a phase II study of nivolumab in combination with ipilimumab for unresectable chemotherapy-naive advanced melanoma.

J Dermatol 2020 Nov 18;47(11):1257-1266. Epub 2020 Aug 18.

Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan.

Nivolumab plus ipilimumab combination is currently one of the preferred regimens for advanced melanoma in recently updated clinical practice guidelines. However, the evidence on the efficacy of the combination for acral or mucosal subtypes remains less robust. This is the final analysis of a multicenter, open-label, uncontrolled phase II study that investigated the long-term efficacy and safety in treatment-naive Japanese patients with advanced melanoma, including acral or mucosal subtypes, and subsequent therapy after discontinuation of the investigational agents. Patients received four doses of nivolumab (1 mg/kg i.v.) in combination with ipilimumab (3 mg/kg i.v.) at 3-week intervals, followed by doses of nivolumab (3 mg/kg i.v.) at 2-week intervals. The median follow-up period was 20.8 months (range, 5.2-35.0). The centrally and locally assessed objective response rates were both 43.3% (13/30; 95% confidence interval [CI], 25.5-62.6). Median progression-free survival was not reached (95% CI, 3.02-not reached), and median overall survival was also not reached (95% CI, 19.52-not reached). The 30-month progression-free survival and overall survival rates were 50.3% and 54.2%, respectively. No new safety concerns were detected. After discontinuation of the investigational agents, 83.3% of patients received some form of subsequent therapy including 43.3% of patients who received nivolumab monotherapy and 26.7% of patients who received radiotherapy. Of the four patients who discontinued the investigational agents because of immune-related adverse events, two received subsequent therapy (nivolumab and ipilimumab, respectively) and the other two showed long-term treatment-free survival (659 and 590 days, respectively). Long-term survival with nivolumab plus ipilimumab was observed in Japanese patients with melanoma including acral and mucosal subtypes, which is consistent with the CheckMate 067 study. Many patients continued to receive some form of treatment safely after stopping treatment with nivolumab plus ipilimumab.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1346-8138.15514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693067PMC
November 2020

Impact of hypertension on left ventricular function in patients after anthracycline chemotherapy for malignant lymphoma.

Int J Cardiol 2021 Jan 13;323:126-132. Epub 2020 Aug 13.

Division of Cardiovascular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.

Background: Hypertension is considered an important risk factors for cancer therapeutics-related cardiac dysfunction (CTRCD) as well as heart failure. However, the impact of hypertension and left ventricular (LV) hypertrophy (LVH), which is associated with hypertension, on LV function in patients treated with anthracycline chemotherapy for malignant lymphoma remains uncertain.

Method: We studied 92 patients with malignant lymphoma and with preserved LV ejection fraction (LVEF). Echocardiography was performed before and two-month after anthracycline chemotherapy. CTRCD was defined as the presence of an absolute decrease in LVEF ≥10% to a final value <53%. LVH was defined as concentric hypertrophy, which was determined as relative wall thickness ≥ 0.42 and LV mass index >95 g/m for females and > 115 g/m for males.

Results: Relative decrease in LVEF after anthracycline chemotherapy in patients with hypertension (n = 23) was significantly higher than that in patients without hypertension (n = 69) (-5.8% [-9.4, -1.3]) vs. (-1.1% [-4.1, 2.5]); P = .005). Moreover, the prevalence of CTRCD in patients with hypertension tended to be higher than in those without hypertension (17% vs. 5%, p = .09). A sequential logistic model for predicting CTRCD, based on baseline clinical variables including major clinical risk factors, was improved by the addition of the complication of hypertension (P = .049), and further improved by the addition of the presence of LVH (P = .023).

Conclusions: Hypertension, especially when complicated by LVH, was found to be associated with LV dysfunction after anthracycline chemotherapy in patients with malignant lymphoma and preserved LVEF. Watchful observation or early therapeutic intervention may thus be needed for such patients by the addition of the presence of LVH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcard.2020.08.019DOI Listing
January 2021

Lymphoplasmacytic lymphoma in a patient with Birt-Hogg-Dubé syndrome.

Int J Hematol 2020 Dec 12;112(6):864-870. Epub 2020 Aug 12.

Department of Medical Oncology and Hematology, Kobe University Hospital, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.

Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disease characterized by benign skin hamartomas, pulmonary cysts leading to spontaneous pneumothorax, and an increased risk of renal cancer. BHD syndrome is caused by germline mutations in the folliculin (FLCN) gene, a putative tumor suppressor, which result in loss of function of the folliculin protein and may cause cancer predisposition. In a 45-year-old woman with anemia, lymphadenopathy, and a history of recurrent spontaneous pneumothorax, F-FDG PET/CT detected diffuse and slight F-FDG accumulation in the bone marrow, enlarged spleen, and systemic multiple enlarged lymph nodes. Genetic examination identified a germline nonsense mutation [c.998C > G (p.Ser333*)] on exon 9 of FLCN. Pathological examination of the lymph node revealed a diffuse neoplastic proliferation of plasmacytoid lymphocytes. The neoplastic lymphoid cells were positive for CD20, CD138, and light chain kappa as per immunohistochemistry and mRNA in situ hybridization, and a MYD88 gene mutation [c.755T > C (p.L252P)] was identified. Accordingly, she was diagnosed with lymphoplasmacytic lymphoma concomitant with BHD syndrome. To the best of our knowledge, this is the first report describing the development of hematological malignancy in a patient with BHD syndrome. The FLCN mutation might contribute lymphomagenesis as an additional mutation cooperating with the MYD88 mutation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-020-02970-2DOI Listing
December 2020

Disseminated cryptococcosis resembling miliary tuberculosis in a patient with acute myeloid leukemia.

J Infect Chemother 2020 Nov 31;26(11):1216-1219. Epub 2020 Jul 31.

Department of Medical Oncology and Hematology, Kobe University Hospital, Japan.

Disseminated cryptococcosis, usually involving the lungs and central nervous system, carries a high risk of morbidity and mortality in immunocompromised hosts. In this report, we describe a case of miliary pulmonary cryptococcosis in a patient with acute myeloid leukemia, initially resembling miliary tuberculosis. The diagnosis of disseminated cryptococcosis was made based on transbronchial lung biopsy with subsequent detection of Cryptococcus neoformans in blood and cerebrospinal fluid. The patient was treated with liposomal amphotericin B as induction therapy, followed by fluconazole as consolidation and maintenance therapies thereafter. The infection was improved immediately, and he successfully underwent hematopoietic stem cell transplantation. The present case serves as a timely reminder that a radiological miliary pattern necessitates a thorough search for a definitive microbiological and histopathological diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jiac.2020.07.004DOI Listing
November 2020

Ibuprofen gargle for chemo- or Chemoradiotherapy-induced Oral Mucositis: a feasibility study.

J Pharm Health Care Sci 2020 1;6:12. Epub 2020 Jun 1.

Department of Pharmacy, Kobe University Hospital, 7-5-2 Kusunoki-Cho, Kobe, Hyogo 650-0017 Japan.

Background: Oral mucositis frequently occurs in cancer patients treated with chemotherapy and chemoradiotherapy (CRT). This study examined the safety and efficacy of ibuprofen gargle in healthy volunteers and patients with chemotherapy- and concomitant CRT-induced oral mucositis.

Methods: We enrolled healthy volunteers and patients with chemotherapy- and CRT-induced oral mucositis. In cohort I, single and multiple doses of ibuprofen gargle (0.6% or 1.0%) were administered to healthy volunteers on day 1 and days 4-10. In cohort II, multiple doses of ibuprofen gargle (0.6%) were administered to patients with complicated grade 2-3 oral mucositis based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The primary endpoint of cohort I was the treatment-related adverse events (TRAEs) as defined by CTCAE version 4.0. The primary endpoint of cohort II was the change in the visual analogue scale (VAS) pain score from before to 15 min after gargle use on day 3. The incidence and severity of TRAEs were assessed based on the CTCAE version 4.0 and a subjective rating scale completed by healthy volunteers and patients.

Results: In cohort I, 9 of 10 healthy volunteers were evaluable for safety. All 9 healthy volunteers reported the TRAE of oral irritation with single or multiple use of the gargle. In cohort II, 10 patients were enrolled and evaluable for safety and 7 of 10 patients were evaluable for efficacy. The mean change in the VAS pain score from before to 15 min after using the gargle on day 3 was - 1.28 (95% confidence interval: - 2.06, - 0.51), and all patients experienced some degree of pain relief (range: - 0.2 to - 2.5). All 10 patients reported the TRAE of oral irritation. No other TRAEs of ibuprofen gargle were observed in the healthy volunteers and patients.

