Efficacy and side-effect profile of tedizolid in the treatment of streptococcal toxic shock syndrome due to clindamycin-resistant Streptococcus pyogenes: A case report.

Oxazolidinones, such as tedizolid and linezolid, are bacteriostatic antibiotics that inhibit protein synthesis. Based on the findings from animal studies and their mechanism of action, these antibiotics are considered for managing toxic shock caused by clindamycin-resistant Group A Streptococcus (GAS; Streptococcus pyogenes). However, clinical reports on their usage in such cases are limited. Herein, we report a case of a 67-year-old woman with chronic myeloid leukemia who presented with fever, facial swelling, and myalgia. She was diagnosed with cellulitis and empirically treated with meropenem. Blood culture later revealed GAS, and she was diagnosed with streptococcal toxic shock syndrome. The antibiotic regimen was adjusted based on sensitivity results, with clindamycin initially replaced by linezolid and later switched to tedizolid owing to concerns about potential bone marrow suppression. Her condition improved, and she was discharged 15 days after admission. Therefore, tedizolid may be a safer option for managing toxic shock syndrome in patients with comorbidities that include thrombocytopenia.

Oncolytic Virus Therapy with HSV-1 for Hematological Malignancies.

Oncolytic herpes simplex virus type 1 (HSV-1) has been investigated to expand its application to various malignancies. Because hematopoietic cells are resistant to HSV-1, its application to hematological malignancies has been rare. Here, we show that the third generation oncolytic HSV-1, T-01, infected and killed 18 of 26 human cell lines and 8 of 15 primary cells derived from various lineages of hematological malignancies. T-01 replicated at low levels in the cell lines. Viral entry and the oncolytic effect were positively correlated with the expression level of nectin-1 and to a lesser extent 3-O-sulfated heparan sulfate, receptors for glycoprotein D of HSV-1, on tumor cells. Transfection of nectin-1 into nectin-1-negative tumor cells made them susceptible to T-01. The oncolytic effects did not appear to correlate with the expression or phosphorylation of antiviral molecules in the cyclic GMP-AMP (cGAS)-stimulator of interferon genes (STING) and PKR-eIF2α pathways. In an immunocompetent mouse model, intratumoral injection of T-01 into lymphoma induced regression of injected, as well as non-injected, contralateral tumors accompanied by abundant infiltration of antigen-specific CD8+ T cells. These data suggest that intratumoral injection of oncolytic HSV-1 may be applicable to systemic hematological malignancies. Nectin-1 expression may be the most useful biomarker for optimal efficacy.

A Case of Tyrosine Kinase Inhibitor-Resistant Chronic Myeloid Leukemia, Chronic Phase with ASXL1 Mutation.

Hematological malignancies, including chronic myeloid leukemia (CML), exhibit ASXL1 mutations; however, the function and molecular mechanism of these mutations remain unclear. ASXL1 was originally identified as tumor suppressor gene, in which loss of function causes myelodysplastic syndrome (MDS). ASXL1 mutations are common and associated with disease progression in myeloid malignancies including MDS, acute myeloid leukemia, and similarly in CML. In MDS, ASXL1 mutations have been associated with poor prognosis; however, the impact of ASXL1 mutations in CML has not been well described. A 31-year-old male was diagnosed as CML-chronic phase (CP). Laboratory findings showed a white blood cell count of 187,200/µL, with asymptomatic splenomegaly. Blast count was 5.0% in peripheral blood and 7.3% in bone marrow. There was no additional chromosomal abnormality except for t(9;22)(q34;q11.2) by chromosomal analysis. At onset, the Sokal score was 1.4, indicating high risk. The patient received tyrosine kinase inhibitor (TKI) therapy, comprising nilotinib ∼600 mg/day, bosutinib ∼600 mg/day, ponatinib ∼45 mg/day, and dasatinib ∼100 mg/day. Nevertheless, after 1.5 years of continuous TKI therapy, the best outcome was a hematological response. Although additional chromosomal aberrations and ABL1 kinase mutations were analyzed repeatedly before and during TKI therapy, known genetic abnormalities were not detected. Thereafter, the patient underwent bone marrow transplantation from an HLA 7/8 matched unrelated donor (HLA-Cw 1 locus mismatch, graft-versus-host direction). The patient achieved neutrophil engraftment, 18 days after transplantation, leading to complete remission with an undetectable level of BCR-ABL1 mRNA. The patient, however, died from graft-versus-host disease and thrombotic microangiopathy after 121 days. Gene sequence analysis of his CML cell before stem cell transplantation revealed ASXL1 mutations. Physiologically, ASXL1 contributes to epigenetic regulation. In the CML-CP patient in this case report, ASXL1 mutation conferred resistance to TKI through obscure resistance mechanisms. Even though a molecular mechanism for TKI resistance in ASXL1 mutation in CML has remained obscure, epigenetic modulation is a plausible mode of CML disease progression. The clinical impact including prognosis of ASXL1 for CML is underscored. And the treatment strategy of CML with ASXL1 mutation has not been established. A discussion of this case was expected to facilitate treatment options.

