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PURPOSE: Long-term GH/IGF-1 excess could increase risk of cancer in acromegaly, but individual levels of these hormones do not relate to this risk. Therefore, we newly investigated longitudinally-measured IGF-1 levels as a potential predictor of cancer in a large NYC acromegaly cohort. METHODS: We conducted a prospective, longitudinal study of 598 acromegaly (309 men, 289 women) and 292 clinically nonfunctioning pituitary adenoma (CNFPA)(140 women, 152 men) patients from the same underlying population. GH and IGF-1 levels were measured longitudinally and outcomes were observed during long-term follow-up. Cumulative exposure to IGF-1 excess was tested as a predictor of cancer. We compared cancer prevalence in acromegaly and CNFPA cohorts and incidence in each to that expected from SEER data. RESULTS: Cancer prevalence by last follow up was 22.6% in acromegaly and 12.7% in CNFPAs (OR = 1.99 (95% CI, 1.34, 2.97)(P=0.0005). Overall SIR for cancer was 1.78 (1.51, 1.81) in the acromegaly and 1.26 (0.89, 1.70) in the CNFPA cohorts. Cumulative exposure to IGF-1 excess, OR=1.278 (1.060, 1.541)(P = 0.01), years from acromegaly diagnosis to cancer or last follow up, OR= 1.03 (1.004, 1.057)(P=0.024), and age at follow up, OR =1.064 (1.047, 1.082)(P<0.001), were predictors of cancer. CONCLUSIONS: Cancer risk is increased in acromegaly, but not in CNFPA patients. Cumulative exposure to IGF-1 excess is a predictor of cancer in acromegaly. Our data suggest that cancer risk in acromegaly relates to the degree and duration of IGF-1 excess and that full appreciation of this risk requires long-term follow up.
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Context: Fracture rate is increased in patients with active acromegaly and those in remission. Abnormalities of bone microstructure are present in patients with active disease and persist despite biochemical control after surgery. Effects of treatment with the GH receptor antagonist pegvisomant on bone microstructure were unknown. Methods: We studied 25 patients with acromegaly (15 men, 10 women). In 20, we evaluated areal bone mineral density (BMD) by dual-energy X-ray absorptiometry and bone turnover markers (BTMs) longitudinally, before and during pegvisomant treatment. After long-term pegvisomant in 17, we cross-sectionally assessed volumetric BMD, microarchitecture, stiffness, and failure load of the distal radius and tibia using high-resolution peripheral quantitative computed tomography (HRpQCT) and compared these results to those of healthy controls and 2 comparison groups of nonpegvisomant-treated acromegaly patients, remission, and active disease, matched for other therapies and characteristics. Results: In the longitudinal study, areal BMD improved at the lumbar spine but decreased at the hip in men after a median â¼7 years of pegvisomant. In the cross-sectional study, patients on a median â¼9 years of pegvisomant had significantly larger bones, lower trabecular and cortical volumetric density, and disrupted trabecular microarchitecture compared to healthy controls. Microstructure was similar in the pegvisomant and acromegaly comparison groups. BTMs were lowered, then stable over time. Conclusion: In this, the first study to examine bone microstructure in pegvisomant-treated acromegaly, we found deficits in volumetric BMD and microarchitecture of the peripheral skeleton. BTM levels remained stable with long-term therapy. Deficits in bone quality identified by HRpQCT may play a role in the pathogenesis of fragility in treated acromegaly.
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The British Journal of Clinical Pharmacology celebrates its 50th anniversary of publication in 2023. Here four previous Editors-in-Chief and the current Editor reflect on the Journal's history and the changes that have occurred during that time.
