Australian wildfires depleted the ozone layer.

Various mechanisms initiated by wildfires thinned the stratospheric ozone layer.

A phase IIb trial of vorinostat in combination with lenalidomide and dexamethasone in patients with multiple myeloma refractory to previous lenalidomide-containing regimens.

Clinical trials of vorinostat, a Class I/II histone deacetylase inhibitor, in combination with proteasome inhibitors and immunomodulatory agents have shown activity in relapsed/refractory multiple myeloma. This phase IIb, open-label, single-institution study evaluated the efficacy of vorinostat in combination with lenalidomide and dexamethasone in lenalidomide-refractory patients. Patients were considered lenalidomide-refractory if they had no clinical response (

Vorinostat in Combination With Lenalidomide and Dexamethasone in Lenalidomide-Refractory Multiple Myeloma.

BACKGROUND: This is a retrospective chart review to evaluate the efficacy of the addition of vorinostat to lenalidomide and dexamethasone in patients with multiple myeloma relapsed/refractory to lenalidomide and dexamethasone. METHODS: Charts from 26 consecutive patients able to obtain commercial vorinostat were analyzed for response and safety data. RESULTS: The overall response rate was 31%, and the clinical beneficial rate was 50%. The median duration of response was 3 months, and the median overall survival was 28.5 months. The most common grade 3 and 4 toxicities were hematologic and metabolic, including neutropenia (44%), thrombocytopenia (53%), and transaminase elevations (aspartate aminotransferase 9% and alanine aminotransferase 6%). No thromboembolic events or febrile neutropenia were observed. CONCLUSION: These observations demonstrate that the addition of vorinostat to patients with lenalidomide- and dexamethasone-refractory multiple myeloma was associated with moderate response and was well-tolerated, warranting further assessment in a larger prospective study.

Phase I study of carfilzomib, lenalidomide, vorinostat, and dexamethasone in patients with relapsed and/or refractory multiple myeloma.

Research has shown that proteasome inhibitors (e.g., carfilzomib), immunomodulatory agents (e.g., lenalidomide), histone deacetylase inhibitors (e.g., vorinostat) and corticosteroids (e.g., dexamethasone) have synergistic anti-multiple myeloma (MM) activity. This phase I dose-escalation study evaluated a regimen combining carfilzomib, lenalidomide, vorinostat and dexamethasone (QUAD) in patients with relapsed and/or refractory MM. Seventeen patients received carfilzomib (15, 20, or 20/27 mg/m(2) ; 30-min infusion; days 1, 2, 8, 9, 15, 16), lenalidomide (15 or 25 mg; days 1-21), vorinostat (300 or 400 mg; days 1-7, 15-21), and dexamethasone (40 mg; days 1, 8, 15, 22) in 28-d cycles. No dose-limiting toxicities were observed; the maximum tolerated dose was not reached. The maximum administered dose was carfilzomib 20/27 mg/m(2) , lenalidomide 25 mg, vorinostat 400 mg, and dexamethasone 40 mg. Common grade ≥3 adverse events included neutropenia (53%), thrombocytopenia (53%) and anaemia (41%). The overall response rate was 53%: 12% of patients achieved a very good partial response (PR) and 41% of patients achieved a PR. At a median follow-up of 10 months, median progression-free survival was 12 months and median overall survival was not reached. Treatment with QUAD was feasible and had encouraging activity in patients with relapsed and/or refractory MM.

Phase 1 study of pomalidomide MTD, safety, and efficacy in patients with refractory multiple myeloma who have received lenalidomide and bortezomib.

This phase 1 dose-escalation study determined the maximum tolerated dose (MTD) of oral pomalidomide (4 dose levels) administered on days 1 to 21 of each 28-day cycle in patients with relapsed and refractory multiple myeloma (RRMM). After four cycles, patients who progressed or had not achieved minimal response (serum and urine M-protein reduction of ≥ 25% and ≥ 50%) could receive dexamethasone 40 mg per week. Safety and efficacy were evaluated. Thirty-eight patients who had received both bortezomib and lenalidomide (median 6 prior therapies) were enrolled; 63% were refractory to both lenalidomide and bortezomib. There were four dose-limiting toxicities (grade 4 neutropenia) at 5 mg per day and so the MTD was 4 mg per day. Rates of peripheral neuropathy and venous thromboembolism were low (≤ 5%). Among the 38 patients enrolled (including 22 with added dexamethasone), 42% achieved minimal response or better, 21% achieved partial response or better, and 3% achieved complete response. Median duration of response, progression-free survival, and overall survival were 4.6, 4.6, and 18.3 months, respectively. Pomalidomide 4 mg per day on days 1 to 21 of each 28-day cycle, with or without dexamethasone (40 mg/week), has encouraging activity with manageable toxicity in RRMM, including those refractory to both lenalidomide and bortezomib. This study is registered at http://www.clinicaltrials.gov as #NCT00833833.

Phase II trial of syncopated thalidomide, lenalidomide, and weekly dexamethasone in patients with newly diagnosed multiple myeloma.

