Cardiac resynchronisation therapy in patients with left bundle branch block with residual conduction

AimTo evaluate whether left bundle branch block with residual conduction (rLBBB) is associated with worse outcomes after cardiac resynchronisation therapy (CRT).MethodsAll consecutive CRT implants at our institution between 2006 and 2013 were identified from our local device registry. Pre- and post-implant patient specific data were extracted from clinical records.ResultsA total of 690 CRT implants were identified during the study period. Prior to CRT, 52.2% of patients had true left bundle branch block (LBBB), 19.1% a pacing-induced LBBB (pLBBB), 11.2% a rLBBB, 0.8% a right bundle branch block (RBBB), and 16.5% had a nonspecific intraventricular conduction delay (IVCD) electrocardiogram pattern. Mean age at implant was 67.5 years (standard deviation [SD] = 10.6), mean left ventricular ejection fraction (LV EF) was 25.7% (SD = 7.9%), and mean QRS duration was 158.4 ms (SD = 32 ms). After CRT, QRS duration was significantly reduced in the LBBB (p < 0.001), pLBBB (p < 0.001), rLBBB (p < 0.001), RBBB (p = 0.04), and IVCD groups (p = 0.03). LV EF significantly improved in the LBBB (p < 0.001), rLBBB (p = 0.002), and pLBBB (p < 0.001) groups, but the RBBB and IVCD groups showed no improvement. There was no significant difference in mortality between the LBBB and rLBBB groups. LV EF post-CRT, chronic kidney disease, hyperkalaemia, hypernatremia, and age at implant were significant predictors of mortality.ConclusionCRT in patients with rLBBB results in improved LV EF and similar mortality rates to CRT patients with complete LBBB. Predictors of mortality post-CRT include post-CRT LV EF, presence of CKD, hyperkalaemia, hypernatremia, and older age at implant.     

The impact of left common pulmonary vein on cryoballoon ablation of atrial fibrillation. A meta-analysis

IntroductionConflicting results regarding the impact of left common pulmonary vein (LCPV) on clinical outcome of atrial fibrillation (AF) ablation with cryoballoon technology have been reported.MethodsWe systematically searched PubMed and Cochrane library for articles that compared the arrhythmia recurrence rate after cryoballoon ablation between patients with normal pattern PVs and patients with LCPV. Studies of first ablation for persistent and paroxysmal AF using the 28 mm Arctic Front Advance, Medtronic cryoballoon (CB-A) reporting clinical success rates at a mean follow-up of ≥12 months were included. Data were analyzed by applying a random effects model.ResultsA total of 5 studies with a total of 1178 patients met our predefined inclusion criteria. After a mean follow-up of 18.4 months, the overall success rate of CB-A ablation among patients with persistent and paroxysmal AF was 57%; in the LCPV group the success rate was 46% and in the normal anatomical pattern group it was 61%. No significant heterogeneity was noted among the studies (I² = 35.8%; Q (df = 3) = 6.23 p-value = 0.18). Arrhythmia recurrence after CB-A ablation was not statistically significant between the two groups (LogOR 0.24; 95% CI [-0.16-0.63]; p-value = 0.23). No significant difference in PNI was observed between the two groups (p-value = 0.693).ConclusionThe presence of LCPV does not affect the long-term outcome of paroxysmal and persistent atrial fibrillation ablation with 28 mm CB-A compared to normal left PVs pattern.     

Premature ventricular contractions in patients with an implantable cardioverter defibrillator cardiac resynchronization therapy device: Results from the UMBRELLA registry

