Satoshi Tamaru

Gene expression profiling of peripheral T-cell lymphoma including γδ T-cell lymphoma

The gene expression profile of peripheral gammadelta T-cell lymphoma (gammadeltaTCL) has not been investigated. Using oligonucleotide microarrays, we analyzed total RNA from 7 patients with gammadeltaTCL (4 hepatosplenic, 1 cutaneous, 1 intestinal, and 1 thyroidal) and 27 patients with alphabetaTCL (11 peripheral TCL-unspecified, 15 angioimmunoblastic TCL, and 1 hepatosplenic). Unsupervised microarray analyses classified all hepatosplenic gammadeltaTCLs into a single cluster, whereas other gammadeltaTCLs were scattered within the alphabetaTCL distribution. We identified a T-cell receptor signature gene set, which accurately classified gammadeltaTCL and alphabetaTCL. A classifier based on gene expression under supervised analysis correctly identified gammadeltaTCL. One case of hepatosplenic alphabetaTCL was placed in the gammadeltaTCL grouping. gammadeltaTCL signature genes included genes encoding killer cell immunoglobulin-like receptors and killer cell lectin-like receptors. Our results indicate that hepatosplenic gammadeltaTCL is a distinct form of peripheral TCL and suggest that nonhepatosplenic gammadeltaTCLs are heterogeneous in gene expression.

Gene expression profiling of diffuse large B-Cell lymphomas supervised by CD5 expression

CD5-positive (CD5+) diffuse large B-cell lymphoma (DLBCL) has a poor prognosis and high incidence of central nervous system (CNS) relapse, even in the rituximab era. To determine the gene expression profile of CD5+ DLBCL, total RNA from 90 patients with DLBCL, including 33 CD5+ DLBCL and 57 CD5-negative (CD5–) DLBCL patients, was examined using Agilent human oligo microarrays. These cases were separated into 78 activated B-cell-like (ABC) DLBCLs and 12 germinal center B-cell-like (GCB) DLBCLs. All cases of CD5+ DLBCL were classified as ABC DLBCLs. The classifier based on gene expression used in a supervised analysis correctly identified CD5 expression in the DLBCL and ABC DLBCL samples. The gene most relevant to CD5 expression was SH3BP5. Enriched GO categories in the CD5+ ABC DLBCL signature gene set included multicellular organismal signaling, transmission of nerve impulse, and synaptic transmission. The present study, which includes the largest reported number of patients with CD5+ DLBCL, confirmed that most CD5+ DLBCLs are ABC DLBCLs, suggesting that therapeutic strategies for ABC DLBCL may be effective for the treatment of CD5+ DLBCL. Our CD5+ ABC DLBCL signature gene set may provide insights into the cause of the high frequency of CNS relapse in CD5+ DLBCL.

Central venous catheter-related thrombosis after replacement therapy for intracranial bleeding in a patient with afibrinogenaemia

T. MATSUMOTO,* H. WADA, S. TAMARU, § Y. SUGIMOTO,* A. FUJIEDA,* K. YAMAMURA,* T. KOBAYASHI,* T. KANEKO, – M. YAMAGUCHI,* T. NOBORI and N. KATAYAMA* *Department of Haematology and Oncology, Mie University Graduate School of Medicine; Haemophilia and Thrombophilia Centre, Mie University Hospital; Clinical Laboratory Medicine, Mie University Graduate School of Medicine; §Institute of Human Reseach Promotion and Drug Development, Mie University Graduate School of Medicine; and –Patient Safety Division, Mie University Hospital, Mie, Japan

Efficacy of transdermal scopolamine for sialorrhea in patients with amyotrophic lateral sclerosis

Abstract Background: Sialorrhea, the excessive flow of saliva from the mouth, causes distress in about half of patients with amyotrophic lateral sclerosis (ALS). Treatments of sialorrhea in ALS include systemic anticholinergic drugs, amitriptyline, botulinum toxin injection, and salivary gland radiotherapy, although each has limitations. Scopolamine transdermal patches have been used to prevent motion sickness since the 1980s but have also been used to treat sialorrhea in oropharyngeal disease, cerebral palsy, and Parkinson’s disease. To date, no blinded, controlled studies of sialorrhea in ALS have been reported. Methods: A crossover, double-blind comparative study was conducted by randomly assigning patients to receive scopolamine or placebo patches for 1 week. Results: A total of 10 patients (three males and seven females; mean age 71.6 years) were enrolled. The mean volume of daily oral suction was decreased with scopolamine treatment. However, there were no significant differences between scopolamine and placebo in terms of a visual analogue scale of sialorrhea severity and difficulty, and the saliva item of the ALS Functional Rating Scale-Revised (ALSFRS-R). Conclusions: Our findings suggest that scopolamine patches might decrease saliva production and relieve sialorrhea in some patients with ALS. However, these findings were not statistically significant for all patients.

