Correlation Between Plasma Catecholamines, Weight, and Diabetes in Pheochromocytoma and Paraganglioma.

CONTEXT: Pheochromocytomas and paragangliomas (PCC/PGL) are neuroendocrine tumors with discrete catecholamine profiles that cause incompletely understood metabolic and physiologic changes. OBJECTIVE: The objective was to evaluate relationships between plasma catecholamines, body weight, and hemoglobin A1c (HbA1c). We hypothesized that individual catecholamines would correlate negatively with weight and glucose control. DESIGN: A retrospective cohort study was performed (1999-2020). Wilcoxon rank-sum tests compared nonparametric, continuous variables; mixed-effect linear modeling (MEM) evaluated relationships between catecholamines and weight or HbA1c. The median study duration was 54.2 months [interquartile range (IQR) 19.0-95.1]. SETTING: Tertiary academic hospital. PATIENTS: 360 patients were identified prospectively by referral to our center for management or surveillance of PCC/PGL. The median age was 59 years (IQR 45-67) and 56.4% (n = 203) were female. MAIN OUTCOME MEASURES: The primary and secondary outcomes were weight and HbA1c, respectively. RESULTS: On multivariable MEM, norepinephrine (P < 0.0005) negatively correlated with weight when all catecholamines and their derivatives were tried in the model, and normetanephrine (P < 0.0005) correlated when only metanephrines were included. In the surgical cohort (n = 272), normetanephrine decreased postoperatively and was inversely associated with weight (P < 0.0005). Elevated norepinephrine or normetanephrine at the study termination, indicative of metastatic and/or recurrent disease (MRD), correlated with weight loss. Norepinephrine and normetanephrine (P < 0.0005) directly correlated with HbA1c. CONCLUSION: Plasma norepinephrine and its metabolite directly correlate with HbA1c and inversely correlate with weight in PCC/PGL. After resection, declining normetanephrine levels correlate with improving HbA1c despite an increase in patient body weight. Persistently elevated catecholamines and decreasing weight are observed in MRD.

Prostate-Specific Antigen Concentrations in Response to Testosterone Treatment of Severely Hypogonadal Men.

CONTEXT: Clinical guidelines recommend measurement of the serum prostate-specific antigen (PSA) concentration during testosterone treatment of hypogonadal men to determine whether the increase is sufficiently high to warrant urologic referral. Prior studies of the effect of testosterone treatment on PSA concentrations have been conducted in men who were mildly to moderately hypogonadal. OBJECTIVE: The objective of this work is to determine the PSA response to testosterone treatment of men who are severely hypogonadal. DESIGN AND SETTING: This retrospective cohort study was conducted at a single academic medical center. PARTICIPANTS: Eighty-five men participated who were severely hypogonadal as a result hypothalamic-pituitary or testicular disease. MAIN OUTCOME MEASURE: Changes in serum PSA concentrations were measured during testosterone treatment for up to 18 months. RESULTS: Testosterone treatment increased the median serum testosterone concentration from 36 ng/dL (interquartile range [IQR], 20-91 ng/dL) at baseline to 395 ng/dL (IQR, 266-542 ng/dL) at 6 to 18 months. This treatment resulted in a median increment in PSA above baseline of 0.70 ng/mL (IQR, 0.10-1.85 ng/mL) at 6 to 18 months. Apropos current Endocrine Society clinical guidelines, 31% of the men experienced a PSA increase above baseline greater than 1.4 ng/mL, and 13% reached an absolute PSA concentration of greater than 4.0 ng/mL. Four men were diagnosed with prostate cancer. CONCLUSIONS: The PSA response to testosterone replacement in men who are severely hypogonadal as a result of pituitary or testicular disease is greater than that previously reported in men with mild to moderate hypogonadism. These results suggest the magnitude of the PSA response to testosterone replacement is related to the degree of hypogonadism.

Clinical Utility of Plasma Cell-Free DNA in Adult Patients with Newly Diagnosed Glioblastoma: A Pilot Prospective Study.