BackgroundPremature ventricular contractions (PVC) are known to reduce the percentage of biventricular (BiV) pacing in patients with cardiac resynchronization (CRT), decreasing the clinical response. The aim of this study was to evaluate the prevalence of a high PVC burden, as well as therapeutic action (pharmacotherapy, catheter ablation or device programming), in a large CRT implantable-defibrillator (CRT-D) population.MethodsPatients with a CRT-D device from the UMBRELLA multicenter prospective remote monitoring registry were included. The PVC count was collected from each remote monitoring transmission. Patients were divided into two high (≥1 transmission ≥200/≥400 PVC/h, respectively) and one low (all transmissions <200 PVC/h) PVC count groups. The PVC burden following a high PVC count transmission was calculated.ResultsOf 1268 patients, 135 (11%) and 43 (3.4%) presented high PVC count (≥200/≥400 PVC/h, respectively). The majority of patients in the high PVC groups were not treated (61 [79%] and 32 [74%], respectively. Considering the untreated patients in the high PVC groups, median PVC/h was 199 (interquartile range [IQR]: 196) and 271 (IQR: 330), respectively. The PVC burden (proportion of time with PVC/h ≥ 200/≥400) was 40% (IQR 70) and 29% (IQR 59), respectively.ConclusionA significant proportion of CRT-D patients presented a high PVC count, however, few received treatment. In the untreated patients with a high PVC count, the PVC burden during follow-up varied substantially. Several consecutive recordings of a high PVC count should be warranted before considering therapeutic action such as catheter ablation.     

Etiology-, Sex-, and Tumor Size-Based Differences in Adrenocorticotropin-Dependent Cushing Syndrome

ObjectiveTo examine demographic, clinical, and biochemical differences in patients with adrenocorticotropin (ACTH)-dependent Cushing syndrome (CS) based on etiology, sex, and tumor size.MethodsThis was a single-center study of 211 patients with ACTH-dependent CS followed for 35 years. Patients were stratified into 3 groups based on etiology: Cushing disease (CD)/transsphenoidal surgery, Cushing disease/total bilateral adrenalectomy (CD/TBA), and ectopic ACTH secretion (EAS). Patients were also stratified based on sex and tumor size (nonvisualized, microadenoma, and macroadenoma).ResultsCD was the commonest cause of ACTH-dependent CS (190; 90%). Most patients presented in the third decade (median age, 29 years). Clinical features, cortisol, and ACTH were significantly greater in the EAS group. The CD/TBA group had more nonvisualized tumors (22% vs 8%; P = .000) and smaller tumor size (4 vs 6 mm; P = .001) compared with the CD/transsphenoidal surgery group. There was female predominance in CD (2.06:1) and male predominance in EAS (2:1). Men had shorter duration of symptoms (2 years; P = .014), were younger (23 years; P = .001), had lower body mass index (25.1 kg/m²; P = .000), and had more severe disease (low bone mineral density, hypokalemia). Macroadenomas were frequent (46; 24.2%), and ACTH correlated with tumor size in CD (r = 0.226; P = .005).ConclusionOur cohort presented at an earlier age than the Western population with a distinct, but slightly lower, female predilection. Patients with CD undergoing TBA had frequent negative imaging. Men had a clinical profile suggesting aggressive disease. Microadenoma and macroadenoma were difficult to distinguish on a clinicobiochemical basis.     

Distinct roles in phagocytosis of the early and late increases of cell surface calreticulin induced by oxaliplatin

Calreticulin (CRT), a chaperone typically located in the endoplasmic reticulum (ER), is known to translocate to the cell surface in response to anticancer drugs. Cell surface CRT (ecto-CRT) on apoptotic or pre-apoptotic cells serves as an “eat me” signal that can promote phagocytosis. In this study, we observed the biphasic (early transient and late sustained) increase of ecto-CRT on HT-29 cells after treatment with oxaliplatin (L-OHP). To investigate the role of ecto-CRT that accumulates in the early and late phases as “eat me” signals, we examined the phagocytosis of HT-29 cells by macrophage-like cells and dendritic cell (DC) -like cells prepared from THP-1 cells. The results indicated that the early ecto-CRT-expressed cells were phagocytosed by immature DC-like cells, and the late ecto-CRT-expressed cells were phagocytosed primarily by macrophage-like cells, while mature DC-like cells did not respond to the either class of ecto-CRT-expressed cells. Both types of phagocytotic events were inhibited by CRT Blocking Peptide, suggesting that such events depended on the ecto-CRT. Our results suggested that the early increase of ecto-CRT is related to phagocytosis as part of immunogenic cell death (ICD), while the late increase of ecto-CRT is related to the removal of apoptotic cells by macrophages.     

