***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Despite aggressive and innovative therapy , patients with multiple myeloma ( MM ) invariably relapse and die of their disease . New options for non‐cytotoxic salvage therapy and additional therapeutic strategies are needed . Arsenic trioxide , an antitumour agent with a multifaceted mechanism of action , induces apoptosis in vitro in MM cell lines and freshly isolated cells from MM patients and , in preliminary studies , displayed clinical activity in patients with late‐stage MM . A phase 2 , multicentre , open‐label study of arsenic trioxide was conducted in 24 MM patients ; eight had relapsed and 16 were refractory to prior therapy . Patients received arsenic trioxide 0·25 mg/kg/d for 5 d/week during the first 2 weeks of each 4‐week cycle . Sixteen patients had grade 3 or 4 neutropenia  and one required antibiotics . Reductions ( 25 % or more ) in serum M‐protein levels occurred in eight of 24 ( 33 % ) patients . An additional six ( 25 % ) patients had stable disease . The median time to response was 67·5 d , with a median duration of response of 130 d. Arsenic trioxide therapy lowered serum creatinine levels in two patients with high baseline values . These data indicate that arsenic trioxide is active and reasonably well tolerated as a single‐agent salvage therapy , even in patients with late‐stage , relapsed and refractory MM In patients with multiple myeloma , there is pre clinical justification to combine arsenic trioxide ( ATO and As(2)O(3 ) ) with DVd ( Doxiltrade mark , vincristine , and dexamethasone ) for newly diagnosed patients . Eleven patients on this phase II trial received 0.15 mg/kg of ATO for five consecutive days followed by four cycles of DVd plus ATO with the ATO at 0.25mg/kg IV twice per week . The most common grade 3 toxicities were hyperglycemia , hyponatremia , and hypocalcemia . There were four partial and no complete responses . We could not demonstrate that the addition of ATO with this schedule improved the response rate of MM to DVd Arsenic has been used since ancient times as a therapeutic agent . However , until recently its use in modern medicine has been restricted to the treatment of a limited number of parasitic infections . In the early 1990s , reports from China described impressive results with arsenic trioxide in patients with de novo , relapsed , and refractory acute promyelocytic leukemia ( APL ) . Other investigators subsequently confirmed these results leading to approval of its use for relapsed or refractory APL in the United States . Investigations of this agent have demonstrated that its efficacy in APL and pre clinical tumor models is dependent upon a number of mechanisms , including induction of apoptosis , effects on cellular differentiation , cell cycling , and tumor angiogenesis . Subsequent pre clinical studies showed significant activity of arsenic trioxide in multiple myeloma ( MM ) . Based on this , in a phase II trial , we have evaluated the activity of arsenic trioxide in 14 patients with relapsed MM , refractory to conventional salvage therapy . With the dose and schedule used , treatment with arsenic trioxide produced responses in three patients and prolonged stable disease in a fourth patient , with the longest response lasting 6 weeks . Although treatment was reasonably well tolerated , in these patients with extensive prior therapy , 11 developed cytopenia , five associated with infectious complications and three developed deep vein thromboses . The results of this small trial support further investigation of this novel drug for the treatment of patients with relapsed or refractory MM Multiple myeloma ( MM ) characterized by proliferation of plasma cells in bone marrow and production of monoclonal immunoglobulin 's . Recently , arsenic trioxide ( ATO ) , has been considered for treatment refractory MM . We assessed the safety and efficacy of ATO for patients with refractory MM . A phase 2 , study of arsenic trioxide was conducted in 12 MM patients , whose refractory to two st and ard therapy . Patients received arsenic trioxide , 0.25 mg/kg/d for 5 d/week during the first 2 consecutive weeks