PURPOSE: The clinical utility of plasma cell-free DNA (cfDNA) has not been assessed prospectively in patients with glioblastoma (GBM). We aimed to determine the prognostic impact of plasma cfDNA in GBM, as well as its role as a surrogate of tumor burden and substrate for next-generation sequencing (NGS). EXPERIMENTAL DESIGN: We conducted a prospective cohort study of 42 patients with newly diagnosed GBM. Plasma cfDNA was quantified at baseline prior to initial tumor resection and longitudinally during chemoradiotherapy. Plasma cfDNA was assessed for its association with progression-free survival (PFS) and overall survival (OS), correlated with radiographic tumor burden, and subjected to a targeted NGS panel. RESULTS: Prior to initial surgery, GBM patients had higher plasma cfDNA concentration than age-matched healthy controls (mean 13.4 vs. 6.7 ng/mL, P < 0.001). Plasma cfDNA concentration was correlated with radiographic tumor burden on patients' first post-radiation magnetic resonance imaging scan (ρ = 0.77, P = 0.003) and tended to rise prior to or concurrently with radiographic tumor progression. Preoperative plasma cfDNA concentration above the mean (>13.4 ng/mL) was associated with inferior PFS (median 4.9 vs. 9.5 months, P = 0.038). Detection of ≥1 somatic mutation in plasma cfDNA occurred in 55% of patients and was associated with nonstatistically significant decreases in PFS (median 6.0 vs. 8.7 months, P = 0.093) and OS (median 5.5 vs. 9.2 months, P = 0.053). CONCLUSIONS: Plasma cfDNA may be an effective prognostic tool and surrogate of tumor burden in newly diagnosed GBM. Detection of somatic alterations in plasma is feasible when samples are obtained prior to initial surgical resection.

Intravenous GLP-1 (7-36) amide for prevention of hyperglycemia during cardiac surgery: a randomized, double-blind, placebo-controlled study.

OBJECTIVE: The authors sought to evaluate the efficacy of an intravenous glucagon-like peptide-1 (GLP-1) infusion, compared with placebo, to mitigate intraoperative hyperglycemia. DESIGN: Prospective, double-blinded, randomized, placebo-controlled. SETTING: University hospital. PARTICIPANTS: Diabetic (non-insulin dependent) and non-diabetic patients undergoing elective cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: Patients were randomized in a 1:1 fashion to GLP-1 (7-36) amide infusion (1.5 pmol/kg/min) or placebo. Insulin was administered intraoperatively to both groups per a standardized protocol. MEASUREMENTS AND MAIN RESULTS: A total of 77 patients were included for analysis (GLP-1, n = 37; placebo, n = 40). Mean blood glucose during cardiopulmonary bypass was 127.5 mg/dL and 142.5 mg/dL (p = 0.002) in the GLP-1 and placebo groups, respectively. Mean blood glucose values during the entire intraoperative course were 12.2 mg/dL lower for subjects given GLP-1 (95% CI 2.3, 22, p = 0.015), independent of time. During the period of cardiopulmonary bypass, mean blood glucose values in subjects given GLP-1 were 14.1 mg/dL lower than those who received placebo (95% CI 3.5, 24.8, p = 0.009), independent of time. The incidence of hypoglycemia did not differ significantly between the 2 groups. CONCLUSIONS: Administration of intravenous GLP-1 (7-36) amide to patients undergoing cardiac surgery significantly reduced their plasma glucose levels intraoperatively and may represent a novel therapeutic strategy to prevent perioperative hyperglycemia.

The effect of age, menopausal state, and breast density on (18)F-FDG uptake in normal glandular breast tissue.