Should We Use Prolactin Adjustment in Bilateral Inferior Petrosal Sinus Sampling to Diagnose Cushing Disease? A Joint Meta-Analysis of Head-to-Head Diagnostic Tests Accuracy Studies

ObjectivePrevious studies have shown inconsistent results regarding the usefulness of prolactin adjustment in bilateral inferior petrosal sinus sampling (BIPSS) in the differential diagnosis of adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome (CS). This meta-analysis compared the diagnostic accuracy of prolactin adjustment versus no adjustment in BIPSS.MethodsThis study searched the PubMed, Embase, Web of Science, Cochrane library, and WanFang databases for published data as of March 2022 on the use of prolactin adjustment in BIPSS to differentially diagnose ACTH-dependent CS. A Bayesian joint bivariate model was used in the head-to-head comparison of the diagnostic accuracy.ResultsThis meta-analysis included a total of 10 studies with 300 patients. The combined sensitivity and specificity for BIPSS without prolactin adjustment were 94.47% (95% CI, 88.67%-98.44%) and 91.14% (95% CI, 57.17%-99.80%), respectively. The combined sensitivity and specificity after prolactin adjustment were 99.97% (95% CI, 99.03%-100.00%) and 80.69% (95% CI, 50.27%-97.82%), respectively. After the prolactin adjustment, the sensitivity of BIPSS to diagnose Cushing disease was improved with a statistically significant difference (difference in sensitivity, 5.39%; 95% CI, 1.37%-11.26%), whereas the decrease in specificity was without a statistically significant difference (difference in specificity, −9.20%; 95% CI, −42.02% to 26.61%).ConclusionThis meta-analysis indicated that prolactin adjustment in BIPSS might help to recognize Cushing disease among patient with ACTH-dependent CS. However, prolactin adjustment may not help identify ectopic ACTH syndrome in BIPSS.     

Mechanical suppression of premature ventricular complexes during catheter ablation procedures

IntroductionMechanical suppression of premature ventricular complexes (PVCs) is not a well-known observation. We retrospectively reviewed this phenomenon in the Ventricular Arrhythmia (VA) ablation procedures performed at Richard L. Roudebush Veterans Health Administration (VHA) center.MethodsData from 40 consecutive patients who underwent VA ablation at VHA, Indianapolis, IN, with 44 VA was included in the study. Demographic and electrophysiological parameter data was collected.ResultsOverall the mean age of the population was 64 ± 11 years. The phenomenon of mechanical suppression was seen in 11 PVCs. The mean age was 59 ± 15 years in the group in which mechanical suppression was seen. Of the 11 cases, the site of earliest activation was seen in the coronary sinus in 8 and in the pulmonary artery in 3. In one case catheter ablation was not performed because of proximity to the left coronary artery system. However, sustained pressure at the site with earliest electrograms (?35 ms) and 95% pacematch resulted in long-term suppression of PVCs. In the cases in which mechanical suppression was seen, there was a statistically significant reduction in PVC burden compared to pre ablation PVC load (1.1% ± 1.50% (post ablation) versus 24.04% ± 13.07% (pre ablation) versus p < 0.05).In all the 11 cases the site of mechanical suppression was also the site with earliest electrograms.ConclusionThis case series illustrates phenomenon of mechanical suppression of PVCs as an indication for good site for successful ablation in unique veteran patient population.     

Hemodynamic monitoring by intracardiac impedance measured by cardiac resynchronization defibrillators: Evaluation in a controlled clinical setting (BIO.Detect HF II study)

