[Immune-mediated neuropathy with anti-ganglioside antibodies in diffuse large B-cell lymphoma].

A 70-year-old man having a mass lesion on his right lower abdomen for 2 months was admitted to our hospital for diagnosis. Upon admission, the patient experienced bilateral upper and lower limb weakness, which aggravated. He underwent nerve conduction study and was diagnosed with axonal neuropathy. Diagnosis of diffuse large B-cell lymphoma (DLBCL) was accomplished via biopsy of the mass lesion, with positive laboratory tests for anti-ganglioside antibodies. Based on these results, immune-mediated DLBCL-induced polyneuropathy was suspected, and chemotherapy (R-CHOP) was immediately started. Limb weakness improved and completely resolved. After six courses of R-CHOP, no evidence of DLBCL was observed on PET/CT (i.e., complete metabolic remission). The patient lived without DLBCL relapse or neurological symptoms after remission. Only few reports regarding immune-mediated polyneuropathy induced by malignant lymphoma are available in the literature, which, together with this case, suggest that prompt control of malignant lymphoma is crucial for favorable prognosis of neuropathy.

Phase II study of oral fludarabine in combination with rituximab for relapsed indolent B-cell non-Hodgkin lymphoma.

Oral fludarabine is more convenient than intravenous fludarabine in an outpatient setting. To assess the efficacy and toxicity of oral fludarabine in combination with rituximab in patients with relapsed indolent B-cell non-Hodgkin lymphoma (B-NHL), we conducted a multicenter phase II study. Patients with relapsed indolent B-NHL with two or fewer prior regimens and up to 16 doses of rituximab were eligible. Patients received 375 mg/m(2) rituximab on day 1, and 40 mg/m(2) oral fludarabine once daily on days 1 through 5 every 28 days for up to six cycles. The primary endpoint was the overall response rate. Forty-one patients were enrolled, including 38 (93%) with follicular lymphoma. Thirty-four patients (83%) had received rituximab as prior therapy. Twenty-seven patients (66%) completed the planned six cycles. Dose reduction of oral fludarabine was required in 17 patients (41%). The overall response rate was 76% (31 of 41 patients; 95% confidence interval, 60-88%) with a complete response rate of 68% (28 of 41 patients; 95% confidence interval, 52-82%). Median progression-free survival for the 41 patients was 19.7 months (95% confidence interval, 12.3-26.5 months). Hematological toxicities, including grade 4 neutropenia (68%), were the most frequent toxicities. Non-hematological toxicities were mild, except for one patient who died of Pneumocystis jiroveci pneumonia 4 months after the protocol treatment. In conclusion, oral fludarabine in combination with rituximab is a highly effective and convenient therapy for patients with relapsed indolent B-NHL who have mostly been pretreated with rituximab.

Efficacy and safety of dasatinib versus imatinib in Japanese patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP): Subset analysis of the DASISION trial with 2-year follow-up.

Dasatinib is a highly potent BCR-ABL kinase inhibitor with established efficacy and safety in imatinib-resistant or -intolerant patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia. In the global phase III DASISION trial in patients with newly diagnosed chronic phase CML (CML-CP), dasatinib was found to have an acceptable safety profile and demonstrated significantly faster and higher rates of complete cytogenetic response (CCyR) and major molecular response (MMR) compared with imatinib. Here, we report the results of a subset analysis of Japanese patients enrolled in the DASISION trial, showing safety and efficacy profiles generally consistent with patients enrolled worldwide, including higher response rates (CCyR, MMR) with dasatinib compared with imatinib and similar high rates of progression-free and overall survival with both therapies. However, the small sample size of the present study limits the strength of these conclusions, and further exploration is needed to confirm any differences observed in Japanese patients compared with the total treated population. These findings support the use of dasatinib 100 mg QD as a first-line treatment in Japanese patients with newly diagnosed CML-CP.

Rac1 GTPase in rodent kidneys is essential for salt-sensitive hypertension via a mineralocorticoid receptor-dependent pathway.

Hypertension is a leading contributor to cardiovascular mortality worldwide. Despite this, its underlying mechanism(s) and the role of excess salt in cardiorenal dysfunction are unclear. Previously, we have identified cross-talk between mineralocorticoid receptor (MR), a nuclear transcription factor regulated by the steroid aldosterone, and the small GTPase Rac1, which is implicated in proteinuric kidney disease. We here show that high-salt loading activates Rac1 in the kidneys in rodent models of salt-sensitive hypertension, leading to blood pressure elevation and renal injury via an MR-dependent pathway. We found that a high-salt diet caused renal Rac1 upregulation in salt-sensitive Dahl (Dahl-S) rats and downregulation in salt-insensitive Dahl (Dahl-R) rats. Despite a reduction of serum aldosterone levels, salt-loaded Dahl-S rats showed increased MR signaling in the kidneys, and Rac1 inhibition prevented hypertension and renal damage with MR repression. We further demonstrated in aldosterone-infused rats as well as adrenalectomized Dahl-S rats with aldosterone supplementation that salt-induced Rac1 and aldosterone acted interdependently to cause MR overactivity and hypertension. Finally, we confirmed the key role of Rac1 in modulating salt susceptibility in mice lacking Rho GDP-dissociation inhibitor α. Therefore, our data identify Rac1 as a determinant of salt sensitivity and provide insights into the mechanism of salt-induced hypertension and kidney injury.

Phase 1/2 clinical study of dasatinib in Japanese patients with chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia.

A phase 1/2 study was conducted to assess the safety and efficacy of dasatinib in Japanese patients with chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) resistant or intolerant to imatinib. In phase 1, 18 patients with chronic phase (CP) CML were treated with dasatinib 50, 70, or 90 mg twice daily to evaluate safety. Dasatinib

Phase II study of oral fludarabine phosphate in relapsed indolent B-Cell non-Hodgkin's lymphoma.

PURPOSE: Although intravenous (IV) fludarabine phosphate is effective against indolent B-cell non-Hodgkin's lymphoma (B-NHL), IV administration for 3 to 5 consecutive days is inconvenient in an outpatient setting. To assess the efficacy and toxicity of oral fludarabine phosphate in patients with indolent B-NHL, we conducted a multicenter phase II study. PATIENTS AND METHODS: Patients with relapsed indolent B-NHL received fludarabine phosphate tablets orally once daily on days 1 through 5 every 28 days for three to six cycles. The efficacy was separately analyzed in a mantle-cell lymphoma (MCL) cohort and indolent B-NHL except for MCL (IL) cohort. The primary end point was the overall response rate (ORR). RESULTS: Fifty-two patients, including 46 in the IL cohort (41 with follicular lymphoma) and six in the MCL cohort, were registered, and all patients were eligible. Forty-one patients (79%) had received rituximab as prior therapy. In the IL cohort, the ORR and complete response rate were 65% (30 of 46 patients; 95% CI, 50% to 79%) and 30% (14 of 46 patients; 95% CI, 18% to 46%), respectively. One of six patients with MCL achieved a partial response. The median times to treatment failure for the 46 patients in the IL cohort and for the six patients in the MCL cohort were 8.6 and 6.1 months, respectively. Hematologic toxicities, including grade 4 neutropenia (37%), were the most frequent toxicities, and nonhematologic toxicities were mild. CONCLUSION: Oral fludarabine phosphate is highly effective in patients with relapsed indolent B-NHL who have mostly been pretreated with rituximab and is more convenient than the IV formulation.