UNLABELLED: Thalidomide and lenalidomide, in combination with dexamethasone, provide response rates ranging from 63%-79% after 4 cycles of therapy. Because of toxicities such as neuropathy and myelosuppression for thalidomide and lenalidomide, respectively, dose escalation has not been pursued. We evaluated a syncopated regimen of alternating weeks of thalidomide and lenalidomide to determine if a modified schedule allows for fewer dose reductions and, subsequently, superior efficacy. Although well tolerated, this phase II trial did not show superior efficacy compared with conventional dosing and scheduling of these agents. INTRODUCTION: Over the past decade, the novel agents thalidomide, lenalidomide, and bortezomib have emerged as effective treatment in patients with multiple myeloma (MM). Initially used in the relapse setting, these agents have been incorporated into frontline treatment algorithms. They have been combined in doublets with corticosteroids, in triplets with alkylators, or with each other. Because thalidomide and lenalidomide have different clinical activity and toxicity profiles, we designed a trial to evaluate a syncopated schedule of thalidomide and lenalidomide with weekly dexamethasone in patients with newly diagnosed MM to determine response and toxicity. PATIENTS AND METHODS: Twenty-two patients with newly diagnosed MM were treated with syncopated thalidomide (200 mg on days 1-7 and 15-21), lenalidomide (25 mg on days 8-14 and 22-28 for the first cycle and 50 mg on the same schedule for subsequent cycles) with weekly dexamethasone (40 mg). Each cycle lasted 28 days. MM parameters were assessed at the end of each cycle. It was intended that the patients proceed to stem cell mobilization and autologous transplantation after 4 cycles of therapy. RESULTS: The median number of cycles administered was 3.5. The overall response was 68%. The regimen was well tolerated by the majority of the patients; only patient discontinued treatment because of toxicity. CONCLUSION: We conclude that a syncopated schedule of thalidomide and lenalidomide with weekly dexamethasone was tolerated well, with no unexpected toxicities. However the response rate, even using lenalidomide at 50 mg, was not superior to standard dosing of thalidomide or lenalidomide plus dexamethasone.

The anion gap and routine serum protein measurements in monoclonal gammopathies.

BACKGROUND AND OBJECTIVES: An abnormal anion gap and an increased total protein and globulin are clues to the diagnosis of monoclonal gammopathy. We explored the utility of these markers in IgG, IgA, IgM, and free light chain monoclonal gammopathies. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The anion gap, Na(+) - (Cl(-) + HCO(3)(-)), corrected for hypoalbuminemia, was calculated in patients with monoclonal gammopathies. Exclusion criteria were serum calcium >10.5 mg/dl and/or creatinine >2 mg/dl. RESULTS: Among 287 patients, 242 remained after applying exclusion criteria (109 IgG, 64 IgA, 21 IgM, and 48 light chain); 36% of 242 patients required correction for hypoalbuminemia. The anion gap was decreased (<10) in 22% of IgG and increased (>15) in 31% of IgA monoclonal gammopathies. IgM did not affect the gap. In light chain gammopathies, the anion gap showed no consistent trend (15% increased, 17% decreased). Mean clonal IgG, IgA, and IgM concentrations were 10-fold higher than mean clonal free light chain concentrations in the respective monoclonal gammopathies (P < 0.001). These paraprotein level disparities were reflected in significantly increased mean serum total protein and globulin concentrations in IgG, IgA, and IgM versus free light chain monoclonal gammopathies, where mean total protein and globulin levels were within normal limits (P < 0.001). CONCLUSIONS: The anion gap was significantly altered in IgG and IgA monoclonal gammopathies, but it was not a sensitive tool for suspecting the diagnosis. In light chain monoclonal gammopathies, the anion gap, total protein, and globulin did not provide reliable diagnostic clues.

TIRAP Ser180Leu polymorphism is associated with Behcet's disease.

OBJECTIVES: The initiating cause of Behçet's disease (BD) is unknown, but an aberrant response to infection has been suggested. In this study, single nucleotide polymorphisms in Toll-like receptors (TLRs) and associated molecules that have a sentinel function at mucosal surfaces were analysed in patients with BD. METHODS: TLR expression was determined by immunohistochemistry in buccal mucosal tissue from patients with BD, in tissue from patients with lichen planus (LP) or pyogenic granuloma (PG) as disease controls, or from healthy individuals. Using SSP-PCR we analysed SNP in CD14, TLR2, TLR4 and TIRAP (TIR domain-containing adaptor protein) in patients with BD from different geographical regions. RESULTS: TLR expression was increased in buccal lesions from patients with BD compared with healthy controls; however, a similar increase was seen in lesion tissue from patients with LP or PG, suggesting that this was a generalized inflammatory response as opposed to a BD-specific response. SNP analysis showed no association between CD14, TLR2 or TLR4 polymorphisms. However, TIRAP 180Leu was significantly associated with BD in UK, but not Middle Eastern, patients. CONCLUSION: TLR expression showed no difference in tissue from patients with BD compared with either disease or healthy controls. Likewise, SNPs in TLR genes were no different from healthy controls. The association with the increased function variant of TIRAP suggests that encounter with a pathogen at mucosal sites will lead to increased cytokine production and tissue damage with persistence of mucosal lesions.

Phase I trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) in patients with advanced multiple myeloma.

A Phase I trial (NCT00109109) of oral vorinostat 200, 250 or 300 mg twice daily for 5 days/week/4-week cycle or 200, 300, or 400 mg twice daily for 14 days/3-week cycle until progressive disease or intolerable toxicity was conducted. Patients with measurable, relapsed/refractory multiple myeloma were eligible. The objectives were to determine maximum tolerated doses (MTDs) and assess activity and safety. Thirteen patients (median age, 63 years; median prior therapies, 3) were enrolled. MTDs were not determined due to early study termination by sponsor decision. One patient (250 mg twice daily 5 days/week) developed dose-limiting toxicity (DLT; grade 3 fatigue). There were no other DLTs and the maximum administered doses were 250 mg twice daily for 5 days/week/4-week cycle and 200 mg twice daily for 14 days/3-week cycle. Drug-related adverse experiences included fatigue, anorexia, dehydration, diarrhea, and nausea and were mostly grade