Replacement of daily load attenuates but does not prevent changes to the musculoskeletal system during bed rest.

The dose-response effects of exercise in reduced gravity on musculoskeletal health have not been well documented. It is not known whether or not individualized exercise prescriptions can be effective in preventing the substantial loss in bone mineral density and muscle function that have been observed in space flight and in bed rest. In this study, typical daily loads to the lower extremities were quantified in free-living subjects who were then randomly assigned to control or exercise groups. Subjects were confined to 6-degree head-down bed rest for 84 days. The exercise group performed individually prescribed 1 g loaded locomotor exercise to replace their free-living daily load. Eleven subjects (5 exercise, 6 control) completed the protocol. Volumetric bone mineral density results from quantitative computed tomography demonstrated that control subjects lost significant amounts of bone in the intertrochanteric and total hip regions (p < 0.0125), whereas the exercise group showed no significant change from baseline in any region (p > 0.0125). Pre-and post-bed rest muscle volumes were calculated from analysis of magnetic resonance imaging data. The exercise group retained a larger percentage of their total quadriceps and gastrocnemius muscle volume (- 7.2% ± 5.9, - 13.8% ± 6.1, respectively) than their control counterparts (- 23.3% ± 5.9, - 33.0 ± 8.2, respectively; p < 0.01). Both groups significantly lost strength in several measured activities (p < 0.05). The declines in peak torque during repeated exertions of knee flexion and knee extension were significantly less in the exercise group than in the control group (p < 0.05) but work done was not significantly different between groups (p > 0.05). The decline in VO2max was 17% ± 18 in exercising subjects (p < 0.05) and 31% ± 13 in control subjects (p = 0.003; difference between groups was not significant p = 0.26). Changes in blood and urine measures showed trends but no significant differences between groups (p > 0.05). In summary, the decline in a number of important measures of musculoskeletal and cardiovascular health was attenuated but not eliminated by a subject-specific program of locomotor exercise designed to replace daily load accumulated during free living. We conclude that single daily bouts of exposure to locomotor exercise can play a role in a countermeasures program during bed rest, and perhaps space flight, but are not sufficient in their own right to ensure musculoskeletal or cardiovascular health.

Evaluation of noncytotoxic DNMT1-depleting therapy in patients with myelodysplastic syndromes.

BACKGROUND: Mutational inactivation in cancer of key apoptotic pathway components, such as TP53/p53, undermines cytotoxic therapies that aim to increase apoptosis. Accordingly, TP53 mutations are reproducibly associated with poor treatment outcomes. Moreover, cytotoxic treatments destroy normal stem cells with intact p53 systems, a problem especially for myeloid neoplasms, as these cells reverse the low blood counts that cause morbidity and death. Preclinical studies suggest that noncytotoxic concentrations of the DNA methyltransferase 1 (DNMT1) inhibitor decitabine produce p53-independent cell-cycle exits by reversing aberrant epigenetic repression of proliferation-terminating (MYC-antagonizing) differentiation genes in cancer cells. METHODS: In this clinical trial, patients with myelodysplastic syndrome (n=25) received reduced decitabine dosages (0.1-0.2 mg/kg/day compared with the FDA-approved 20-45 mg/m2/day dosage, a 75%-90% reduction) to avoid cytotoxicity. These well-tolerated doses were frequently administered 1-3 days per week, instead of pulse cycled for 3 to 5 days over a 4- to 6-week period, to increase the probability that cancer S-phase entries would coincide with drug exposure, which is required for S-phase-dependent DNMT1 depletion. RESULTS: The median subject age was 73 years (range, 46-85 years), 9 subjects had relapsed disease or were refractory to 5-azacytidine and/or lenalidomide, and 3 had received intensive chemoradiation to treat other cancers. Adverse events were related to neutropenia present at baseline: neutropenic fever (13 of 25 subjects) and septic death (1 of 25 subjects). Blood count improvements meeting the International Working Group criteria for response occurred in 11 of 25 (44%) subjects and were highly durable. Treatment-induced freedom from transfusion lasted a median of 1,025 days (range, 186-1,152 days; 3 ongoing), and 20% of subjects were treated for more than 3 years. Mutations and/or deletions of key apoptosis genes were frequent (present in 55% of responders and in 36% of nonresponders). Noncytotoxic DNMT1 depletion was confirmed by serial BM γ-H2AX (DNA repair/damage marker) and DNMT1 analyses. MYC master oncoprotein levels were markedly decreased. CONCLUSION: Decitabine regimens can be redesigned to minimize cytotoxicity and increase exposure time for DNMT1 depletion, to safely and effectively circumvent mutational apoptotic defects. TRIAL REGISTRATION: Clinicaltrials.gov NCT01165996. FUNDING: NIH (R01CA138858, CA043703); Department of Defense (PR081404); Clinical and Translational Science Award (CTSA) (UL1RR024989); and the Leukemia and Lymphoma Society (Translational Research Program).

A novel lunar bed rest analogue.