UNLABELLED: Theoretically, the degree of (18)F-FDG uptake in the glandular tissues of the normal breast can affect the detection of breast cancer. The aim of this prospective study was to investigate relationships among age, menopausal state, and breast density and determine whether they affect (18)F-FDG uptake in normal glandular breast tissue. METHODS: Among 250 newly diagnosed breast cancer patients, 149 patients (mean age +/- SD, 50.9 +/- 9.70 y; range, 32-77 y) were analyzed because they had normal contralateral breasts confirmed by MRI, mammography, and (18)F-FDG PET examinations. PET images were acquired 60 +/- 2 min after the administration of (18)F-FDG (5.2 MBq/kg of body weight). The maximum and average standardized uptake value (SUVmax and SUVavg, respectively) of (18)F-FDG were calculated in the normal breast. Patients were divided into groups according to qualitative breast density and menopausal state. Descriptive statistics and 2-factorial analysis of covariance were used to assess the effects of qualitative breast density, menopausal state, and age on SUVmax and SUVavg. Pearson chi(2) was used to test the relationship between menopausal state and qualitative breast density. RESULTS: The average age of patients with nondense breasts was significantly higher than that of patients with dense breasts (P < 0.01). Also, breast density related to menopausal state (P < 0.05). Dense breasts had an average SUVmax of 1.243 and mean SUVavg of 0.694, whereas nondense breasts had a mean SUVmax of 0.997 and mean SUVavg of 0.592. Analysis of covariance indicated that density and the linear effect of age were significant with regard to both SUVmax and SUVavg. After removing the linear effect of age, menopausal state had no effect on SUVmax and SUVavg. CONCLUSION: (18)F-FDG uptake significantly decreases as age increases and breast density decreases. Age and qualitative breast density are independent factors and significantly affect (18)F-FDG uptake for both SUVmax and SUVavg. Menopausal state had no effect on SUVmax and SUVavg.

Functional polymorphisms of folate-metabolizing enzymes in relation to homocysteine concentrations in systemic lupus erythematosus.

OBJECTIVE: To determine if functional polymorphisms of folate/homocysteine pathway enzymes are associated with homocysteine concentrations and/or coronary artery calcification (CAC) scores in patients with systemic lupus erythematosus (SLE) and controls. METHODS: We investigated 163 SLE patients and 160 controls. Functional polymorphisms in 6 genes in the folate/homocysteine pathway were genotyped: 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C>T, MTHFR 1298A>C, cystathionine ss-synthase (CBS) 844ins68, methionine synthase (MTR) 2756A>G, methionine synthase reductase (MTRR) 66A>G, thymidylate synthase (TYMS) 1494del6, and dihydrofolate reductase (DHFR) c.86+60_78. RESULTS: Homocysteine levels were higher in African American SLE patients than Caucasian patients and African American controls. Genotype distributions were significantly different in African American and Caucasian controls for 6 of the 7 polymorphisms. Genotype distributions for each polymorphism did not differ significantly between SLE patients and controls even after stratification by race. Glomerular filtration rate was strongly negatively correlated to homocysteine levels, and was therefore adjusted for as a covariate in the models of the effects of the polymorphisms on homocysteine levels. In SLE patients none of the 7 polymorphisms was associated with homocysteine concentrations. In Caucasian controls only MTHFR 677C>T and 1298A>C showed effects on homocysteine similar to what would be expected from the literature. There were no genotypic associations with median CAC scores in SLE patients or controls with and without stratification by race. CONCLUSION: Polymorphisms in folate/homocysteine metabolizing enzymes do not predict higher homocysteine levels or CAC scores in patients with SLE.

In vivo magnetic resonance detects rapid remodeling changes in the topology of the trabecular bone network after menopause and the protective effect of estradiol.