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Publicações Periódicas como Assunto , Farmacologia ClínicaRESUMO
Purpose: Fractures are increased in patients with acromegaly, both before and after successful acromegaly treatment. Abnormalities of bone microstructure, which may underlie this fragility, are present in active acromegaly but to what extent these improve with acromegaly treatment or persist despite biochemical remission remains unclear. To examine these questions, we studied the effects of acromegaly treatment and remission on bone quality. Methods: Sixty-five women and men with acromegaly were studied. Subgroups underwent assessments of areal bone mineral density by dual x-ray absorptiometry, trabecular bone score (TBS), and volumetric bone mineral density, microarchitecture, stiffness and failure load of the distal radius and tibia by high-resolution peripheral quantitative tomography in a longitudinal study before and after acromegaly treatment and in a cross-sectional study in which patients were compared to sex-, age-, and body mass index-matched healthy controls. Results: In the longitudinal study, significant increases in total, cortical, and trabecular densities at the radius and tibia and increased stiffness and failure load of the tibia occurred with acromegaly treatment. In the cross-sectional study, patients in biochemical remission after surgery had larger bones, lower trabecular and cortical volumetric density, and disrupted trabecular microarchitecture compared to controls. TBS did not change with acromegaly treatment but correlated with some microstructural parameters. Conclusion: We show, for the first time, that volumetric bone mineral density and microarchitecture of the peripheral skeleton improve with acromegaly treatment but remain abnormal in patients in remission after surgery compared to controls. These abnormalities, known to be associated with fractures in other populations, may play a role in the pathogenesis of persistent fragility in treated acromegaly.
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AIM: To investigate the relationship between systemic exposure to hydroxychloroquine (HCQ) and its metabolite desethylhydroxychloroquine (DHCQ) and clinical outcome in severely ill patients treated with a standard oral dose regimen of HCQ during the first wave of COVID-19 in New York City. METHODS: We correlated retrospective clinical data with drug exposure prospectively assessed from convenience samples using population pharmacokinetics and Bayesian estimation. Systemic exposure was assessed in 215 patients admitted to ICU or COVID-ward for whom an interleukin-6 level was requested and who were still alive 24 hours after the last dose of HCQ. Patients received oral HCQ 600 mg twice daily on day 1 followed by 4 days of 400 mg daily. RESULTS: Fifty-three precent of the patients were intubated at 5.4 ± 6.4 days after admission and 26.5% died at an average of 32.2 ± 19.1 days. QTc at admission was 448 ± 34 ms. Systemic exposure to HCQ and DHCQ demonstrated substantial variability. Cumulative area under the serum concentration-time curve up to infinity for HCQ was 71.4 ± 19.3 h mg/L and for DHCQ 56.5 ± 28.3 h mg/L. Variability in systemic exposure was not clearly explained by renal function, liver function or inflammatory state. In turn, systemic exposure did not correlate with intubation status, survival or QTc prolongation. CONCLUSION: This study in severely ill patients was not able to find any relationship between systemic exposure to HCQ and DHCQ and clinical outcome at a routine dose regimen and adds to the growing body of evidence that oral HCQ does not alter the course of disease in COVID-19 patients.
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COVID-19 , Hidroxicloroquina , Humanos , Hidroxicloroquina/efeitos adversos , Cidade de Nova Iorque , Estudos Retrospectivos , Teorema de BayesRESUMO
Introduction: Uveal melanoma (UM) is associated with poor outcomes in the metastatic setting and harbors activating mutations resulting in upregulation of MAPK signaling in almost all cases. The efficacy of selumetinib, an oral allosteric inhibitor of MEK1/2, was limited when administered at a continual dosing schedule of 75 mg BID. Preclinical studies demonstrate that intermittent MEK inhibition reduces compensatory pathway activation and promotes T cell activation. We hypothesized that intermittent dosing of selumetinib would reduce toxicity, allow for the administration of increased doses, and achieve more complete pathway inhibition, thus resulting in improved antitumor activity. Methods: We conducted a phase Ib trial of selumetinib using an intermittent dosing schedule in patients with metastatic UM. The primary objective was to estimate the maximum tolerated dose (MTD) and assess safety and tolerability. Secondary objectives included assessment of the overall response rate (RR), progression-free survival (PFS) and overall survival (OS). Tumor biopsies were collected at baseline, on day 3 (on treatment), and between days 11-14 (off treatment) from 9 patients for pharmacodynamic (PD) assessments. Results: 29 patients were enrolled and received at least one dose of selumetinib across 4 dose levels (DL; DL1: 100 mg BID; DL2: 125 mg BID; DL3: 150 mg BID; DL4: 175 mg BID). All patients experienced a treatment-related adverse event (TRAE), with 5/29 (17%) developing a grade 3 or higher TRAE. Five dose limiting toxicities (DLT) were observed: 2/20 in DL2, 2/5 in DL3, 1/1 in DL4. The estimated MTD was 150 mg BID (DL3), with an estimated probability of toxicity of 29% (90% probability interval 16%-44%). No responses were observed; 11/29 patients achieved a best response of stable disease (SD). The median PFS and OS were 1.8 months (95% CI 1.7, 4.5) and 7.1 months (95% CI 5.3, 11.5). PD analysis demonstrated at least partial pathway inhibition in all samples at day 3, with reactivation between days 11-14 in 7 of those cases. Conclusions: We identified 150 mg BID as the MTD of intermittent selumetinib, representing a 100% increase over the continuous dose MTD (75 mg BID). However, no significant clinical efficacy was observed using this dosing schedule.