INTRODUCTION: Humans will eventually return to the Moon and thus there is a need for a ground-based analogue to enable the study of physiological adaptations to lunar gravity. An important unanswered question is whether or not living on the lunar surface will provide adequate loading of the musculoskeletal system to prevent or attenuate the bone loss that is seen in microgravity. Previous simulations have involved tilting subjects to an approximately 9.5 degrees angle to achieve a lunar gravity component parallel to the long-axis of the body. However, subjects in these earlier simulations were not weight-bearing, and thus these protocols did not provide an analogue for load on the musculoskeletal system. METHODS: We present a novel analogue which includes the capability to simulate standing and sitting in a lunar loading environment. A bed oriented at a 9.5 degrees angle was mounted on six linear bearings and was free to travel with one degree of freedom along rails. This allowed approximately 1/6 body weight loading of the feet during standing. "Lunar" sitting was also successfully simulated. RESULTS: A feasibility study demonstrated that the analogue was tolerated by subjects for 6 d of continuous bed rest and that the reaction forces at the feet during periods of standing were a reasonable simulation of lunar standing. During the 6 d, mean change in the volume of the quadriceps muscles was -1.6% +/- 1.7%. DISCUSSION: The proposed analogue would appear to be an acceptable simulation of lunar gravity and deserves further exploration in studies of longer duration.

Phase 2 study of the lenalidomide and azacitidine combination in patients with higher-risk myelodysplastic syndromes.

Lenalidomide and azacitidine each have activity in myelodysplastic syndromes (MDS) patients, where both microenvironment and cell-regulatory mechanisms contribute to disease pathogenesis. The objective of this multicenter, phase 2 expansion trial was to determine the efficacy and safety of combination therapy with azacitidine (75 mg/m(2)/d for 5 days) and lenalidomide (10 mg/d for 21 days; 28-day cycle) in patients with higher-risk MDS. Among 36 patients enrolled (18 phase 1, 18 phase 2), median age was 68 years (range, 47-78 years) and follow-up was 12 months (range, 3-55 years). IPSS categories included intermediate-1 (n = 5 patients with excess blasts), intermediate-2 (20), and high (11). Common grade 3/4 nonhematologic adverse events included febrile neutropenia (22% of patients), other infection (11%), pulmonary (11%), cardiac (11%), constitutional (11%), and dermatologic (11%). The overall response rate (per modified MDS International Working Group criteria) was 72%: 16 patients (44%) achieved a complete response (CR), and 10 (28%) had hematologic improvement. Median CR duration was 17+ months (range, 3-39+); median overall survival was 37+ months (range, 7-55+) for CR patients, and 13.6 months for the entire cohort (range, 3-55). TET2/DNMT3A/IDH1/2 mutational status was associated with response in a limited number of patients. The lenalidomide/azacitidine combination is well-tolerated and highly active in treating greater-risk MDS.

A Phase 2 study of combination therapy with arsenic trioxide and gemtuzumab ozogamicin in patients with myelodysplastic syndromes or secondary acute myeloid leukemia.

BACKGROUND: Higher-risk myelodysplastic syndromes (MDS) are similar pathobiologically to acute myeloid leukemia (AML), particularly in older adults. AML therapies thus may have activity in MDS. In the current study, phase 2 study data of arsenic trioxide (ATO) and gemtuzumab ozogamicin (GO) in CD33-positive patients with MDS and secondary AML (sAML) were presented. METHODS: Between June 2004 and February 2006, 30 patients with higher-risk MDS or sAML received ATO (at a dose of 0.25 mg/kg intravenously for 5 days during Week 1, then twice weekly during Weeks 2-12) and GO (at a dose of 3 mg/m(2) on Day 8) for 1 or 2 cycles of 12 weeks each. The primary endpoint was response as per MDS or AML International Working Group (IWG) criteria. Adverse events were collected throughout treatment. Patients were followed for a minimum of 3 years for survival. RESULTS: The median patient age was 69 years. A total of 18 patients had MDS, 12 had sAML, and 19 had been previously treated. Seventeen patients (57%) completed ≥1 cycle, and 7 patients (23%) completed 2 cycles. IWG responses occurred in 9 patients (30%) according to IWG MDS criteria (including 2 of 7 patients who failed hypomethylating agents) and 3 of 12 AML patients (25%) according to IWG AML criteria. Grade 3/4 (according to National Cancer Institute Common Toxicity Criteria [version 3.0]) thrombocytopenia occurred in 47% of patients, neutropenia in 63%, and anemia in 37% of patients. The median overall survival was 9.7 months (28.6 months in responders and 7.6 months in nonresponders; P <.001). Patients who completed 2 cycles of therapy spent a median of 13 days in the hospital. CONCLUSIONS: Combination therapy with ATO and GO was found to have acceptable response rates and toxicity, and may be a viable treatment option to standard induction therapy, particularly for patients who fail therapy with hypomethylating agents.

Demonstration of additional benefit in adding lenalidomide to azacitidine in patients with higher-risk myelodysplastic syndromes.

Lenalidomide and azacitidine are active in MDS patients, and may complement each other by targeting the bone marrow microenvironment and the malignant clone. A recent Phase I trial testing the lenalidomide and azacitidine combination yielded encouraging results; however, lenalidomide's contribution was unclear. In this study, 18 higher-risk MDS patients were treated with the combination for seven cycles, after which lenalidomide was discontinued in eight patients who achieved a complete response, with azacitidine monotherapy continuing until disease progression. We report on three patients who relapsed on monotherapy with excess blasts at 12, 19, and 24 months, in whom lenalidomide was then resumed in combination with azacitidine. Each patient, one with normal cytogenetics at relapse; one with a 18 abnormality; and one with del(4q25), recaptured a complete response that was sustained for 5, 7, and 7+ months. We conclude that the addition of lenalidomide to azacitidine provides additional clinical benefit over azacitidine monotherapy.