A multicentre phase II study of vorinostat in patients with relapsed or refractory indolent B‐cell non‐Hodgkin lymphoma and mantle cell lymphoma

Although initial rituximab‐containing chemotherapies achieve high response rates, indolent B‐cell non‐Hodgkin lymphoma (B‐NHL), such as follicular lymphoma (FL), is still incurable. Therefore, new effective agents with novel mechanisms are anticipated. In this multicentre phase II study, patients with relapsed/refractory indolent B‐NHL and mantle cell lymphoma (MCL) received vorinostat 200 mg twice daily for 14 consecutive days in a 21‐d cycle until disease progression or unacceptable toxicity occurred. The primary endpoint was overall response rate (ORR) in FL patients and safety and tolerability in all patients. Secondary endpoints included progression‐free survival (PFS). Fifty‐six eligible patients were enrolled; 50 patients (39 with FL, seven with other B‐NHL, and four with MCL) were evaluable for ORR, and 40 patients had received rituximab‐containing prior chemotherapeutic regimens. For the 39 patients with FL, the ORR was 49% [95% confidence interval (CI): 32·4, 65·2] and the median PFS was 20 months (95% CI: 11·2, 29·7). Major toxicities were manageable grade 3/4 thrombocytopenia and neutropenia. Vorinostat offers sustained antitumour activity in patients with relapsed or refractory FL with an acceptable safety profile. Further investigation of vorinostat for clinical efficacy is warranted.     

A case of bleeding duodenal ulcer with pemphigus vulgaris during steroid therapy

We report a rare case of bleeding duodenal ulceration in the different form of pemphigus vulgaris (PV). A 52-year-old female was diagnosed with acute pharyngitis and administered methylprednisolone. After several days, melena and many blisters were noted on her body. Endoscopy revealed blood oozing from the second part of a duodeneal ulcer around the major duodenal papilla. After initial endoscopic hemostasis, we observed a large regional, shallow duodenal ulcer. The blisters were suspected to represent the Nikolsky’s sign. The histological findings of her skin were characterized by suprabasal acantholysis and mixed inflammatory cell infiltrates, including scattered eosinophils. There were no other significant findings on skin biopsy or by direct immunofluorescence. Enzyme-linked immunosorbent assay showed an elevated titer of anti-desmoglein 3 autoantibodies in her serum, and the patient was finally diagnosed with mucosal-dominant PV. Although we performed multiple biopsies from the esophagus, stomach and duodenum, the samples did not contain significant findings to enable us to distinguish from pemphigus vulgaris. Corticosteroids remain an essential component of PV treatment. When clinicians encounter PV development during steroid therapy, upper gastrointestinal complications should be considered and diagnostic endoscopy conducted.     

The immunobiology of colitis and cholangitis in interleukin-23p19 and interleukin-17a deleted dominant negative form of transforming growth factor beta receptor type ii mice

Dominant negative form of transforming growth factor beta receptor type II (dnTGFβRII) mice, expressing a dominant negative form of TGFβ receptor II under control of the CD4 promoter, develop autoimmune colitis and cholangitis. Deficiency in interleukin (IL)-12p40 lead to a marked diminution of inflammation in both the colon and the liver. To distinguish whether IL-12p40 mediates protection by the IL-12 or IL-23 pathways, we generated an IL-23p19(-/-) dnTGFβRII strain deficient in IL-23, but not in IL-12; mice were longitudinally followed for changes in the natural history of disease and immune responses. Interestingly, IL-23p19(-/-) mice demonstrate dramatic improvement in their colitis, but no changes in biliary pathology; mice also manifest reduced T-helper (Th)17 cell populations and unchanged IFN-γ levels. We submit that the IL-12/Th1 pathway is essential for biliary disease pathogenesis, whereas the IL-23/Th17 pathway mediates colitis. To further assess the mechanism of the IL-23-mediated protection from colitis, we generated an IL-17A(-/-) dnTGFβRII strain deficient in IL-17, a major effector cytokine produced by IL-23-dependent Th17 cells. Deletion of the IL-17A gene did not affect the severity of either cholangitis or colitis, suggesting that the IL-23/Th17 pathway contributes to colon disease in an IL-17-independent manner. These results affirm that the IL-12/Th1 pathway is critical to biliary pathology in dnTGFβRII mice, whereas colitis is caused by a direct effect of IL-23. (HEPATOLOGY 2012).     

A case of malignant peritoneal mesothelioma successfully treated with systemic chemothrapy

A 64-year-old man with a 2-month history of abdominal distension was admitted for transient cerebral ischemic attack. A CT scan revealed massive ascites. Laparoscopy showed multiple whitish nodules on the visceral peritoneum and the omentum. Peritoneal biopsy revealed tumor cells consistent with malignant peritoneal mesothelioma (MPeM). Pemetrexed in combination with cisplatin was administered because it has been reported to be active in patients with MPeM. However his disease progressed. As second-line therapy paclitaxel was tried which yielded a complete response (CR). Eighteen months later he developed abdominal pain of the right upper region where a CT scan showed a mass with surrounding inflammation. As third-line therapy, gemcitabine was administered and again resulted in a CR. He is alive at 3 years from first presenting. Searches for case studies published in medical journals on MPeM were carried out, and 59 cases were analyzed in comparison with this case.     

Effects of tacrolimus on dermatomyositis and polymyositis: a prospective, open, non-randomized study of nine patients and a review of the literature

Dermatomyositis (DM) and polymyositis (PM) are often refractory to conventional therapy with corticosteroids sometimes combined with immune-suppressing agents and can lead to severe disability if these treatments are unsuccessful. In this prospective, open, non-randomized study, we examined the efficacy of tacrolimus (FK506), an immunosuppressant, in nine patients with DM (n?=?5) or PM (n?=?4) who did not respond to previous therapy. Outcomes included compound muscle strength, ambulatory status, and serum creatine kinase activity measured at intervals after starting tacrolimus. At 6?months after the introduction of tacrolimus, all five patients with DM and three patients with PM showed clinical improvements. Patients with a disease duration of <4?years and those with trough level of tacrolimus >5?ng/ml tended to have better outcomes than those with longer disease duration or lower trough levels. There were no side effects other than moderate hypertension and aggravation of diabetes mellitus. Tacrolimus was beneficial in the majority of patients with PM or DM refractory to corticosteroid therapy. It was also effective in four patients who were previously treated with other immunosuppressants or intravenous immunoglobulin combined with corticosteroids. These results warrant further studies as to the efficacy of tacrolimus compared to other immunosuppressing agents.