INTRODUCTION: Estrogen depletion after menopause is accompanied by bone loss and architectural deterioration of trabecular bone. The hypothesis underlying this work is that the microMRI-based virtual bone biopsy can capture the temporal changes of scale and topology of the trabecular network and that estrogen supplementation preserves the integrity of the trabecular network. MATERIALS AND METHODS: Subjects studied were early postmenopausal women, 45-55 yr of age (N = 65), of whom 32 were on estrogen (estradiol group), and the remainder were not (control group). Early menopause was defined by amenorrhea for 6-24 mo and elevated serum follicle-stimulating hormone (FSH) concentration. The subjects were evaluated with three imaging modalities at baseline and 12 and 24 mo to determine the temporal changes in trabecular and cortical architecture and density. microMRI of the distal radius and tibia was performed at 137 x 137 x 410-microm(3) voxel size. The resulting bone volume fraction maps were Fourier interpolated to a final voxel size of 45.7 x 45.7 x 136.7 microm(3), binarized, skeletonized, and subjected to 3D digital topological analysis (DTA). Skeletonization converts trabecular rods to curves and plates to surfaces. Parameters quantifying scale included BV/TV, whereas DTA parameters included the volume densities of curves (C) and surface (S)-type voxels, as well as composite parameters: the surface/curve ratio (S/C), and erosion index (EI, ratio of the sum of parameters expected to increase with osteoclastic resorption divided by the sum of those expected to decrease). For comparison, pQCT of the same peripheral locations was conducted, and trabecular density and cortical structural parameters were measured. Areal BMD of the lumbar vertebrae and hip was also measured. RESULTS: Substantial changes in trabecular architecture of the distal tibia, in particular as they relate to topology of the network, were detected after 12 mo in the control group. S/C decreased 5.6% (p < 0.0005), and EI increased 7.1% (p < 0.0005). Most curve- and profile-type voxels (representative of trabecular struts), increased significantly (p < 0.001). Curve and profile edges resulting from disconnection of rod-like trabeculae increased by 9.8% and 5.1% (p = 0.0001 and <0.001, respectively). Similarly, DXA BMD in the spine and hip decreased 2.6% and 1.3% (p < 0.0001 and <0.005, respectively), and pQCT cortical area decreased 3.6% (p = 0.0001). However, neither trabecular density nor BV/TV changed. Furthermore, none of the parameters measured in the estradiol group were significantly different after 12 mo. Substantial differences in the mean changes from baseline between the estradiol treatment and control groups, in particular after 24 mo, were observed, with relative group differences as large as 13% (S/C, p = 0.005), and the relative changes in the two groups had the opposite sign for most parameters. The observed temporal alterations in architecture are consistent with remodeling changes that involve gradual conversion of plate-like to rod-like trabecular bone along with disconnection of trabecular elements, even in the absence of a net loss of trabecular bone. The high-resolution 3D rendered images provide direct evidence of the above remodeling changes in individual subjects. The radius structural data indicated similar trends but offered no definitive conclusions. CONCLUSIONS: The short-term temporal changes in trabecular architecture after menopause, and the protective effects of estradiol ensuring maintenance of a more plate-like TB architecture, reported here, have not previously been observed in vivo. This work suggests that MRI-based in vivo micromorphometry of trabecular bone has promise as a tool for monitoring osteoporosis treatment.

Homocysteine levels and disease duration independently correlate with coronary artery calcification in patients with systemic lupus erythematosus.

OBJECTIVE: To compare the incidence and extent of coronary artery calcification (CAC) as measured by electron beam computed tomography (EBCT) in patients with systemic lupus erythematosus (SLE) and controls, and to identify variables associated with CAC in patients with SLE. METHODS: Female patients with SLE and matched controls were recruited; EBCT of the coronary arteries was performed, and laboratory values (including the homocysteine concentration, the lipid level, the high-sensitivity C-reactive protein [hsCRP] concentration, the glomerular filtration rate [GFR], and the level of soluble CD154 [sCD154]) were determined. For patients, the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index and the SLE Disease Activity Index scores were recorded. Tests of association between the CAC score and the above-mentioned variables were performed. RESULTS: The incidence of CAC was higher in patients with SLE than in controls (P = 0.009), and patients had a higher mean raw CAC (rCAC) score (87.9 versus 9.6 in controls; P = 0.02). In particular, more CAC-positive patients than CAC-positive controls had rCAC scores above the 75th percentile (P = 0.003). Among both patients and controls, those with CAC were approximately 10 years older than those without CAC. In addition to age, a significant determinant of positive CAC status in both groups was the number of cardiovascular risk factors. In patients with SLE, CAC was associated with a higher homocysteine concentration, a lower GFR, and longer disease duration. In controls, the total cholesterol level correlated positively with CAC. When multivariate logistic regression methods were applied to candidate explanatory variables, homocysteine concentration, age, and disease duration (but not the levels of sCD154 or hsCRP) contributed significantly to CAC status. The methylenetetrahydrofolate reductase C677T genotype was not a predictor of hyperhomocysteinemia or CAC status. CONCLUSION: Among patients with SLE, the homocysteine concentration, the GFR, age, and disease duration were associated with CAC. CAC occurred more frequently and was more extensive in patients with SLE than in controls, suggesting that EBCT could be used to detect premature atherosclerosis in the former group. An elevated homocysteine concentration might identify patients with SLE who are likely to have premature atherosclerosis and who would benefit from evaluation of CAC by EBCT.