BackgroundIn patients with cardiac resynchronization therapy defibrillators (CRT-Ds), intracardiac impedance measured by dedicated CRT-D software may be used to monitor hemodynamic changes. We investigated the relationship of hemodynamic parameters assessed by intracardiac impedance and by echocardiography in a controlled clinical setting.MethodsThe study enrolled 68 patients (mean age, 66 ± 9 years; 74% males) at 12 investigational sites. The patients had an indication for CRT-D implantation, New York Heart Association class II/III symptoms, left ventricular ejection fraction 15%–35%, and a QRS duration ≥150 ms. Two months after a CRT-D implantation, hemodynamic changes were provoked by overdrive pacing. Intracardiac impedance was recorded at rest and at four pacing rates ranging from 10 to 40 beats/min above the resting rate. In parallel, echocardiography measurements were performed. We hypothesized that a mean intra-individual correlation coefficient (r_mean) between stroke impedance (difference between end-systolic and end-diastolic intracardiac impedance) measured by CRT-D and the aortic velocity time integral (i.e., stroke volume) determined by echocardiography would be significantly larger than 0.65.ResultsThe hypothesis was evaluated in 40 patients with complete data sets. The r_mean was 0.797, with a lower confidence interval bound of 0.709. The study hypothesis was met (p = 0.007). A stepwise reduction of stroke impedance and stroke volume was observed with increasing heart rate.ConclusionsIntracardiac impedance measured by implanted CRT-Ds correlated well with the aortic velocity time integral (stroke volume) determined by echocardiography. The impedance measurements bear potential and are readily available technically, not requiring implantation of additional material beyond standard CRT-D system.     

Systemic levels of the soluble co-inhibitory immune checkpoints,CTLA-4, LAG-3, PD-1/PD-L1 and TIM-3 are markedly increased in basal cell carcinoma

Although co-inhibitory immune checkpoint proteins are primarily involved in promoting cell-cell interactions that suppress adaptive immunity, especially tumor immunity, the soluble cell-free variants of these molecules are also detectable in the circulation of cancer patients where they retain immunosuppressive activity. Nevertheless, little is known about the systemic levels of these soluble co-inhibitory immune checkpoints in patients with various subtypes of basal cell carcinoma (BCC), which is the most invasive and treatment-resistant type of this most commonly-occurring malignancy. In the current study, we have measured the systemic concentrations of five prominent co-inhibitory immune checkpoints, namely CTLA-4, LAG-3, PD-1/PD-L1 and TIM-3, as well as those of C-reactive protein (CRP) and vitamin D (VD), in a cohort of patients (n = 40) with BCC, relative to those of a group of control participants, using the combination of multiplex bead array, laser nephelometry and ELISA technologies, respectively. The median systemic concentrations of CRP and VD were comparable between the two groups; however, those of all five immune checkpoints were significantly elevated (P = 0.0184 - P = < 0.00001), with those of CTLA-4 and PD-1 being highly correlated (r = 0.87; P < 0.00001). This seemingly novel finding not only identifies the existence of significant systemic immunosuppression in BCC, but also underscores the therapeutic promise of immune checkpoint targeted therapy, as well as the potential of these proteins to serve as prognostic/predictive biomarkers in BCC.     

Associations of Urinary Polycyclic Aromatic Hydrocarbons With Bone Mineral Density at Specific Body Sites in U.S. Adults,National Health and Nutrition Examination Survey 2001 to 2004

ObjectiveWe aimed to analyze the association between certain types of urinary polycyclic aromatic hydrocarbons (PAHs) and bone mineral density (BMD) at specific sites of the body.MethodsA total of 2978 eligible participants from the National Health and Nutrition Examination Survey 2001 to 2004 were included in this study. Data of 8 urinary PAHs and BMDs of 3 skeleton sites and the total body were analyzed. Univariate and multivariate linear regression analyses were performed to explore the association between urinary PAHs and BMDs. Subgroup analyses stratified by sex and body mass index were also performed.ResultsAfter adjustment for all confounders, elevated 3-fluorene (β = 0.046; 95% confidence intervals [CIs], 0.007-0.084) and 2-fluorene (β = 0.054; 95% CI, 0.007-0.100) levels were associated with greater left arm BMD, whereas no statistical differences were observed in the relationship between other PAHs and BMDs (all P > .05). Higher 3-fluorene and 2-fluorene levels were still associated with increased left arm BMD in men (P < .05), whereas the higher 2-phenanthrene level was related to decreased left arm BMD (β = ?0.062; 95% CI, ?0.105 to ?0.019), right arm BMD (β = ?0.059; 95% CI, ?0.091 to ?0.027), and total BMD (β = ?0.065; 95% CI, ?0.119 to ?0.012) in women. Similar results were also found in different body mass index populations (all P < .05).ConclusionCertain urinary PAHs are associated with BMDs at specific body sites. Future studies are needed to illustrate the mechanisms behind the association to establish a causal relationship.     