Regulatory T cell inhibition by dasatinib is associated with natural killer cell differentiation and a favorable molecular response-The final results of the D-first study.

We evaluated the effects of regulatory T cell (Treg) inhibition during dasatinib treatment on the anticancer immune response, particularly on natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). Fifty-two newly diagnosed Japanese patients with chronic myeloid leukemia (CML) in the chronic phase were enrolled in the D-first study; all received 100 mg of dasatinib once daily and were followed for at least 36 months. The cumulative deep molecular response (DMR, MR4) rate was 65% by 36 months; the 3-year overall survival was 96%. CD4+ T cell counts were stable, whereas the proportion of CD4+CD25+CD127low (Treg) cells decreased in a time-dependent manner. The DMR rate by18 months was significantly better in low Treg patients (<5.7% at 12 months) compared to the remaining patients (odds ratio 4.07). NK cell and CTL counts at several time points were inversely correlated with Treg counts. Furthermore, the degree of NK cell differentiation (CD3-CD57+/CD3-CD56+) was closely and inversely correlated with the proportion of Treg cells throughout the observation period, and showed a gradually increasing trend. In conclusion, our results demonstrate that Treg inhibition by dasatinib contributes to better treatment response through enhancement of the immune system, particularly via NK cell differentiation.

Association of pleural effusion with an early molecular response in patients with newly diagnosed chronic-phase chronic myeloid leukemia receiving dasatinib: Results of a D-First study.

Despite the efficacy and safety of dasatinib treatment for chronic-phase chronic myeloid leukemia (CML-CP), adverse effects such as pleural effusion (PE) are still a serious concern. We determined the clinical significance of PE incidence using patient data derived from the D-First clinical study. In the present study, chest radiography and quantification of specific lymphocyte subsets were performed routinely after initiation of dasatinib treatment. Among 52 patients with newly diagnosed CML-CP, 17 (33%) developed PE within 18 months after initial dasatinib administration, but all cases were moderate (Grade 1, 10 patients; Grade 2, 7 patients). CD56+ lymphocyte counts at 1 month correlated significantly with the incidence of PE, whereas lymphocytosis did not. The major molecular response (MMR) rate at 3 months (although not at later times) was significantly higher in PE-positive patients than PE-negative patients (59% versus 24%, respectively; P=0.013). Deep molecular response rates did not differ significantly between the PE groups at any time point during the observation period. Our results suggest that an immune-mediated mechanism involving natural killer cells underlies the development of PE in patients receiving dasatinib for 18 months. This mechanism likely promotes transient tumor regression in patients newly diagnosed with CML-CP.

Charlson comorbidity index predicts poor outcome in CML patients treated with tyrosine kinase inhibitor.