Conclusion: Despite oral irritation, the ibuprofen gargle appeared to be safe and effective for the pain related to chemo- or CRT-induced oral mucositis. However, ibuprofen-related oral irritation warrants further formulation improvement.

Trial Registration: This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000014433).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40780-020-00168-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262752PMC
June 2020

MYC amplification on double minute chromosomes in plasma cell leukemia with double IGH/CCND1 fusion genes.

Cancer Genet 2020 04 27;242:35-40. Epub 2020 Jan 27.

Division of Medical Oncology/Hematology, Department of Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.

In multiple myeloma (MM), MYC rearrangements that result in increased MYC expression are associated with an aggressive form of MM and adverse outcome. However, the consequences of MYC amplification in MM remain unclear. Here, we describe an unusual case of plasma cell leukemia (PCL) harboring MYC amplification on double minute chromosomes (dmin). A 79-year-old woman was initially diagnosed as having BJP-κ type MM with bone lesions. After seven months, the disease progressed to secondary PCL: leukocytes 49.1 × 10/L with 77% plasma cells showing lymphoplasmacytic appearance. The bone marrow was infiltrated with 76% plasma cells immunophenotypically positive for CD38 and negative for CD45, CD19, CD20, and CD56. The karyotype by G-banding and spectral karyotyping was 48,XX,der(14)t(11;14)(q13;q32),+der(14)t(14;19)(q32;q13.1),+18,6~95dmin[15]/46,XX[5]. Fluorescence in situ hybridization detected multiple MYC signals on dmin and double IGH/CCND1 fusion signals on der(14)t(11;14) and der(14)t(14;19). Most plasma cells were diffusely and strongly positive for MYC and CCND1 by immunohistochemistry. The patient died of progressive disease after one week. MYC amplification led to high expression of MYC and rapid disease progression, indicating its clinical significance in the pathogenesis of MM/PCL. MYC amplification on dmin may be a very rare genetic event closely associated with the progression to PCL and coexistence of IGH/CCND1 fusions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cancergen.2020.01.049DOI Listing
April 2020

Amrubicin for Patients With Platinum-refractory Small-cell Prostate Cancer: Two Case Reports.

Clin Genitourin Cancer 2020 06 7;18(3):e324-e329. Epub 2020 Jan 7.

Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clgc.2019.12.017DOI Listing
June 2020

Band 3 ectopic expression in colorectal cancer induces an increase in erythrocyte membrane-bound IgG and may cause immune-related anemia.

Int J Hematol 2020 May 30;111(5):657-666. Epub 2020 Jan 30.

Division of Medical Oncology/Hematology, Department of Medicine, Kobe University Hospital, Kobe, Hyogo, Japan.

Autoimmune hemolytic anemia (AIHA) is a rare comorbidity in colorectal cancer (CRC) and has an unknown etiology. Previously, we described an AIHA case secondary to CRC with ectopic band 3 expression. Herein, we investigated ectopic band 3 expression and erythrocyte membrane-bound IgG in a CRC cohort. Between September 2016 and August 2018, 50 patients with CRC and 26 healthy controls were enrolled in the present study. The expression of band 3 and SLC4A1 mRNA was observed in 97% of CRC surgical specimens. Although clinical AIHA was not observed in any patient with CRC, a direct antiglobulin test was positive in 10 of the patients in the CRC group (p = 0.01). Flow cytometry revealed significantly increased erythrocyte membrane-bound IgG among patients with CRC compared to healthy controls (mean ± standard deviation; 38.8 ± 4.7 vs. 29.9 ± 15.6, p = 0.012). Normocytic anemia was observed, including in cases negative for fecal occult blood, suggesting a shortened erythrocyte life-span due to increased membrane-bound IgG. Immunoprecipitation revealed increased anti-band 3 autoantibodies in patients' sera. Mouse experiments recapitulated this phenomenon. We also confirmed that band 3 expression is controlled by 5'AMP-activated protein kinase under hypoxic conditions. These findings increase our understanding of the etiology of cancer-related anemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-020-02831-yDOI Listing
May 2020

Phase 1b/2 study of blinatumomab in Japanese adults with relapsed/refractory acute lymphoblastic leukemia.

Cancer Sci 2020 Apr 11;111(4):1314-1323. Epub 2020 Feb 11.