The impact of continuous pulse oximetry monitoring on intensive care unit admissions from a postsurgical care floor.

Continuous pulse oximetry (CPOX) has the potential to increase vigilance and decrease pulmonary complications and thus decrease intensive care unit (ICU) admissions. In a randomized nonblinded study of 1219 subjects we compared the effects of CPOX and standard monitoring on the rate of transfer to an ICU from a 33-bed postcardiothoracic surgery care floor. There was no difference in the rate of ICU readmission between the CPOX and standard monitor groups. Despite older age and comorbidity, estimated cost to time of censoring (enrollment to completion of the study) was less in the monitored patients who required ICU transfer than in the unmonitored patients who required ICU transfer (mean estimated cost difference of 28,195 dollars; P = 0.04). Use of CPOX altered the reasons that patients were transferred to an ICU but did not affect the rate of transfer. The duration, and thus estimated cost, of ICU stay was significantly less in the CPOX-monitored group. The potential for CPOX to allow for early intervention, or perhaps prevention of pulmonary complications, needs to be explored. Routine CPOX monitoring did not reduce transfer to ICU, mortality, or overall estimated cost of hospitalization, and it is unclear if there is any real benefit from the application of this technology in patients on a general care floor who are recovering from cardiothoracic surgery.

Treatment of cutaneous T-cell lymphoma with combined immunomodulatory therapy: a 14-year experience at a single institution.

OBJECTIVE: To determine the efficacy of multimodality biologic response therapy for patients with cutaneous T-cell lymphoma (CTCL). DESIGN: Retrospective cohort study over a 14-year period. SETTING: Tertiary care university hospital. PATIENTS: A consecutive sample of patients was studied, all 47 of whom carried the clinical and laboratory diagnosis of CTCL: 68% of patients had stage III or IV disease, and 89% had circulating malignant T cells. INTERVENTIONS: All 47 patients received photopheresis for 6 or more cycles. Thirty-one patients received treatment with a combination of photopheresis and 1 or more systemic immunostimulatory agents, including interferon alfa, interferon gamma, sargramostim, or systemic retinoids for 3 or more months. MAIN OUTCOME MEASURES: Differences in pretreatment prognostic factors, response rates, and survival between patients receiving multimodality therapy and single-modality therapy or historical controls. RESULTS: A total of 79% of patients responded to therapy: 26% had complete remission, and 53% had a partial remission. Median survival from initiation of therapy was 74 months. Median survival for patients with stages III and IV and peripheral blood involvement was 55 months compared with 31 months for historical controls. Compared with the photopheresis monotherapy group, the patients receiving combination immunomodulatory therapy had a worse prognosis at the time of treatment initiation based on multiple prognostic factors. The positive response rates and median survival times were 84% and 74 months, respectively, compared with 75% and 66 months, respectively, for the combination immunomodulatory and photopheresis monotherapy groups (P =.47 for positive response rates and P =.51 for survival). CONCLUSIONS: Patients with advanced CTCL and multiple poor prognostic factors who receive treatment with combination immunomodulatory therapy experience higher clinical response rates and longer survival than historical controls. Although the group who received combination therapy had worse prognostic factors at baseline, they had better response rates and overall survival compared with those receiving photopheresis monotherapy.