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The approach utilized a systematic review of the medical literature executed with specifically designed criteria that focused on the etiologies and pathogenesis of hypoparathyroidism. Enhanced attention by endocrine surgeons to new knowledge about parathyroid gland viability are reviewed along with the role of intraoperative parathyroid hormone (ioPTH) monitoring during and after neck surgery. Nonsurgical etiologies account for a significant proportion of cases of hypoparathyroidism (~25%), and among them, genetic etiologies are key. Given the pervasive nature of PTH deficiency across multiple organ systems, a detailed review of the skeletal, renal, neuromuscular, and ocular complications is provided. The burden of illness on affected patients and their caregivers contributes to reduced quality of life and social costs for this chronic endocrinopathy. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Hipoparatireoidismo , Humanos , Hipoparatireoidismo/etiologia , Hipoparatireoidismo/fisiopatologia , Hormônio Paratireóideo/química , Hormônio Paratireóideo/metabolismo , Qualidade de Vida , Glândulas Paratireoides/patologia , Glândulas Paratireoides/cirurgiaRESUMO
Monitoring tacrolimus trough concentrations is important for optimal immunosuppression in solid organ transplant recipients. Available assays generally correlate well with each other but little attention is given to patients in whom tacrolimus metabolite concentrations might be elevated, which could lead to artificially increased tacrolimus concentrations assessed by cross-reacting immunoassays. We addressed this hypothesis by investigating the correlation between four different assays (two immunoassays and two mass-spectrometry assays) in both a population with normal and a population with high dose requirements. Routine blood samples were collected in 37 control (CO) and 72 high dose patients (HD). Tacrolimus was measured with a CMIA, an ECLIA and two LCMS assays. Results were investigated using Deming regression analysis, Pearson correlation coefficients, Bland-Altman plots and by calculating bias. The CMIA demonstrated a positive bias of 23-26% compared with both LCMS assays. The correlation between CMIA and LCMS assays was good for the CO (r = 0.96) but less so for the HD group (r = 0.91). The ECLIA showed a positive bias of 11-13% compared with both LCMS assays. The correlation between ECLIA and LCMS assays was also good for the CO (r = 0.95) but again less for the HD group (r = 0.93). The correlation for both LCMS assays was excellent for either group (r > 0.99) with no bias. CMIA, ECLIA and LCMS assays for tacrolimus therefore correlate well for trough concentrations from solid organ transplant recipients. However, inter-assay differences exist, which seem more pronounced in patients who need a high dose of tacrolimus to reach a trough concentration in the therapeutic range.
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Imunossupressores , Tacrolimo , Bioensaio , Monitoramento de Medicamentos/métodos , Humanos , Imunoensaio/métodos , Espectrometria de MassasRESUMO
Uveal melanoma (UM) is a rare subset of melanoma characterized by the presence of early initiating GNAQ/11 mutations, with downstream activation of the PKC, MAPK, and PI3Kα pathways. Activity has been observed with the PKC inhibitors sotrastaurin (AEB071) and darovasertib (IDE196) in patients with UM. Inhibition of the PI3K pathway enhances PKC inhibition in in vivo models. We therefore conducted a phase Ib study of sotrastaurin in combination with the PI3Kα inhibitor alpelisib to identify a tolerable regimen that may enhance the activity of PKC inhibition alone. Patients with metastatic uveal melanoma (n = 24) or GNAQ/11 mutant cutaneous melanoma (n = 1) were enrolled on escalating dose levels of sotrastaurin (100-400 mg BID) and alpelisib (200-350 mg QD). The primary objective was to identify the maximum tolerated dose (MTD) of these agents when administered in combination. Treatment-related adverse events (AE) occurred in 86% (any grade) and 29% (Grade 3). No Grade 4-5-related AEs occurred. Dose Level 4 (sotrastaurin 200 mg BID and alpelisib 350 mg QD) was identified as the maximum tolerated dose. Pharmacokinetic analysis demonstrated increasing concentration levels with increasing doses of sotrastaurin and alpelisib, without evidence of interaction between agents. Pharmacodynamic assessment of pMARCKS and pAKT protein expression with drug exposure suggested modest target inhibition that did not correlate with clinical response. No objective responses were observed, and median progression-free survival was 8 weeks (range, 3-51 weeks). Although a tolerable dose of sotrastaurin and alpelisib was identified with pharmacodynamic evidence of target inhibition and without evidence of a corresponding immunosuppressive effect, limited clinical activity was observed.
