Non-operative Management of Spontaneous Gastropleural Fistula Caused by Primary Gastric Diffuse Large B-cell Lymphoma.

We herein report a 79-year-old man diagnosed with primary gastric diffuse large B-cell lymphoma (DLBCL) with gastropleural fistula (GPF), successfully treated by chemotherapy without surgery. If primary gastric DLBCL perforates during chemotherapy, surgery is often warranted. Our patient's computed tomography findings showed loculated pleural effusion with air foci in the left lower lobe, suggesting GPF. After six cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy, the fistula fully closed, and complete remission was achieved. In conclusion, while gastric DLBCL can exhibit spontaneous GPF, it can be treated with chemotherapy alone, which was well-tolerated in our patient.

Determination of Venetoclax Concentration in Plasma Using High-Performance Liquid Chromatography.

Venetoclax is an oral B-cell lymphoma-2 protein inhibitor. It is a key drug for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia. However, venetoclax is administered at a fixed dose, irrespective of body surface area or weight. Furthermore, the plasma concentration of venetoclax varies widely between individuals and is influenced by diet. Therefore, individualized dosing using therapeutic drug monitoring (TDM) may help to optimize treatment in clinical practice. In this study, we aimed to develop a simple method to determine venetoclax concentrations in plasma. The analysis required the extraction of a 50-µL plasma sample and precipitation of proteins using acetonitrile extraction. Venetoclax and the internal standard (12.5-µg/mL ibrutinib) were separated by high-performance liquid chromatography (HPLC). The calibration curve was linear over the plasma venetoclax concentration range 0.25-10 µg/mL with a coefficient of determination (r2) of 0.9999. The coefficients of intra-day and inter-day validation were 0.8-4.1% and 1.3-3.3%, respectively. The assay accuracy was -2.8 to 1.6%, and the recovery was >97.2%. These results demonstrate a very simple, novel and sensitive HPLC-UV-based method for determining the concentration of plasma venetoclax, and confirm its applicability to the TDM of venetoclax in a clinical setting.

Utility of therapeutic drug monitoring of venetoclax in acute myeloid leukemia.

The favorable outcomes of venetoclax-based regimens in older adults with acute myeloid leukemia (AML) may result in its regimen becoming the standard treatment. However, the dosage of venetoclax is fixed, irrespective of body surface area (BSA) or weight. Therefore, individualized dosing using therapeutic drug monitoring (TDM) may help optimize treatment in a safe and effective manner. Twelve patients with AML who received venetoclax-based treatment were enrolled in this study. Blood samples were collected before venetoclax administration, and the minimum plasma concentration (Cmin) was evaluated. The concentration of venetoclax was evaluated using a simple, sensitive, and cost-effective assay using high-performance liquid chromatography, as described previously. The median age was 74 (70-85) years. Ten patients received venetoclax in combination with azacitidine and one patient received low-dose cytarabine (LDAC). The patients BSA ranged from 1.345 to 1.912 m2 (median 1.543). The dose of venetoclax was 400 mg with azacitidine, and 600 mg with LDAC. In four patients who were taking CYP3A4 inhibitors, venetoclax was reduced to 50 mg according to the prescribing information. The Cmin ranged from 0.39 to 2.49, and the patient taking itraconazole showed highest Cmin regardless of the reduction of venetoclax. Most patients showed higher Cmin compared to the data from previous clinical trials, and BSA and venetoclax concentrations showed a negative correlation. Many Asian AML patients > 75 years old are petite and receive CYP3A4 inhibitors. Therefore, the TDM of venetoclax may be useful.

High-Performance Liquid Chromatography for Ultra-Simple Determination of Plasma Voriconazole Concentration.

Voriconazole is an antifungal drug used to treat invasive aspergillosis. Voriconazole exhibits nonlinear behavior and considerable individual variability in its pharmacokinetic profile. Invasive aspergillosis has a poor prognosis, and failure of treatment owing to low voriconazole blood levels is undesirable. Thus, therapeutic drug monitoring (TDM) of voriconazole is recommended. However, plasma voriconazole concentration is rarely measured in hospitals, and the TDM of voriconazole is not widely practiced in Japan. We aimed to develop an ultra-simple method to measure plasma voriconazole concentration. Ten microliters of plasma sample was extracted, and proteins were precipitated using methanol extraction. Voriconazole and ketoconazole (internal standard) were separated using high-performance liquid chromatography. A calibration curve was prepared, which was linear over plasma voriconazole concentrations of 0.125−12.5 µg/mL, with a coefficient of determination of 0.9999. The intra-day and inter-day validation coefficients were 0.9−2.2% and 1.3−6.1%, respectively. The assay accuracy was −4.2% to 1.6%, and recovery was >97.8%. Our ultra-simple, sensitive, and inexpensive high-performance liquid chromatography ultraviolet method to determine plasma voriconazole concentration will help improve the voriconazole TDM implementation rate and contribute to effective and safe voriconazole use.