of each 4-week cycle with 2 week rest . Patients who completed one 4-week cycle were evaluated for response to treatment . Twelve patients with refractory multiple myeloma received ATO . Disease assessment was based the amount of serum proteins electrophoresis . Of the10 patients ; stable disease was observed in four patients ( 33 % ) , progression disease in five patients ( 41.6 % ) , complete response in one patient ( 3.8 % ) and the remaining two patients could not be assessed for a response ( because of increased liver enzymes after the first week ) . Some adverse events : increase liver enzymes and serum creatinine , neutropenia , pruritus , nausea , vomiting , lower extremities edema , noninfectious diarrhea was observed . These results indicate that ATO is active and well tolerated as a single-agent salvage therapy , even in patients with late-stage , refractory MM We assessed the safety and efficacy of melphalan , arsenic trioxide ( ATO ) and ascorbic acid ( AA ) ( MAC ) combination therapy for patients with multiple myeloma ( MM ) who failed more than two different prior regimens . Patients received melphalan ( 0·1 mg/kg p.o . ) , ATO ( 0·25 mg/kg i.v . ) and AA ( 1 g i.v ) on days 1–4 of week 1 , ATO and AA twice weekly during weeks 2–5 and no treatment during week 6 of cycle 1 ; during cycles 2–6 , the schedule remained the same except ATO and AA were given twice weekly in week 1 . Objective responses occurred in 31 of 65 ( 48 % ) patients , including two complete , 15 partial and 14 minor responses . Median progression‐free survival and overall survival were 7 and 19 months respectively . Twenty‐two patients had elevated serum creatinine levels ( SCr ) at baseline , and 18 of 22 ( 82 % ) showed decreased SCr levels during treatment . Specific grade 3/4 haematological ( 3 % ) or cardiac adverse events occurred infrequently . Frequent grade 3/4 non‐haematological adverse events included fever/chills ( 15 % ) , pain ( 8 % ) and fatigue ( 6 % ) . This steroid‐free regimen was effective and well tolerated in this heavily pretreated group . These results indicate that the MAC regimen is a new therapeutic option for patients with relapsed or refractory MM Arsenic trioxide ( ATO ) is synergistic with ascorbic acid ( AA ) and melphalan against myeloma both in vitro and in vivo . The aim of this r and omized phase II trial was to determine the safety and efficacy of a combination of ATO , melphalan , and AA as preparative regimen in 48 patients undergoing autologous hematopoietic stem cell transplantation ( ASCT ) for multiple myeloma ( MM ) . Forty-eight patients received melphalan 200 mg/m2 i.v . over 2 days and AA 1000 mg i.v . over 7 days in 3 treatment arms : no ATO ( arm 1 ) , ATO 0.15 mg/kg i.v . x 7 days ( arm 2 ) , and ATO 0.25 mg/kg i.v . x 7 days ( arm 3 ) . No dose-limiting toxicity , engraftment failure , or nonrelapse mortality ( NRM ) was seen in the first 100 days post-ASCT . Complete responses ( CR ) were seen in 12 of 48 patients ( 25 % ) , with an overall response rate ( ORR = CR + PR ) of 85 % . Median progression-free survival ( PFS ) was 25 months ; median overall survival ( OS ) has not yet been reached . There was no significant difference in CR , PFS , or OS among the 3 treatment arms , and no adverse effect of ATO on melphalan pharmacokinetics . Addition of ATO + AA to high-dose melphalan is safe and well tolerated as a preparative regimen for MM Purpose : This Phase I study assessed the feasibility of concomitant arsenic trioxide ( ATO ) , ascorbic acid ( AA ) , and bortezomib ( Velcade ™ ) ( AAV ) for patients with relapsed/refractory multiple myeloma . Experimental Design : ATO ( 0.25 mg/kg ) and AA ( 1 g ) were given with an escalating dose of bortezomib ( 1 mg/m2 or 1.3 mg/m2 IV bolus on days 1 and 8 of a 21-day cycle ) . Results : Ten patients ( median age 62 years ) , with a median of 3 prior regimens , were enrolled . Four ( 40 % ) patients achieved clinical benefit , with one patient achieving a durable partial response . No formal DLTs were encountered . Conclusion : AAV combination was feasible and demonstrated some benefits in this heavily pretreated population Arsenic