Although the Sokal and Hasford scoring systems are well-known prognostic models specific to chronic myeloid leukemia (CML), whether they can effectively predict outcomes in elderly CML patients with comorbidities has not been fully elucidated. We evaluated the association between comorbidity at diagnosis with treatment outcome and survival in chronic phase CML patients. A questionnaire was administered to patients diagnosed with CML between 2001 and 2012 and treated with tyrosine kinase inhibitors (TKIs). The Charlson comorbidity index (CCI) was used to determine concomitant diseases. In total, 79 patients (33 females; median age, 57 years) were enrolled. CCI scores at diagnosis were between 2 and 11. At the last follow-up, 46 patients showed a major molecular response. Complete cytogenetic response was achieved in 73.4 % of the cases 12 months after TKI administration. We observed only five deaths during the 55.5-month median follow-up period. The risk categories (low/intermediate/high) associated with Sokal and Hasford scores were 33/27/7 and 21/43/3, respectively. The 27 cases with a CCI score >3 had significantly poorer survival after diagnosis (52 cases had a CCI score <2). CCI scores were inversely associated to overall survival. Concomitant comorbidity at diagnosis is associated with poor outcome in CML patients treated with TKIs.

Early cytotoxic lymphocyte expansion contributes to a deep molecular response to dasatinib in patients with newly diagnosed chronic myeloid leukemia in the chronic phase: results of the D-first study.

Dasatinib is one of the key treatment options for chronic myeloid leukemia (CML) patients. Increase in lymphocyte counts has been known to be predictive of a good treatment response under dasatinib treatment as a second line therapy. However, clinical significance of lymphocyte dynamics in the upfront setting has yet to be clarified. To investigate the significance of lymphocyte dynamics in newly diagnosed chronic phase (CP)-CML, patient data of D-First study (ClinicalTrials.gov NCT01464411) were analyzed. Fifty-two CML-CP patients enrolled to this study were treated with dasatinib (100 mg day(-1) ) and all were followed-up for 18 months. The incidence of lymphocyosis was observed in 14 (27%), but it was not associated with deep molecular response achievement. However, natural killer (NK) cell or cytotoxic T lymphocyte (CTL) counts at 1 month were significantly higher in patients with deep molecular response (DMR) by 18 months compared to those without DMR. When the patients were divided into two groups according to those calculated thresholds by receiver operating characteristic curve (407/µL for NK cells and 347/µL for CTLs), the cumulative DMR rates by 18 months were significantly better in higher value group compared to lower value group. In contrast, regulatory T cell counts were significantly lower at 12 and 15 months in patients achieved DMR. These results suggest the presence of dual effects of dasatinib on immune system through the cytotoxic lymphocytes activation and Treg deregulation in different periods in newly diagnosed CML-CP.

Shorter halving time of BCR-ABL1 transcripts is a novel predictor for achievement of molecular responses in newly diagnosed chronic-phase chronic myeloid leukemia treated with dasatinib: Results of the D-first study of Kanto CML study group.

To investigate the factors that affect molecular responses on dasatinib treatment in patients with chronic-phase chronic myeloid leukemia (CML-CP), we performed a clinical trial named the "D-First study." Fifty-two patients with newly diagnosed CML-CP were enrolled in this study and received 100 mg dasatinib once daily. A deep molecular response (DMR) was defined as <50 copies/µg RNA of BCR-ABL1 transcript value corrected by GAPDH, which ensures <0.01% of BCR-ABL1 transcript value according to International Scale (BCR-ABL1(IS)). The halving time for BCR-ABL1 transcripts was calculated using transcript levels before dasatinib treatment, transcript levels after 3 months of treatment, and the treatment time between these two points. In terms of molecular response, 38 of 51 (75%) patients reached major molecular response (MMR) by 12 months, and the rate of DMR by 18 months was 59% (30/51). While both BCR-ABL1 transcript levels before treatment and a shorter halving time of BCR-ABL1 transcripts (≤14 days) were significant factors affecting achievement of MMR by 12 months, the Sokal score at diagnosis was not associated with MMR. Importantly, the halving time was the only factor that predicted achievement of DMR by 18 months. We showed that patients with CML-CP treated with dasatinib can be stratified according to the early treatment response as determined by the halving time of BCR-ABL1 transcripts. These data emphasize the significance of the early response from dasatinib treatment in achieving a DMR. (ClinicalTrials.gov; NCT01464411).

Association of higher methotrexate dose with lymphoproliferative disease onset in rheumatoid arthritis patients.