Thyroid Immune-Related Adverse Events in Patients with Cancer Treated with anti-PD1/anti-CTLA4 Immune Checkpoint Inhibitor Combination: Clinical Course and Outcomes

ObjectiveThyroid immune-related adverse events (irAEs) have been reported to have prognostic significance among patients with cancer treated with anti-programmed cell death-1 (PD1) and anti-programmed death-ligand 1 monotherapies. We evaluated the clinical course and predictors of thyroid irAEs in relation to outcomes of patients with advanced cancer treated with combination anti-PD1/anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4).MethodsWe conducted a regional study and identified patients with advanced cancer who received ≥1 cycle of combination anti-PD1/anti-CTLA4 between 2015 and 2019 in Hong Kong. Thyroid function tests (TFTs) were monitored every 3 weeks. Thyroid irAE was defined by ≥2 abnormal TFTs after initiation of combination anti-PD1/anti-CTLA4 in the absence of other causes.ResultsOne hundred and three patients were included (median age: 59 years; 71.8% men). About 45% had prior anti-PD1 exposure. Upon median follow-up of 6.8 months, 17 patients (16.5%) developed thyroid irAEs, where 6 initially presented with thyrotoxicosis (overt, n = 4; subclinical, n = 2) and 11 with hypothyroidism (overt, n = 2; subclinical, n = 9). Eventually, 10 patients (58.8%) required continuous thyroxine replacement. Systemic steroid was not required in all cases. Prior anti-PD1 exposure (odds ratio, 3.67; 95% CI, 1.19–11.4; P = .024) independently predicted thyroid irAEs. Multivariable Cox regression analysis revealed that occurrence of thyroid irAEs was independently associated with better overall survival (adjusted hazard ratio, 0.34; 95% CI, 0.17–0.71; P = .004).ConclusionThyroid irAEs are common in routine clinical practice among patients with advanced cancer treated with anti-PD1/anti-CTLA4 combination and might have potential prognostic significance. Regular TFT monitoring is advised for timely treatment of thyroid irAEs to prevent potential morbidities.     

Long COVID in Patients With Mild to Moderate Disease: Do Thyroid Function and Autoimmunity Play a Role?

ObjectivePost-acute sequelae of coronavirus disease 2019 (COVID-19) or long COVID (LC) is an emerging global health issue. Fatigue is a common feature. Whether thyroid function and autoimmunity play a role is uncertain. We aimed to evaluate the prevalence and predictors of LC and the potential role of thyroid function and autoimmunity in LC.MethodsWe included consecutive adults without a known thyroid disorder who were admitted to a major COVID-19 center for confirmed COVID-19 from July to December 2020. Thyroid function tests and antithyroid antibodies were measured for all patients on admission and at follow-up. LC was defined by the presence or persistence of symptoms upon follow-up.ResultsIn total, 204 patients (median age, 55.0 years; 95 men [46.6%]) were reassessed at a median of 89 days (interquartile range, 69-99) after acute COVID-19. Of the 204 patients, 41 (20.1%) had LC. Female sex (adjusted odds ratio, 2.48; P = .018) and severe acute respiratory syndrome coronavirus 2 polymerase chain reaction cycle threshold value of <25 on admission (adjusted odds ratio, 2.84; P = .012) independently predicted the occurrence of LC. Upon follow-up, most abnormal thyroid function tests in acute COVID-19 resolved, and incident thyroid dysfunction was rare. Nonetheless, we observed incident antithyroid peroxidase (anti-TPO) positivity. Although baseline or follow-up thyroid function tests were not associated with the occurrence of LC, among 172 patients with symptomatic acute COVID-19, symptom resolution was more likely in those with positive anti-TPO upon follow-up (P = .043).ConclusionLC is common among COVID-19 survivors, with females and those with higher viral load in acute COVID-19 particularly being vulnerable. The observation of incident anti-TPO positivity warrants further follow-up for thyroid dysfunction. Whether anti-TPO plays a protective role in LC remains to be elucidated.     