Primary splenic histiocytic sarcoma successfully treated with splenectomy: a case report and literature review.

A 61-year-old woman was referred to our hospital with refractory thrombocytopenia and splenomegaly. She was diagnosed with immune thrombocytopenia 3 years prior to admission and received steroid therapy. However, her platelet count started decreasing six months prior to admission. A diagnostic and therapeutic splenectomy was performed, which led to the diagnosis of histiocytic sarcoma. The patient's platelet count recovered promptly after splenectomy, and she was in complete remission for over a year.

Challenging Diagnosis of Pure Erythroid Leukemia: A Case Report and Literature Review.

Pure erythroid leukemia (PEL) is an extremely rare type of acute myeloid leukemia (AML), accounting for fewer than 1% of all AML cases. A 72-year-old man presented with severe fatigue. His bone marrow aspiration contained myeloperoxidase negative abnormal cells that were aggregating and depicting epithelial adhesion, suggesting the possibility of solid tumor metastasis. His general condition deteriorated during medical diagnosis, and he died soon after starting chemotherapy. PEL appeared to be the definitive diagnosis after evaluating the histopathological findings, which were obtained after his death. With atypical morphological features, immunophenotypic and karyotypic approaches must be integrated for PEL assessment.

Feasibility of the imatinib stop study in the Japanese clinical setting: delightedly overcome CML expert stop TKI trial (DOMEST Trial).

BACKGROUND: Treatment-free remission (TFR), the ability to maintain a molecular response (MR), occurs in approximately 50% of patients with chronic myelogenous leukemia (CML) treated with tyrosine kinase inhibitors (TKIs). METHODS: A multicenter phase 2 trial (Delightedly Overcome CML Expert Stop TKI Trial: DOMEST Trial) was conducted to test the safety and efficacy of discontinuing imatinib. Patients with CML with a sustained MR of 4.0 or MR4.0-equivalent for at least 2 years and confirmed MR4.0 at the beginning of the study were enrolled. In the TFR phase, the international scale (IS) was regularly monitored by IS-PCR testing. Molecular recurrence was defined as the loss of MR4.0. Recurrent patients were immediately treated with dasatinib or other TKIs including imatinib. RESULTS: Of 110 enrolled patients, 99 were evaluable. The median time from diagnosis to discontinuation of imatinib was 103 months, and the median duration of imatinib therapy was 100 months. Molecular recurrence-free survival rates were 69.6%, 68.6% and 64.3% at 6, 12, and 24 months, respectively. After discontinuation of imatinib therapy, 26 patients showed molecular recurrence, and 25 re-achieved deep MR after dasatinib treatment. Molecular response MR4.0 was achieved in 23 patients within 6 months and 25 patients within 12 months. Multivariate analysis revealed that a longer time from diagnosis to discontinuation of imatinib therapy (p = 0.0002) and long duration of imatinib therapy (p = 0.0029) predicted a favorable prognosis. CONCLUSIONS: This DOMEST Trial showed the feasibility of TKI discontinuation in a Japanese clinical setting.

[A case of primary effusion lymphoma with elevation of ADA activity in pleural effusion].

A 74-year-old man was referred to our hospital with complaint of dyspnea and left pleural effusion. The pleural effusion was exudative and lymphocytic with elevation of adenosine deaminase (ADA). Antitubercular agents were administered on a diagnosis of tuberculous pleuritis, but the pleural effusion did not improve. After he had been followed up with diuretic agents during about 2 years, he suffered cardiac tamponade and right pleural effusion. We diagnosed primary effusion lymphoma based on the cytology findings of the pleural effusion. The measurement of ADA activity in pleural effusions was useful for diagnosis of tuberculous pleuritis, but not only tuberuculous pleuritis but also lymphoma or other diseases can show elevation of ADA activity in pleural effusions.

A case presenting with rapid renal damage caused by immunoglobulin D lambda-type multiple myeloma accompanied by granular lymphocyte proliferative disorder.