trioxide ( As2O3 ) is a known environmental toxicant and potent chemotherapeutic agent . Significant correlation has been reported between arsenic exposure ( including consumption of arsenic-contaminated water and clinical use of As2O3 ) and dysfunction in the nervous system . In this study , we aim ed to eluci date the effect of resveratrol with neuroprotective activities on As2O3-induced oxidative damage and cerebral cortex injury . Twenty-four healthy Chinese Dragon Li cats of either sex were r and omly divided into four groups : control ( 1 ml/kg physiological saline ) , As2O3 ( 1 mg/kg ) , resveratrol ( 3 mg/kg ) and As2O3 ( 1 mg/kg ) + resveratrol ( 3 mg/kg ) . As2O3+resveratrol-treated group were given resveratrol ( 3 mg/kg ) 1 h before As2O3 ( 1 mg/kg ) administration . Pretreatment with resveratrol upregulated the activities of antioxidant enzymes and attenuated As2O3-induced increases in reactive oxygen species and malondialdehyde production . In addition , resveratrol attenuated the As2O3-induced reduction in the level of reduced glutathione and the ratio of reduced glutathione to oxidised glutathione , and accumulation of arsenic in the cerebral cortex . These findings support neuroprotective effect of resveratrol on As2O3 toxicity in feline brain and provide a better underst and ing of the mechanism that resveratrol modulates As2O3-induced oxidative damage and a stronger rational for clinical use of resveratrol to protect brain against the toxicity of arsenic The therapeutic effect of arsenic trioxide ( As2O3 ) in the treatment of acute promyelocytic leukemia ( APL ) was evaluated among 15 APL patients at relapse after all-trans retinoic acid ( ATRA ) induced and chemotherapy maintained complete remission ( CR ) .  As2O3 was administered intravenously at the dose of 10 mg/d . Clinical CR was achieved in nine of 10 ( 90 % ) patients treated with As2O3 alone and in the remaining five patients treated by the combination of As2O3 and low-dose chemotherapeutic drugs or ATRA . During the treatment with As2O3 , there was no bone marrow depression and only limited side effects were encountered . Pharmacokinetic studies , which were performed in eight patients , showed that after a peak level of 5.54 micromol/L to 7.30 micromol/L , plasma arsenic was rapidly eliminated , and the continuous administration of As2O3 did not alter its pharmacokinetic behaviors . In addition , increased amounts of arsenic appeared in the urine , with a daily excretion accounting for approximately 1 % to 8 % of the total daily dose administered . Arsenic contents in hair and nail were increased , and the peak content of arsenic could reach 2.5 to 2.7 microg/g tissue at CR . On the other h and , a decline of the arsenic content in hair and nail was observed after withdrawal of the drug . We conclude that As2O3 treatment is an effective and relatively safe drug in APL patients refractory to ATRA and conventional chemotherapy Purpose : This multicenter , open-label , phase I/II dose escalation study assessed the safety/tolerability and initial efficacy of arsenic trioxide/bortezomib/ascorbic acid ( ABC ) combination therapy in patients with relapsed/refractory multiple myeloma . Experimental Design : Enrolled in six cohorts , patients were given arsenic trioxide ( 0.125 or 0.250 mg/kg ) , bortezomib ( 0.7 , 1.0 , or 1.3 mg/m2 ) , and a fixed dose of ascorbic acid ( 1 g ) i.v . on days 1 , 4 , 8 , and 11 of a 21-day cycle for a maximum of eight cycles . The primary end point was safety/tolerability of the ABC regimen . Results : Twenty-two patients ( median age , 63 years ) were enrolled , having failed a median of 4 ( range , 3 - 9 ) prior therapies . One occurrence of  grade 4 thrombocytopenia  was observed . One patient had  asymptomatic arrhythmia and withdrew from the study . Objective responses were observed in 6 ( 27 % ) patients , including two partial responses and four minor responses . Median progression-free survival was 5 months ( 95 % confidence interval , 
    Output:
    
Although ATO-based combination treatment was well tolerated by most patients , most trials found that ATO has limited effects on MM patients .