OBJECTIVE: Methotrexate (MTX) is used as an anchor drug for rheumatoid arthritis (RA). Lymphoproliferative disease (LPD) occasionally develops in patients treated with MTX, and is known as MTX-associated LPD (MTX-LPD). Although MTX-LPD occurs mainly in RA patients, it has not been established if MTX administration is an independent risk factor for LPD in RA patients. We examined the clinical characteristics of MTX-LPD in Japanese RA patients and attempted to determine the risk factors for MTX-LPD development. METHODS: We performed a nested case-control study on RA patients. We enrolled 5,753 RA patients from Kagawa, Japan. In age- and sex-matched patients, we separated patients who did not develop LPD under MTX treatment (MTX non-LPD group) from those that did (MTX-LPD group) and conducted a comparative examination. We used multivariate analysis to determine the independent risk factors for MTX-LPD onset. RESULTS: There were 28 patients in the MTX-LPD group and 125 patients in the MTX non-LPD group. Multivariate analysis of the parameters extracted by univariate analysis revealed that the mean MTX dose was a risk factor for MTX-LPD after adjusting for age; therefore, higher MTX dose is associated with LPD onset in RA patients. CONCLUSION: MTX is an independent risk factor for LPD onset in Japanese RA patients.

H2-receptor antagonist influences dasatinib pharmacokinetics in a patient with Philadelphia-positive acute lymphoblastic leukemia.

We recently reported in this journal that administration of acid suppressant such as an H2-receptor antagonist (H2RA) and a proton pump inhibitor can decrease the absorption of dasatinib from the gastrointestinal tract, thereby resulting in a significant decrease in its plasma concentration. Here, we report a patient treated with dasatinib and H2RA famotidine for whom the total area under the total plasma concentration-time curve (AUC(0-12)) of dasatinib dramatically increased after cessation of famotidine from 505.7 to 1,816.3 ng·h/mL. This is the first report to confirm the drug interaction between dasatinib and H2RA by using sequential pharmacokinetic profiling.

[Effective treatment with rituximab for primary thrombotic thrombocytopenic purpura complicated with multiple cerebral infarctions].

A 22-year-old woman was diagnosed with thrombotic thrombocytopenic purpura (TTP). She had a high fever and disorientation without renal dysfunction. She immediately underwent plasma exchange and prednisolone treatment, but they proved ineffective. She subsequently suffered from left major cerebral infarction with right-side hemiplegia. Therefore, 375 mg/m(2) of rituximab was administered weekly from day 14 with informed consent. Immediate improvements were noted in not only the hematological and biochemical parameters such as platelet count, hemoglobin level, rate of fragmented red cells, and serum LDH level but also the neurological symptoms and MRI findings. The universal histopathologic findings of TTP are characterized by hyaline thrombi formed by the aggregation of platelets, mostly in small arterioles and capillaries. Therefore, abnormal findings are rarely detected by imaging modalities such as CT and MRI. Moreover, TTP with major stroke is an extremely rare occurrence. In conclusion, we present a patient with refractory TTP with major cerebral infarction, who was effectively treated with rituximab.

Localized extraosseous Ewing's sarcoma of the chest wall resected by video-assisted thoracoscopic surgery.

Extraosseous Ewing's sarcoma (ES) is a small round cell tumor arising in soft tissue that was undifferentiated histologically from classic ES of bone. It frequently affects children and adolescents, with an unfavorable prognosis. Herein, we report a case of localized extraosseous ES of the chest wall resected by video-assisted thoracoscopic surgery (VATS). An asymptomatic 40-year-old man presented with an abnormal shadow on chest radiography. Chest computed tomography showed a 1.5-cm solid tumor on the chest wall. VATS was undertaken for the undiagnosed tumor. Thoracoscopic findings showed a hemispheric tumor with a smooth surface on the chest wall. The tumor was diagnosed with an extraosseous ES by pathological and cytogenetic examinations. As adjuvant therapy, the patient was treated with radiotherapy, followed by multiagent chemotherapy. There have been few reported cases in which VATS was used for extraosseous ES of chest wall, so our case was thought to be very rare.

Evaluation of QOL for stem cell transplantation recipients by SF-36 and FACT-BMT: preliminary results of FACT-BMT for Japanese patients.

