Acromegaly may present a unique type of lipodystrophy characterized by reduced storage of AT in central depots and a shift of excess lipid to IMAT. After surgery, this pattern partially reverses, but differentially in men and women. These findings have implications for understanding the role of GH in body composition and metabolic risk in acromegaly and other clinical settings of GH use.

Balanced pools of deoxyribonucleoside triphosphate precursors are required for DNA replication, and alterations of this balance are relevant to human mitochondrial diseases including mitochondrial neurogastrointestinal encephalopathy. In this disease, autosomal recessive TYMP mutations cause severe reductions of thymidine phosphorylase activity; marked elevations of the pyrimidine nucleosides thymidine and deoxyuridine in plasma and tissues, and somatic multiple deletions, depletion and site-specific point mutations of mitochondrial DNA. Thymidine phosphorylase and uridine phosphorylase double knockout mice recapitulated several features of these patients including thymidine phosphorylase activity deficiency, elevated thymidine and deoxyuridine in tissues, mitochondrial DNA depletion, respiratory chain defects and white matter changes. However, in contrast to patients with this disease, mutant mice showed mitochondrial alterations only in the brain. To test the hypothesis that elevated levels of nucleotides cause unbalanced deoxyribonucleoside triphosphate pools and, in turn, pathogenic mitochondrial DNA instability, we have stressed double knockout mice with exogenous thymidine and deoxyuridine, and assessed clinical, neuroradiological, histological, molecular, and biochemical consequences. Mutant mice treated with exogenous thymidine and deoxyuridine showed reduced survival, body weight, and muscle strength, relative to untreated animals. Moreover, in treated mutants, leukoencephalopathy, a hallmark of the disease, was enhanced and the small intestine showed a reduction of smooth muscle cells and increased fibrosis. Levels of mitochondrial DNA were depleted not only in the brain but also in the small intestine, and deoxyribonucleoside triphosphate imbalance was observed in the brain. The relative proportion, rather than the absolute amount of deoxyribonucleoside triphosphate, was critical for mitochondrial DNA maintenance. Thus, our results demonstrate that stress of exogenous pyrimidine nucleosides enhances the mitochondrial phenotype of our knockout mice. Our mouse studies provide insights into the pathogenic role of thymidine and deoxyuridine imbalance in mitochondrial neurogastrointestinal encephalopathy and an excellent model to study new therapeutic approaches.

Rationale and Objectives Based on their association with malignant proliferation, using noninvasive phosphorus MR spectroscopic imaging (31P MRSI), we measured the tumor content of the phospholipid-related phosphomonoesters (PME), phosphoethanolamine and phosphocholine and its correlation with treatment outcome in newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients receiving standard first-line chemotherapy. Experimental Design The PME value normalized to nucleoside triphosphates (PME/NTP) was measured using 31P MRSI in tumor masses of 20 DLBCL patients prior to receive standard first-line chemotherapy. Response at six months was complete in 13 patients and partial in seven. Time to treatment failure (TTF) was ≤11 months in eight patients, from 18 to 30 months in three, and ≥ 60 months in nine. Results On a t-test, the pretreatment tumor PME/NTP mean value (SD, n) of patients with a complete response at six months was 1.42 (0.41, 13), which was significantly different from the value of 2.46 (0.40, 7) in patients with partial response (p < 0.00001). A Fisher test significantly correlated the PME/NTP values with response at six months (sensitivity and specificity at 0.85, p < 0.004) while a Cox proportional hazards regression significantly correlated the PME/NTP values with TTF (hazard ratio=5.21, p < 0.02). A Kaplan-Meier test set apart a group entirely composed of patients with TTF ≤ 11 months (hazard ratio=8.66, p<0.00001). Conclusion The pretreatment tumor PME/NTP values correlated with response to treatment at six months and time to treatment failure in newly diagnosed DLBCL patients treated with first-line chemotherapy and therefore they could be used to predict treatment outcome in these patients.

Adipose tissue (AT) mass, especially visceral (VAT), is reduced in active acromegaly and rises with treatment. Although the effect of acromegaly and its therapy on marrow AT(MAT) is unknown, data in other populations and in vitro, suggest a reciprocal relationship between GH and marrow adiposity. In other groups, VAT and MAT are associated with reduced bone quality and increased vertebral fracture (VF) risk. Therefore, since acromegaly patients have an increased VF incidence, we examined the relationships of VAT and MAT to bone quality in acromegaly. We studied 65 acromegaly subjects (40 men, 25 women, range 18.7-74 yr.) before (n=20) or before and after (n=45) acromegaly therapy by total body multi-slice MRI(n=159)(measurement of VAT, subcutaneous (SAT) and total (TAT) adipose tissue mass), DXA (BMD (n=120) and body composition (n=145)) and HRpQCT (n=35) (microarchitecture of the tibia and radius). Marrow lipid spectra of the tibial diaphysis were acquired by 1 H MRS (PRESS technique)(1.5T MR scanner, Philips) and percentages of bone marrow lipids were quantified (n=53). GH and IGF-1 (n=159) and bone turnover markers (BTM)(n=49) were measured. We examined the relationship between MAT or VAT and GH, IGF-1, age, weight, mass of other MRI measured AT depots, and selected DXA and HRpQCT parameters previously shown to differ in acromegaly compared to healthy subjects and to be associated in other groups with fracture. Data were analyzed by Pearson correlation and the generalized estimating equation (GEE). MAT directly correlated with VAT (r=.249, p=.023) and by HRpQCT (n=13) with bone size (radius: total area (r=.678, p=.01), tibia: total area (r=.535, p=.05)) and trabecular number (r=.543, p=.055). VAT was inversely associated with GH (β= -.017, p<.001), IGF-1 level (expressed as % upper normal limit) (β= -0.004, p=.049) and BTMs (N-Mid Osteocalcin (β= -.0223, p<0.001); CTX (β= -.7283, p=.0134)). VAT was positively associated with age (β=.034, p=.053), weight (β=.072, p <.0001) and with HRpQCT measured bone size (radius: total area (β=.0073, p=.0098); tibia: total area (β= .0049, p <.0001)) and trabecular number (tibia: β=1.9321, p=.0096), and inversely associated with cortical thickness (radius: β= -2.8477, p= .074; tibia: β= -2.3341, p=.0497), trabecular thickness (tibia: β= -92, p<.0001) and total body density (radius β= -.0102, p=.0353; tibia: β= -.0149, p=.003). In summary, VAT is inversely related to acromegaly disease activity, consistent with its known rise as acromegaly is treated. We found that greater VAT is associated with larger bone size and lower bone turnover, but also with some less favorable aspects of bone microarchitecture. MAT correlated with VAT and, in a small number of subjects, with bone size. Whether rising adiposity and reductions in bone turnover with acromegaly therapy are relevant to the skeletal fragility reported in treated acromegaly warrants further study.