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BACKGROUND: The kidney is essential for glucose and insulin metabolism. Living kidney donors (LKDs) experience a reduction in glomerular filtration rate of 25 to 30 mL/min after donor nephrectomy. Little is known about the effect of glomerular filtration rate decline on insulin sensitivity in LKDs. METHODS: We conducted a prospective pilot study on 9 LKDs (N = 9) who underwent dynamic metabolic testing (mixed meal tolerance test) to measure proxies of insulin sensitivity (homeostatic model assessment of insulin resistance, the area under curve [AUC] for insulin/glucose ratio, and Matsuda insulin sensitivity index) before and 3 months after donor nephrectomy. The primary outcome was the change in insulin sensitivity indices (delta [post-nephrectomy - pre-nephrectomy]). RESULTS: Four of the donors had a body mass index (BMI) between 32.0 and 36.7 predonation. Post-donor nephrectomy, compared with prenephrectomy values, median insulin AUC increased from 60.7 to 101.7 hr*mU/mL (delta median 33.3, P = .04) without significant change in median glucose AUC levels from 228.9 to 209.3 hr*mg/dL (delta median 3.2, P = .77). There was an increase in the median homeostatic model assessment of insulin resistance from 2 to 2.9 (delta median 0.8, P = .03) and the AUC insulin/glucose ratio from 30.9 to 62.1 pmol/mmol (delta median 17.5, P = .001), whereas the median Matsuda insulin sensitivity index decreased from 5.9 to 2.9 (delta median -2, P = .05). The changes were more pronounced in obese (BMI >32) donors. CONCLUSION: LKDs appear to have a trend toward a decline in insulin sensitivity post-donor nephrectomy in the short term, especially in obese donors (BMI >32). Further investigation with a larger sample size and longer follow-up is needed.
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Resistência à Insulina , Transplante de Rim , Doadores Vivos , Adulto , Idoso , Feminino , Humanos , Rim , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Nefrectomia/efeitos adversos , Projetos Piloto , Estudos Prospectivos , Adulto JovemRESUMO
INTRODUCTION: Duodeno-gastroesophageal reflux aspiration is associated with chronic lung allograft dysfunction (CLAD). Reflux aspirate can contain bile acids (BA), functional molecules in the gastro-intestinal tract with emulsifying properties. We sought to determine and quantify the various BA species in airways of the lung transplant recipients to better understand the various effects of aspirated BA that contribute to post-transplantation outcomes. METHODS: Bronchial washings (BW) were prospectively collected from lung transplant recipients and subsequently assayed by liquid chromatography-mass spectrometry for 13 BA and 25 lipid families. Patients were monitored for CLAD, rejection, inflammation and airway infections. RESULTS: Detectable BA were present in 45/50 patients (90%) at 3 months after transplant. Elevated BA and predominance of conjugated species were independent predictors of CLAD (hazard ratio 7.9; 95% confidence interval 2.7-23.6; p < 0.001 and 7.3; 2.4-22; p < 0.001, respectively) and mortality (hazard ratio 4.4; 1.5-12.7; p = 0.007 and 4.8; 1.4-15.8; p = 0.01, respectively). High BA associated with increased positive bacterial cultures (60% vs 25%, p = 0.02). Primary conjugated species independently correlated with the rate of bacterial cultures during the first-year post-transplant (Beta coefficient: 0.77; 0.28-1.26; p = 0.003) and changes in airway lipidome and cytokines. CONCLUSIONS: Higher BA levels and predominance of conjugated BA are independent predictors of chronic lung allograft dysfunction, mortality and bacterial infections. Primary conjugated BA are related to distinct changes in airway lipidome and inflammatory cytokines. This elucidates novel evidence into the mechanism following BA aspiration and proposes novel markers for prediction of adverse post-transplant outcomes.