A Case of Hyperammonemia Associated with High Dihydropyrimidine Dehydrogenase Activity

Over the past decades, 5-Fluorouracil (5-FU) has been widely used to treat several types of carcinoma, including esophageal squamous cell carcinoma. In addition to its common side effects, including diarrhea, mucositis, neutropenia, and anemia, 5-FU treatment has also been reported to cause hyperammonemia. However, the exact mechanism responsible for 5-FU-induced hyperammonemia remains unknown. We encountered an esophageal carcinoma patient who developed hyperammonemia when receiving 5-FU-containing chemotherapy but did not exhibit any of the other common adverse effects of 5-FU treatment. At the onset of hyperammonemia, laboratory tests revealed high dihydropyrimidine dehydrogenase (DPD) activity and rapid 5-FU clearance. Our findings suggested that 5-FU hypermetabolism may be one of the key mechanisms responsible for hyperammonemia during 5-FU treatment.

Pertuzumab, trastuzumab and eribulin mesylate therapy for previously treated advanced HER2-positive breast cancer: a feasibility study with analysis of biomarkers

The standard treatment for advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer is the triple combination of pertuzumab, trastuzumab and docetaxel, but some patients cannot tolerate taxane. To explore a non-taxane triple therapy, we conducted a feasibility study of pertuzumab, trastuzumab and eribulin mesylate (PTE) therapy for previously treated advanced HER2-positive breast cancer with analyses of quality of life and biomarkers. Ten patients were enrolled, two of whom had a history of docetaxel allergy. The median number of prior regimens was 3. The most common Grade 3 toxicities were leukopenia (70%) and neutropenia (70%). Grade 4 or 5 adverse events were not observed. An improving trend for the Functional Assessment of Cancer Therapy-Breast (FACT-B) score at 3 months was observed. Eight cases were included in the biomarker analysis. The peripheral CD8+ T cell/ CD4+Foxp3+ regulatory T cells (Tregs) ratio was significantly increased (p = 0.039). The frequency of peripheral Tregs was associated with the trastuzumab trough concentration (p = 0.019). In a non-clinical analysis, Eribulin mesylate significantly inhibited Ser473 Akt phosphorylation in PIK3CA wild-type cells and mutated cells. These results suggest that PTE therapy is a feasible and promising option for advanced HER2-positive breast cancer. Further investigation is warranted.

Antialbuminuric effect of eplerenone in comparison to thiazide diuretics in patients with hypertension

This study investigated the effects and safety of eplerenone or thiazide diuretics in patients with hypertension and albuminuria (pretreatment urinary albumin/creatinine ratio ≥10 mg/gCr) treated with an angiotensin II receptor blocker. The primary end point was the mean percent change in the urinary albumin/creatinine ratio from baseline to 48 weeks. An efficacy analysis was performed in 195 patients (98 in the eplerenone group and 97 in the thiazide group). Systolic and diastolic blood pressures at 48 weeks were similar in the two groups. The mean percent change in the urinary albumin/creatinine ratio from baseline to 48 weeks was similar in the two groups (P=.804). In the safety analysis, the withdrawal rates for adverse events were similar in both groups. The antialbuminuric effects and safety of eplerenone therapy were similar to those of thiazide diuretics when combined with an angiotensin II receptor blocker in patients with hypertension and albuminuria.

Genetic Risk Factors Associated With Antiemetic Efficacy of Palonosetron, Aprepitant, and Dexamethasone in Japanese Breast Cancer Patients Treated With Anthracycline-based Chemotherapy

Introduction: Breast cancer patients often receive anthracycline‐based chemotherapy, and chemotherapy‐induced nausea and vomiting (CINV) remains one of the most uncomfortable and distressing adverse reactions. Poor control of CINV reduces the relative dose intensity of chemotherapy agents, which has been associated with poor clinical outcomes and shorter survival. The aim of the present study was to identify genetic risk factors associated with anthracycline‐based CINV. Patients and Methods: We evaluated CINV attributable to anthracycline‐based chemotherapy in Japanese breast cancer patients treated with an antiemetic regimen that included palonosetron, aprepitant, and dexamethasone. Furthermore, we investigated the associations between CINV and single nucleotide polymorphisms in 6 candidate genes. Results: Emesis episodes were rarely observed in the 125 patients included in the present survey (7.2%; n = 9); however, significant nausea occurred in more than one half of the patients (52.8%; n = 66). In particular, acute significant nausea was not effectively controlled. Multivariate logistic regression analysis revealed that the ABCG2 (rs2231142) AA genotype is significantly associated with acute significant nausea (odds ratio, 4.87; 95% confidence interval, 1.01‐23.60; P = .049). Conclusion: The findings of the present study provide significant insights for developing personalized antiemetic strategies for breast cancer patients receiving anthracycline‐based chemotherapy.