BACKGROUND: Quality of life (QOL) measurement is a powerful instrument for assessing medical morbidity from the patient's perspective. We measured the QOL of patients undergoing autologous and allogeneic stem cell transplantation (SCT) in Japan to validate the FACT-BMT scale in comparison to SF-36. METHODS: We performed a cross-sectional survey for transplant recipients receiving treatment at our outpatient clinic. Recipients undergoing autologous and allogeneic SCT between October 2002 and March 2006 were eligible. Participants completed both the Medical Outcomes Study 36-Item Short Form (SF-36) and a Functional Assessment of Cancer Therapy survey specific to bone marrow transplantation (FACT-BMT). RESULTS: Thirty-six patients were enlisted, including 24 post-autologous SCT patients and 12 post-allogeneic SCT patients. The median time required to answer all questions was 9 and 11 minutes for SF-36 and FACT-BMT surveys, respectively. Cronbach's a was over 0. 7 for all domains in both SF-36 and FACT-BMT. Inter-scale correlations between all domains except for BP in SF-36 and BMT in FACT-BMT had correlation coefficients greater than 0. 4. The internal consistencies of both surveys were confirmed in Japanese patients. CONCLUSIONS: Our study indicated the feasibility and partial validity of FACT-BMT in a one-time follow-up of QOL for Japanese patients after SCT.

[Fever profile of febrile neutropenia in patients treated with cancer chemotherapy for hematological malignancies].

It is important to diagnose infectious events in cancer patients during chemotherapy. Since many of them have complications of febrile neutropenia (FN), determining its cause is critical for their treatment course. We analyzed all febrile events (>38.0 degrees C, single axillary temperature) in hospitalized cancer patients treated at Shizuoka Cancer Center over a period of 8 months. Based on the clinical presentation at the onset, we estimated the cause of fever and classified it as infection, tumor fever, immunologic reaction or unknown. Clinical presentations found at the onset of FN were categorized into 4 groups: (1) oral mucositis, and (2) respiratory, (3) gastrointestinal and (4) cutaneous findings. We detected 85 febrile episodes (median age 58, range 26 approximately 86; 37 males and 48 females). Neutropenia was observed (500/mL) in 52. 9% (45/85) of the patients and clinical symptoms were detected in 74.1% (63/85). In eleven of 18 infection-proven cases, we successfully predicted the infection focus at the onset of fever. Multivariate analysis revealed that initial high fever, antimicrobial prophylaxis, cutaneous findings and severe neutropenia were important influencing factors in predicting infectious disease during FN. Physical examination can support the diagnosis of the cause of fever in FN patients.

The utility of FDG-PET for managing patients with malignant lymphoma: analysis of data from a single cancer center.

OBJECTIVE: (18)F-fluorodeoxyglucose (FDG) positron-emission tomography (PET) has been widely applied to malignant lymphoma both for initial staging and response evaluation. The objective is to compare the efficacy of the less common, but more easily implemented modality, CT, with that of FDG. METHODS: We retrospectively reviewed consecutive patients diagnosed with malignant lymphoma in our hospital between October 2002 and March 2006, and compared the efficacy of FDG-PET and CT. The standard reference was defined by the pathology and clinical course of patients followed for more than 3 months. RESULTS: Thirty-three cases for staging and 62 cases for response evaluation after treatment were included. We calculated the sensitivity and specificity of each modality. The accuracy of the diagnostic modality was evaluated using receiver operating characteristic (ROC) analysis. The sensitivity and specificity of the initial staging were 87% and 100% on CT evaluation and 87% and 100% on FDG-PET, respectively. Sensitivity and specificity of the re-staging were 81% and 78% on CT evaluation and 82% and 97% on FDG-PET, respectively. The diagnostic accuracy of FDG-PET was comparable with that of CT both in initial staging and response evaluation. The maximum standardized uptake value was not associated with patient survival. In subgroup analysis, a tendency of lower sensitivity in the initial staging was found in FDG-PET for follicular lymphoma and CT for diffuse large B-cell lymphoma. CONCLUSION: Although different staging procedures appear better suited to certain subtypes of lymphoma, in general CT imaging might be as useful as FDG-PET in initial staging in selected patients.