A 30-Year,Single-Center Experience of Unilateral Adrenalectomy for Primary Bilateral Macronodular Adrenal Hyperplasia

ObjectiveThe aim was to assess the short- and long-term outcomes of unilateral adrenalectomy (UA) in patients with primary bilateral macronodular adrenal hyperplasia (PBMAH).MethodsWe conducted a retrospective study of 124 patients with PBMAH who underwent UA.ResultsOne hundred sixteen patients were available for follow-up (median, 28.5 months). Cushingoid features remitted in 43 of 65 patients (70.8%) with overt Cushing syndrome (CS). Hypertension and diabetes mellitus improved in 79 of 96 (82.3%) and 29 of 42 patients (69.0%), respectively. Glucocorticoid insufficiency developed in 7 of 116 patients (6.0%) after the surgery, and it resolved in all the patients during follow-up. The mean 24-hour urinary free cortisol level decreased gradually from 456.02 ± 422.33 mg/24 h at baseline to 84.47 ± 70.06 mg/24 h within 3 months and then increased progressively in some patients. Sixty-four of the 116 patients (55.2%) had biochemical recurrence and 43 patients (67.2%) underwent contralateral adrenalectomy. The median time interval between the second operation and the first UA was 24 months. Patients with overt CS had a larger surgical-side or contralateral adrenal volume than patients without overt CS. Patients with a contralateral adrenal volume of >33.54 mL or with a preoperative urinary free cortisol level of >216.08 mg/24 h were more likely to have recurrence.ConclusionThe efficiency of UA is transient for the majority of patients, and the indications should be strictly limited to those with subclinical or milder CS. Patients who undergo successful UA still require close life-time follow-up for the recurrence of hypercortisolism.     

Impact of baseline telomere length on survival and chemotherapy related toxicity in breast cancer patients receiving (neo)adjuvant anthracycline containing chemotherapy

PurposeThe aim of this study is to assess baseline mean leukocyte telomere length (TL) as a potential predictive factor for chemotherapy toxicity and a prognostic marker for long-term outcome in early breast cancer (BC) patients.Methods445 BC patients were selected, diagnosed between 2007 and 2010 with early BC and treated with (neo)adjuvant fluorouracil, epirubicin and cyclophosphamide (FEC) or with FEC and Docetaxel (FEC-D). RT-qPCR was performed on germline DNA samples collected at diagnosis before any treatment, to measure mean leukocyte TL. Uni- and multivariable logistic regression or Cox proportional hazard regression analyses were carried out to assess correlation between baseline TL and toxicity parameters (derived from the medical chart) or longer-term outcome.ResultsBaseline TL correlated with age as expected (p = 0.005), but not with febrile neutropenia (n = 97), left ventricular ejection fraction >10% decrease (n = 17) nor other toxicity endpoints measured (all p > 0.05). TL was neither associated with overall survival, breast cancer specific survival or distant disease-free survival (all p > 0.05).ConclusionsBaseline TL is not associated with chemotherapy-related toxicity nor long-term outcome in BC patients.     

Unique features of epicardial ventricular arrhythmias/premature ventricular complexes ablated from coronary venous system in veteran population

IntroductionVentricular arrhythmias/premature ventricular complexes (VA/PVCs) that can be ablated from within the coronary venous system (CVS) have not been described in the United States Veterans Health Administration (VHA) population. We retrospectively studied the VA/PVCs ablations that were performed in the VHA population.MethodsData from 42 consecutive patients who underwent VA/PVCs ablation at Veterans Affairs Hospital, Indianapolis, IN, with 44 VA/PVCs was included in the study. Patients were divided into two groups (CVS group [n = 10], and non-CVS group [n = 32]) based on where the earliest pre-systolic activation was seen with >95% pacematch.ResultsThe mean age in CVS group was 65 ± 8 years versus 64 ± 12 years (p = 0.69) in non-CVS group. Overall there was a statistically significant reduction in PVC burden post ablation (27.7% (pre-ablation) versus 4.7% (post-ablation). In the 10 patients in the CVS group, either ablation or catheter-related mechanical trauma resulted in complete (n = 6 [60%]) or partial (n = 4 [40%]) long-term suppression of VA/PVCs. Right bundle branch block-type VA/PVC (9/11: 82%) was the most common morphology in the CVS group, whereas in the non-CVS group, this type was seen in only 3/33 (9%). The CVS group (25% of total VA/PVCs) had shorter activation time compared to non CVS group.ConclusionIn our experience VA/PVCs with electrocardiograms suggestive of epicardial origin can often be safely and successfully ablated within the coronary venous system. These arrhythmias have unique features in Veterans patient population.     