National Cancer Center Hospital, Tokyo, Japan.

Adult patients with relapsed/refractory (R/R) B-precursor acute lymphoblastic leukemia (ALL) have a poor prognosis. Blinatumomab is a bispecific T-cell engager (BiTE) immuno-oncology therapy with dual specificity for CD19 and CD3 that redirects patients' CD3-positive cytotoxic T cells to lyse malignant and normal B cells. We conducted an open-label, phase 1b/2 study to determine the safety, pharmacokinetics, efficacy and recommended dose of blinatumomab in Japanese adults with R/R B-precursor ALL. Patients received 9 μg/day blinatumomab during week 1 and 28 μg/day during weeks 2-4, with a 2-week treatment-free interval (6-week cycle); patients received 28 μg/day blinatumomab in subsequent cycles. Primary endpoints were the incidence of dose-limiting toxicities (DLT) in phase 1b and complete remission (CR)/CR with partial hematologic recovery (CRh) within the first two cycles in phase 2. A total of 26 patients enrolled and 25 (96%) reported grade ≥3 adverse events (mostly cytopenias). There were no DLT. CR/CRh within two cycles was achieved by 4 of 5 patients (80%) in phase 1b and 8 of 21 patients (38%) in phase 2. Among patients with evaluable minimal residual disease, 4 (100%) in phase 1b and 3 (38%) in phase 2 had a complete MRD response. Median RFS for 8 patients who achieved CR/CRh in phase 2 was 5 (95% CI: 3.5-6.4) months; median OS was not estimable. There were no significant associations between maximum cytokine levels or percentage of specific cell types during cycle 1 and response. Consistent with global studies, blinatumomab appeared to be safe and efficacious in Japanese adults with R/R ALL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cas.14322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156857PMC
April 2020

Asciminib in Chronic Myeloid Leukemia after ABL Kinase Inhibitor Failure.

N Engl J Med 2019 12;381(24):2315-2326

From the South Australian Health and Medical Research Institute and the University of Adelaide, Adelaide, SA, Australia (T.P.H., D.Y., D.M.R.); Memorial Sloan Kettering Cancer Center, New York (M.J.M., M.S.T., J.H.P.); University of Texas M.D. Anderson Cancer Center, Houston (J.E.C.); Kobe University Graduate School of Medicine, Kobe (H.M.), and the National Cancer Center Hospital East, Chiba (Y.M.) - both in Japan; Hôpital Saint-Louis, Paris (D.R.), and the University of Bordeaux, Bordeaux (F.-X.M.) - both in France; Dana-Farber Cancer Institute, Boston (D.J.D.); Sapienza University, Rome (M.B.); Singapore General Hospital, Singapore (Y.-T.G.); University of Michigan Comprehensive Cancer Center, Ann Arbor (M.T.); Universitätsklinikum Jena, Jena (A.H.), Charité Hospital, Berlin (P.C.), and the Department for Hematology-Oncology, Goethe University Hospital, Frankfurt am Main (F.L.) - all in Germany; University of Cardiff, Cardiff, United Kingdom (O.O.); Veterans Affairs Portland Health Care System (M.C.H.) and Oregon Health and Science University Knight Cancer Institute (M.C.H., B.J.D.), Portland; Hospital de la Princesa and Instituto de Investigación Sanitaria Princesa, Madrid (J.L.S.); Huntsman Cancer Institute, University of Utah, Salt Lake City (M.W.N.D.); Amsterdam University Medical Centers, VU University Medical Center, Amsterdam (J.J.W.M.J.); Novartis Pharma, Basel, Switzerland (D.H., Y.D., C.M., F.H.-P., K.G.V.); and Seoul St. Mary's Hematology Hospital, Catholic University of Korea, Seoul, South Korea (D.-W.K.).

Background: Asciminib is an allosteric inhibitor that binds a myristoyl site of the BCR-ABL1 protein, locking BCR-ABL1 into an inactive conformation through a mechanism distinct from those for all other ABL kinase inhibitors. Asciminib targets both native and mutated BCR-ABL1, including the gatekeeper T315I mutant. The safety and antileukemic activity of asciminib in patients with Philadelphia chromosome-positive leukemia are unknown.