MPS 10-08 Renoprotective effect of eplerenone in comparison to thiazide diuretic in hypertensive patients with chronic kidney disease

Objective: The aim of the present study was to compare the anti-albuminuric effect of addition of eplerenone and thiazide diuretic to hypertensive patients with chronic kidney disease treated with angiotensin II receptor blocker (ARB). This study is sub-analysis of OWASE (Optimal hypertension therapy With Aldosterone blocker SElara) study that we presented in the 37th annual scientific meeting of the Japanese Society of Hypertension. Design and Method: The present study was a multicenter, prospective, open-label randomized, controlled study. We enrolled hypertensive patients, who had received an ARB, with albuminuria (pre-treatment urinary albumin/creatinine [Cr] ratio [UACR] 30–300 mg/gCr), and an estimated glomerular filtration rate (eGFR) ≥36 ml/min/1.73 m2. Eligible patients were randomly assigned to either receive eplerenone (50 mg daily) or thiazide diuretic (hydrochlorothiazide 12.5 mg daily or trichlormethiazide 1 mg daily) with standard antihypertensive therapy for 48 weeks. The primary end point was the mean percent change in the UACR from baseline to 48 weeks. Results: Of the assigned patients, 68 (42 in the eplerenone group and 26 in the thiazide diuretic group) were included in the efficacy analysis. Baseline UACR was similar in the two groups (eplerenone, 121.7 mg/gCr; thiazide diuretic, 99.4 mg/gCr, P = 0.230). Baseline systolic blood pressure was significantly higher in the thiazide diuretic group than the eplerenone group (eplerenone, 143.7 mmHg; thiazide diuretic, 155.4 mmHg, P = 0.001), however, achieved systolic blood pressure was similar in the two groups at 48 weeks (eplerenone, 135.5 mmHg; thiazide diuretic, 137.6 mmHg, P = 0.609). In the primary efficacy analysis, the mean percent change in the UACR from baseline to 48 weeks was similar in the two groups (eplerenone, −31.9%; thiazide diuretic, −37.6%, P = 0.735). Conclusions: The renoprotective effect of eplerenone combined therapy was similar to thiazide diuretic when combined with ARB in hypertensive patients with CKD. Figure. No caption available.

Abstract P4-13-21: A pilot study of pertuzumab, trastuzumab and eribulin for patients with advanced HER2 positive breast cancer

[Introduction] The triple therapy of pertuzumab, trastuzumab and taxanes (docetaxel or paclitaxel) is coming into widespread use, because of the beneficial effects on HER2 positive breast cancer. However, we don9t have enough information about the efficacy and safety of other agents with trastuzumab and pertuzumab (TP). We studied triple therapy of pertuzumab, trastuzumab and eribulin (PTE) for advanced HER2 positive breast cancer to assess the efficacy, safety and QOL prospectively (UMIN000012018). [Patients and methods] Responses were assessed by RECIST criteria v1.1. Adverse events (AEs) were graded according to CTCAE v4.0. Patients with advanced HER2 positive breast cancer were treated with pertuzumab (840 mg loading then 420 mg, day 1), trastuzumab (8 mg/kg loading then 6 mg/kg, day 1), and eribulin (1.4 mg/m2, day 1 and 8) every 3 weeks. Dose reduction was allowed when patients developed febrile neutropenia, grade 3-5 non-hematologic toxicity or skipped day 8 eribulin administration because of neutrophil count [Results] Ten patients were enrolled. Median age of patients was 60 years-old (35-75). Median number of prior chemoregimen for metastatic disease was 3 (0-5). Two patients had a history of docetaxel allergy. Median number of PTE cycle was 6 (3-12). Eight patients reduced eribulin doses 1.4 mg/m2 to 1.1 mg/m2 because of AEs (2 patients), skipped day 8 eribulin (4 patients), or physician9s choice (2 patients). One complete response, 1 partial response and 5 stable disease were achieved at 3 months. Two patients (1 CR and 1 SD) stopped eribulin and received TP as maintenance therapy. At 3 months, all 3 patients with progressive disease developed brain metastasis. Two patients had extracranial progressive lesions, but 1 patient had partial response for extracranial disease. The common treatment-related AEs were leukopenia, neutropenia, lymphopenia diarrhea, hypokalemia and stomatitis. Grade 3 AEs were leukopenia (7 patients), neutropenia (8 patients), lymphopenia (2 patients), febrile neutropenia (1 patient), hypokalemia (1 patient) and peripheral neuropathy (1 patient). Grade 4/5 AEs were not observed. Nine patients could be assessed QOL. FACT-B TOI, FACT-G and FACT-B total score had a tendency to be improved at 3 months. [Conclusion] The PTE therapy showed appropriate clinical effect for extracranial lesions and maintained QOL of patients with advanced HER2 positive breast cancer. It may be a choice for patients who have taxane-resistant diseases or a history of taxane allergy. Many patients needed to reduce eribulin dosage. When the PTE therapy is referred to advanced HER2 positive breast cancer patients as a palliative chemotherapy, eribulin (1.1mg/m2) might be a reasonable dosage. Citation Format: Ishihara M, Tamaru S, Oda H, Yamashita Y, Tono Y, Mizuno T, Katayama N. A pilot study of pertuzumab, trastuzumab and eribulin for patients with advanced HER2 positive breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-21.