Low Diagnostic Utility of Overnight High-Dose Dexamethasone Suppression Test in ACTH-Dependent Cushing’s Syndrome

ObjectiveOvernight high-dose dexamethasone suppression test (ON-HDDST) is a simple test to localize the source of ACTH in patients with ACTH-dependent Cushing’s syndrome (CS). However, previous studies have reported its varying accuracy. We studied the utility of ON-HDDST in diagnosing Cushing’s disease (CD) in a series of patients with CD and ectopic ACTH syndrome (EAS).MethodsWe conducted a retrospective study of 88 patients with ACTH-dependent CS (plasma ACTH > 20.0 pg/mL), who underwent an ON-HDDST. CD and EAS were diagnosed in 68 and 20 patients, respectively. Patients were investigated using MRI of the sellar region, CT of the thorax/abdomen, Gallium-68-DOTANOC PET scan, and bilateral inferior petrosal sinus sampling as required.ResultsPatients with EAS had a significantly higher serum cortisol after ON-HDDST than patients with CD (median [IQR], 19.9 [12.4-31.1] μg/dL vs 9.9 [5.1-25.0] μg/dL, P <.01). A suppressed ON-HDDST (≥50% fall from baseline) was noted in 44 (65%) patients with CD and 3 (15%) patients with EAS (P <.0001). Among patients with CD, cortisol suppression >50% was noted in 35 (76%) of patients with microadenoma and 7 (44%) with macroadenoma. Among patients with EAS, ON-HDDST was suppressed in 1 of 6 patients (17%) with an occult tumor and 2 of 14 patients (14%) with a localized tumor. The ROC curve plotted for the percentage suppression of cortisol had an area under the curve (AUC) of 0.72 (P =.01). The best test parameters, with 65% sensitivity, 85% specificity, 94% positive predictive value, 42% negative predictive value, and 69% accuracy, were at 50% cutoff level.ConclusionThe ON-HDDST had a poor diagnostic value in differentiating CD and EAS.     

Comparison of Preoperative Alpha-blockade for Resection of Paraganglioma and Pheochromocytoma

ObjectivePhenoxybenzamine (nonselective, noncompetitive alpha-blocker) is the preferred drug for preoperative treatment of pheochromocytoma, but doxazosin (selective, competitive alpha-blocker) may be equally effective. We compared the efficacy of doxazosin vs phenoxybenzamine.MethodsWe conducted a prospective study of patients undergoing pheochromocytoma or paraganglioma resection by randomizing pretreatment with phenoxybenzamine or doxazosin at a single tertiary referral center. The high cost of phenoxybenzamine led to high crossover to doxazosin. Randomization was halted, and a consecutive historical cohort of phenoxybenzamine patients was included for a case-control study design. The efficacy of alpha-blockade was assessed with preinduction infusion of incremental doses of phenylephrine. The primary outcomes were mortality, cardiovascular complications, and intensive care unit admission. The secondary outcomes were hemodynamic instability index (proportion of operation outside of hemodynamic goals), adequacy of blockade by the phenylephrine titration test, and drug costs.ResultsTwenty-four patients were prospectively enrolled (doxazosin, n = 20; phenoxybenzamine, n = 4), and 15 historical patients treated with phenoxybenzamine were added (total phenoxybenzamine, n = 19). No major cardiovascular complications occurred in either group. The phenylephrine dose-response curves showed less blood pressure rise in the phenoxybenzamine than in the doxazosin group (linear regression coefficient = 0.008 vs 0.018, P = .01), suggesting better alpha-blockade in the phenoxybenzamine group. The median hemodynamic instability index was 14% vs 13% in the phenoxybenzamine and doxazosin groups, respectively (P = .56). The median highest daily cost of phenoxybenzamine was $442.20 compared to $5.06 for doxazosin.ConclusionPhenoxybenzamine may blunt intraoperative hypertension better than doxazosin, but this difference did not translate to fewer cardiovascular complications and is offset by a considerably increased cost.     