Methods: In this phase 1, dose-escalation study, we enrolled 141 patients with chronic-phase and 9 with accelerated-phase chronic myeloid leukemia (CML) who had resistance to or unacceptable side effects from at least two previous ATP-competitive tyrosine kinase inhibitors (TKIs). The primary objective was to determine the maximum tolerated dose or the recommended dose (or both) of asciminib. Asciminib was administered once or twice daily (at doses of 10 to 200 mg). The median follow-up was 14 months.

Results: Patients were heavily pretreated; 70% (105 of 150 patients) had received at least three TKIs. The maximum tolerated dose of asciminib was not reached. Among patients with chronic-phase CML, 34 (92%) with a hematologic relapse had a complete hematologic response; 31 (54%) without a complete cytogenetic response at baseline had a complete cytogenetic response. A major molecular response was achieved or maintained by 12 months in 48% of patients who could be evaluated, including 8 of 14 (57%) deemed to have resistance to or unacceptable side effects from ponatinib. A major molecular response was achieved or maintained by 12 months in 5 patients (28%) with a T315I mutation at baseline. Clinical responses were durable; a major molecular response was maintained in 40 of 44 patients. Dose-limiting toxic effects included asymptomatic elevations in the lipase level and clinical pancreatitis. Common adverse events included fatigue, headache, arthralgia, hypertension, and thrombocytopenia.

Conclusions: Asciminib was active in heavily pretreated patients with CML who had resistance to or unacceptable side effects from TKIs, including patients in whom ponatinib had failed and those with a T315I mutation. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02081378.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa1902328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724923PMC
December 2019

A Case of Multi-System Langerhans Cell Histiocytosis with Local Invasion of the Orbital Apex.

Case Rep Ophthalmol 2019 Sep-Dec;10(3):319-326. Epub 2019 Sep 19.

Division of Ophthalmology, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan.

Langerhans cell histiocytosis (LCH) is characterised by tissue destruction caused by the abnormal proliferation of pathogenic dendritic cells. We report a rare case of multi-system LCH with local invasion of the orbital apex. A 56-year-old woman suffered from a decrease of visual acuity in the left eye caused by central scotoma and the limitation of eye movement in all directions. Magnetic resonance imaging revealed an enhanced lesion in the left orbital apex, suggesting optic nerve compression. She had been diagnosed with eosinophilic granuloma 24 years previously. Two weeks after the current presentation, we admitted the patient for optic canal and orbital apex decompression and subtotal tumour resection. Histopathological analysis confirmed the diagnosis of LCH. Post-surgical treatment with low-dose cytarabine was initiated for the residual tumour. However, it was ceased because of myelosuppression-induced pyelonephritis. After surgery, the central scotoma disappeared on day 5 and eye movement palsy resolved by 6 months. After the cessation of cytarabine, she has received low-dose steroid therapy for 2 years with no recurrence. Early surgical intervention with low-dose steroid therapy can lead to recovery of visual acuity and resolve eye movement palsy in patients with lesions of the orbital apex caused by multi-system LCH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000502946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873077PMC
September 2019

miR-221 Targets QKI to Enhance the Tumorigenic Capacity of Human Colorectal Cancer Stem Cells.

Cancer Res 2019 10 15;79(20):5151-5158. Epub 2019 Aug 15.

Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan.

miRNAs are key players in the integrated regulation of cellular processes and shape many of the functional properties that define the "cancer stem cell" (CSC) phenotype. Little is known, however, about miRNAs that regulate such properties in human colorectal carcinoma. In this study, we compared the expression levels of 754 miRNAs between paired samples of EpCAM/CD44 cancer cells (enriched in CSCs) and EpCAM/CD44 cancer cells (with CSC depletion) sorted in parallel from human primary colorectal carcinomas and identified miR-221 as the miRNA that displayed the highest level of preferential expression in EpCAM/CD44 cancer cells. High levels of miR-221 expression were associated with Lgr5 cells in mouse colon crypts and reduced survival in patients with colorectal carcinoma. Constitutive overexpression of miR-221 enhanced organoid-forming capacity of both conventional colorectal carcinoma cell lines and patient-derived xenografts (PDX) . Importantly, constitutive downregulation of miR-221 suppressed organoid-forming capacity and substantially reduced the tumorigenic capacity of CSC populations from PDX lines . Finally, the most abundant splicing isoform of the human () gene, , was identified as a functional target of miR-221; overexpression of miR-221-reduced QKI-5 protein levels in human colorectal carcinoma cells. As expected, overexpression of QKI-5 suppressed organoid-forming capacity and tumorigenic capacity of colorectal carcinoma PDX cells . Our study reveals a mechanistic link between miR-221 and QKI and highlights their key role in regulating CSC properties in human colorectal cancer. SIGNIFICANCE: These findings uncover molecular mechanisms underlying the maintenance of cancer stem cell properties in colon cancer. http://cancerres.aacrjournals.org/content/canres/79/20/5151/F1.large.jpg.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-18-3544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801097PMC
October 2019