A 69-year-old man was referred to our hospital for severe anemia. The atypical lymphocyte count, including granular lymphocytes, was 2,750/µL. Lymphocyte surface marker analysis showed CD3+, CD5+, CD16+, and CD56+ cells. Mixed T cell- and natural killer cell-type granular lymphocyte proliferative disorder (GLPD) was diagnosed. Because his serum creatinine levels deteriorated rapidly over the next 3 months, from 0.96 to 3.27 mg/dL, he was admitted to our hospital. The serum levels of immunoglobulins (Ig) other than IgD had decreased, and monoclonal protein was detected in the gamma-globulin region. Immunoelectrophoresis revealed IgD and lambda (λ) proteins in the serum and λ-type Bence-Jones protein in the urine. Renal biopsy examination revealed widespread tubular atrophy and interstitial fibrosis, and cast formation with λ protein deposits in tubular lumens, indicating cast nephropathy. These results indicated that the rapid renal damage was caused by IgD λ-type multiple myeloma accompanied by GLPD. The clinical course of GLPD is not usually aggressive and the findings of physical examinations are not significant. GLPD is usually associated with cytopenia (neutropenia or anemia), viral infections, collagen diseases, neoplasms such as malignant lymphoma, or chronic infections. To date, there are only 2 case reports of GLPD accompanied by multiple myeloma but without renal function or renal histological findings. When the clinical course of GLPD is aggressive and is accompanied with rapid renal damage, multiple myeloma should be considered as a complication.

Influenza A infection triggers thrombotic thrombocytopenic purpura by producing the anti-ADAMTS13 IgG inhibitor.

A 68-year-old Japanese woman infected with influenza A developed thrombotic thrombocytopenic purpura (TTP) 2 days after having a fever. Routine laboratory tests on admission suggested a diagnosis of disseminated intravascular coagulation. However, ADAMTS13 assays showed an extremely low level of plasma ADAMTS13 activity with a high titer of anti-ADAMTS13 inhibitor (IgG). Despite high-dose methylprednisolone therapy with daily plasma exchange for 3 consecutive days, the patient died of pulmonary congestion complicated by cardiac failure. Our experience here provides the first evidence that influenza A infection is sufficient to trigger TTP by producing the anti-ADAMTS13 IgG inhibitor.

CD34+CD7+ leukemic progenitor cells may be involved in maintenance and clonal evolution of chronic myeloid leukemia.

PURPOSE: We analyzed CD34+ cells coexpressing CD7 in chronic myeloid leukemia (CML) in chronic phase (CP) or accelerated phase (AP) to clarify their role in progression or regression of the disease during treatment. EXPERIMENTAL DESIGN: Enumeration of CD34+CD7+ cells was done on bone marrow nucleated cells from normal donors and CML patients. Fluorescence in situ hybridization analysis was done on sorted CD34+CD7+and CD34+CD7- cells to examine the occupancy rate of each fraction by BCR-ABL+ cells with or without additional cytogenetic abnormalities. RESULTS: The proportion of CD34+CD7+cells was significantly affected by the treatment outcome and/or the disease status as follows: 20.5 +/- 10.4% in normal donors (n = 22), 18.1 +/- 10.2% in CP with major cytogenetic response (n = 14), 53.0 +/- 12.9% in CP at diagnosis (n = 18), 55.0 +/- 15.8% in CP with minor or no cytogenetic response (n = 28), and 70.2 +/- 18.1% in AP (n = 6). The proportion of CD34+CD7+cells decreased in parallel with cytogenetic improvement in individual patients. In six untreated CP patients, the ratio of BCR-ABL+ cells was comparable between each fraction. In three patients with major cytogenetic response, the ratio of BCR-ABL+ cells was remarkably lower in CD34+CD7- cells than in CD34+CD7+cells. In three AP patients with additional cytogenetic abnormalities, extra signals were detected at a much higher rate in CD34+CD7+ cells than in CD34+CD7- cells. CONCLUSIONS: Our results suggest that CD34+CD7+ cells may be involved in maintenance and clonal evolution of BCR-ABL+ cells in CML.

A case of Epstein-Barr virus-associated natural killer/T-cell lymphoma presenting as dermatomyositis: extranodal relapse after 7 years in remission.

A 56-year-old Japanese man was admitted to our hospital due to a fever of unknown origin. He had had a history of extranodal natural killer (NK)/T-cell lymphoma, nasal type, and had been in complete remission for 7 years until June 2003, when he developed high fever, eyelid swelling, and muscular weakness. Serum creatine kinase levels were elevated. Histopathological examination of skin and muscle biopsy specimens revealed subcutaneous infiltration of lymphoid cells positive for CD3, CD56, and Epstein-Barr virus-encoded small nuclear RNA-1. We report this unique case of Epstein-Barr virus-associated lymphoma mimicking dermatomyositis.