[Fungal blood stream infection, its pathogen and antifungal susceptibility in cancer patients].

It is important to correctly diagnose fungal bloodstream infection in cancer patients. Antifungal susceptibility testing (AST)supplies useful information for the management of invasive fungal infection. We analyzed fungi isolated from blood samples in Shizuoka Cancer Center over a period of 6 years, and detected 59 strains including yeast(57 isolates) and mold(Aspergillus fumigatus, Scedosporium sp). The clinical background was reviewed using the medical record. The major fungi isolated from blood were Candida albicans(39.0%), followed by C. glabrata(22.0%), C. parapsilosis (20.3%), and C. tropicalis(13.6%). AST was carried out for 32 strains out of 59, according to the National Committee of Clinical Laboratory Standards (NCCLS)M-27-A-2 method. Among 32 strains, 7 isolates were resistant to fluconazole and 8 to itraconazole. Through the research period, the distribution of MIC values for azole agents did not change widely; however, the values for micafungin increased between the former and latter periods. In order to estimate the efficacy of antifungal agents, it is thought that continuous monitoring and the establishment of a standard method to evaluate the sensitivity of antifungal drugs are necessary.

[Comparison of salvage chemotherapy regimen ACES with ESHAP for refractory or relapsed malignant lymphoma].

Standard salvage chemotherapy for refractory or relapsed malignant lymphoma has not been defined. The efficacy and feasibility of the ACES regimen, consisting of carboplatin at 100 mg/m(2) on day 1 to 4, etoposide at 80 mg/m(2) on day 1 to 4, high-dose Ara-C at 2 g/m(2) on day 5 and methylprednisolone at 500 mg/day for 5 days, for refractory or relapsed lymphoma were retrospectively reviewed in comparison with the ESHAP regimen. The subjects were 29 patients, including 7 aggressive follicular lymphomas, 16 large B cell lymphomas and 6 Hodgkin lymphomas. Characteristics of patients with ESHAP (19 cases) and the ACES (10 cases) group were as follows: male/female ratio, 10/9 and 3/7; median age, 49 (range, 31-72) and 54 (22-65); and initial clinical stage (I and II / III / IV), 5/8/6 and 1/1/8, respectively. Among the 29 patients, complete response was achieved in 68% (13/19) in ESHAP and 40% (4/10) in ACES.Progression-free survival and overall survival were 31.3% and 34.3%, respectively. Hematological toxicity was not significantly different between the two groups, and renal toxicity was significantly higher in ESHAP (52%) than ACES (0%). We concluded that the ACES regimen had a possibility of effective consolidation therapy for the elderly aiming to undergo autologous stem cell transplantation.

[Comparison of regimen-related toxicity between high-dose melphalan and ICE as a preparatory regimen for autologous stem cell transplantation].

Chemotherapy-susceptive multiple myeloma (MM) has an indication for high-dose melphalan (HDM) followed by autologous stem cell transplantation (auto-SCT). HDM was a most simple and convenient regimen among various preparatory regimens, because of rapid infusion divided over 2 days. In order to assess the potential of auto-SCT by HDM in a outpatient setting, we evaluated the toxicities of HDM compared with the ICE regimen generally applied to patients with refractory or relapsed lymphoma. We reviewed 27 cases of auto-SCT from April 2003 to December 2004. The preparatory regimen was HDM (melphalan 200 mg/m(2)) for 18 cases of multiple myeloma and ICE therapy (ifosfamide 12 g/m (2), carboplatin 1,200 mg/m(2), etoposide 800 mg/m2) for 9 malignant lymphomas. Gastrointestinal (GI) adverse events for a patient per hospital day were 0.93 for myeloma and 0.95 for lymphoma (no significant differences), with GI toxicity of more than grade 3, 0.08 and 0.12, respectively (p=0.07). Hematological toxicity was not significantly different between the 2 therapies. The clinical toxicity of HDM was milder compared to ICE, especially regarding the speculated GI-associated nutritional disorders. We thus concluded that outpatient auto-SCT could be validated first in myeloma patients treated by HDM with careful supportive treatments, thereby avoiding regimen-related severe adverse events.