Detection of a novel CBFB-MYH11 fusion transcript in acute myeloid leukemia M1 with inv(16)(p13q22).

Cancer Genet 2020 02 24;241:72-76. Epub 2019 Jul 24.

Department of Medical Oncology and Hematology, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe City 650-0017, Japan.

Acute myeloid leukemia (AML) with an inv(16)(p13q22) or t(16;16)(p13;q22) chromosomal abnormality represents one of the most common subtypes of de novo cases. These chromosomal rearrangements result in multiple CBFB-MYH11 fusion transcripts, with type-A being the most frequent. We here describe a unique case of de novo AML-M1, with inv(16)(p13q22), leading to an unusual CBFB-MYH11 fusion transcript, and der(7)t(7;11)(q31;q21). The fusion transcript involves a CBFB exon 5 with a breakpoint at nucleotide 754, an insertion of a 13-bp sequence of CBFB intron 5 at the fusion point, and the MYH11 exon 27 with a breakpoint at nucleotide 3464. To our knowledge, this CBFB-MYH11 fusion transcript has never been reported previously. The clinical characteristics of the present case are in line with previous reports suggesting that rare CBFB-MYH11 fusion transcripts lead to aberrant characteristics such as an atypical cytomorphology and additional cytogenetic abnormalities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cancergen.2019.07.005DOI Listing
February 2020

Efficacy and safety of nivolumab in Japanese patients with uterine cervical cancer, uterine corpus cancer, or soft tissue sarcoma: Multicenter, open-label phase 2 trial.

Cancer Sci 2019 Sep 3;110(9):2894-2904. Epub 2019 Sep 3.

Medical Oncology and Hematology, Kobe University Hospital, Kobe, Japan.

Nivolumab is a human monoclonal antibody against the immune checkpoint receptor programmed death-1, inhibiting binding to programmed death-ligand 1 or 2 (PD-L1 or PD-L2). This phase 2 study evaluated the efficacy and safety of nivolumab in patients with advanced/recurrent uterine cervical cancer, uterine corpus cancer, or soft tissue sarcoma (STS). Patients received nivolumab 240 mg at 2-week intervals. Primary endpoint was objective response rate; secondary endpoints included overall survival, progression-free survival, and safety. PD-L1 expression and microsatellite-instability (MSI) status were analyzed as potential efficacy biomarkers. Objective response rate was 25%, 23%, and 0% in patients with cervical cancer (n = 20), corpus cancer (n = 22), and STS (n = 21), respectively. The lower 80% confidence intervals of objective response rates in patients with cervical or corpus cancer exceeded the threshold rate (5%); the primary endpoint was met in cervical and corpus cancer, but not in STS. Median progression-free survival was 5.6, 3.4, and 1.4 months, and 6-month overall survival was 84%, 73%, and 86% in cervical cancer, corpus cancer, and STS, respectively. The objective response rate was higher in patients with cervical cancer with PD-L1-positive (n = 5/15; 33%) versus PD-L1-negative (n = 0/5; 0%) tumors. The two patients with corpus cancer classified as MSI-high responded; the six patients classified as microsatellite stable did not respond. Overall, nivolumab showed acceptable toxicity in all cohorts, with evidence of clinical activity in uterine cervical or corpus cancer, but not in STS. PD-L1 expression in cervical cancer and MSI-high in corpus cancer may predict clinical activity of nivolumab in these cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cas.14148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726684PMC
September 2019

Tetrasomy 8 and isochromosome 7q in CD5-positive hepatosplenic T-cell lymphoma with leukemic presentation.

Int J Hematol 2019 Nov 24;110(5):521-523. Epub 2019 Jul 24.

Division of Medical Oncology/Hematology, Department of Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-019-02708-9DOI Listing
November 2019