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Ácidos e Sais Biliares/análise , Líquido da Lavagem Broncoalveolar/química , Citocinas/análise , Lipídeos/análise , Transplante de Pulmão/efeitos adversos , Pulmão/metabolismo , Adulto , Biomarcadores/análise , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
LESSONS LEARNED: Oral selective HDAC6 inhibitors could allow for decreased toxicity compared to pan-class inhibitors, and increased ease of use. ACY-1215 is well tolerated and led to disease stabilization in 50% of patients treated on a twice-daily dosing schedule. Rational drug combinations with ACY-1215 improve efficacy in patients with lymphoma. Biomarkers such as XBP-1 level or HDAC6-score may improve patient selection. BACKGROUND: ACY-1215, ricolinostat, is an oral, first-in-class isoform-selective HDAC6 inhibitor. HDAC6 is a class IIb deacetylase and plays a critical role in protein homeostasis via the unfolded protein response (UPR). Lymphocytes generate a large repertoire of antibodies and depend on an activated UPR to maintain proteostasis. Lymphomas utilize this biology to evade programmed cell death. In preclinical models of lymphoma, ACY-1215 disrupted proteostasis, triggering apoptosis. METHODS: We translated these findings into a multi-institution, open-label, dose-escalation phase Ib/II study aimed to determine the safety and efficacy in patients with relapsed and refractory lymphoma. RESULTS: Twenty-one patients with heavily pretreated lymphoma were accrued. Patients in the phase Ib portion were enrolled on one of two dose cohorts [Arm A: 160 mg daily (n = 3) or Arm B: 160 mg twice daily (n = 10)]. ACY-1215 was well tolerated. There were no dose limiting toxicities. Most adverse events were grade 1-2, including diarrhea (57%), nausea (57%), and fatigue (43%). Grade 3-4 toxicities were rare and included anemia (9.5%) and hypercalcemia (9.5%). An additional 8 patients were enrolled on the phase II portion, at 160 mg twice daily. Sixteen patients were evaluable for response. ACY-1215 did not result in any complete or partial responses in patients treated. Eight patients had stable disease (50%) lasting a median duration of 4.5 months, all of whom were treated twice daily. Disease progressed in eight patients (50%) at cycle 2. Five patients were not evaluable due to disease progression prior to cycle 2. The median PFS was 56 days. CONCLUSION: ACY-1215 is an oral selective HDAC6 inhibitor that was safe in patients with relapsed and refractory lymphoid malignancies and led to disease stabilization in half of the evaluable patients.
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Inibidores de Histona Desacetilases , Linfoma Folicular , Desacetilase 6 de Histona , Inibidores de Histona Desacetilases/efeitos adversos , Humanos , Ácidos Hidroxâmicos , PirimidinasRESUMO
CONTEXT: Outcome of acromegaly surgery is assessed by IGF-1 and glucose-suppressed GH, but whether the latter provides additional clinically relevant information when IGF-1 is normal is unclear. The role of GH suppression testing after surgery requires clarification. METHODS: We studied 97 acromegaly patients with normal IGF-1 after surgery by measuring GH after oral glucose longitudinally, initially at ≥ 3 months after surgery and repeated one or more times ≥ 1 year later. Nadir GH was categorized as normal or abnormal relative to the 97.5th percentile of nadir GH in 100 healthy subjects, which were ≤ 0.14 µg/L (DSL IRMA) or ≤ 0.15 µg/L(IDS iSYS). Signs and symptoms scores and insulin resistance were followed longitudinally. RESULTS: Of 68 patients with initial normal GH suppression 63 (93%) remained in remission and of 29 with initial abnormal GH suppression, 9 (31%) recurred. Recurrence was more common in patients with abnormal suppression (P < 0.001). A total of 14 patients recurred, including 5 with normal GH suppression progressing to abnormal and then recurrence. Overall, serial signs and symptoms and insulin resistance assessments did not identify patients with abnormal suppression or recurrence. CONCLUSION: Risk of recurrence after surgery is increased for patients with a normal IGF-1 level, but abnormal GH suppression. We newly find, using both our and others' cut-offs, that while normal suppression predicts long-term remission in most patients, some can progress from normal to abnormal suppression and then recurrence after many years of follow up. Nadir GH levels are of prognostic value in acromegaly patients with normal IGF-1 levels after surgery.