Impact of Pancreatic Neuroendocrine Tumor on Mortality in Patients With von Hippel-Lindau Disease

ObjectiveThe main causes for morbidity and mortality in von Hippel-Lindau (VHL) disease are central nervous system hemangioblastoma and clear cell renal cell carcinoma, but the effect of VHL-related pancreatic neuroendocrine tumors (PNET) on patient outcome is unclear. We assessed the impact of PNET diagnosis in patients with VHL on all-cause mortality (ACM) risk.MethodsWe used the Surveillance, Epidemiology, and End Results database. Of 16 344 patients, 170 had VHL based on clinical diagnostic criteria, and 510 patients had PNET (91 VHL-related and 419 sporadic).ResultsSurvival analysis demonstrated a lower ACM among patients with VHL-related PNET compared to patients with sporadic PNET (log-rank test, P = .011). Among patients with VHL, ACM risk was higher with vs without PNET (P = .029). The subgroup analysis revealed a higher ACM risk with metastatic PNET (sporadic P = .0031 and VHL-related P = .08) and a similar trend for PNET diameter ≥3 cm (P = .06 and P = 0.1 in sporadic and VHL-related PNET, respectively). In a multivariable analysis of patients with VHL, diagnosis with PNET by itself was associated with a trend of lower risk for ACM, while presence of metastatic PNET was independently associated with increased ACM risk.ConclusionDiagnosis with PNET is not associated with a higher ACM risk in VHL by itself. The independent association of advanced PNET stage with higher mortality risk emphasizes the importance of active surveillance for detecting high-risk PNET at an early stage to allow timely intervention.     

DIA-Based Proteomics Identifies IDH2 as a Targetable Regulator of Acquired Drug Resistance in Chronic Myeloid Leukemia

Drug resistance is a critical obstacle to effective treatment in patients with chronic myeloid leukemia. To understand the underlying resistance mechanisms in response to imatinib mesylate (IMA) and adriamycin (ADR), the parental K562 cells were treated with low doses of IMA or ADR for 2 months to generate derivative cells with mild, intermediate, and severe resistance to the drugs as defined by their increasing resistance index. PulseDIA-based (DIA [data-independent acquisition]) quantitative proteomics was then employed to reveal the proteome changes in these resistant cells. In total, 7082 proteins from 98,232 peptides were identified and quantified from the dataset using four DIA software tools including OpenSWATH, Spectronaut, DIA-NN, and EncyclopeDIA. Sirtuin signaling pathway was found to be significantly enriched in both ADR-resistant and IMA-resistant K562 cells. In particular, isocitrate dehydrogenase (NADP(+)) 2 was identified as a potential drug target correlated with the drug resistance phenotype, and its inhibition by the antagonist AGI-6780 reversed the acquired resistance in K562 cells to either ADR or IMA. Together, our study has implicated isocitrate dehydrogenase (NADP(+)) 2 as a potential target that can be therapeutically leveraged to alleviate the drug resistance in K562 cells when treated with IMA and ADR.     

Are We Restoring Thyroid Hormone Signaling in Levothyroxine-Treated Patients With Residual Symptoms of Hypothyroidism?

IntroductionLevothyroxine (LT4) at doses that maintain the serum thyroid-stimulating hormone levels within the normal range constitutes the standard of care for the treatment of hypothyroidism. After a few months, this eliminates the signs and symptoms of overt hypothyroidism in the majority of patients, owing to the endogenous activation of thyroxine to triiodothyronine, the biologically active thyroid hormone. Still, a small percentage of the patients (10%-20%) exhibit residual symptoms, despite having normal serum thyroid-stimulating hormone levels. These symptoms include cognitive, mood, and metabolic deficits, with a significant impairment in psychological well-being and quality of life.ObjectiveTo provide a summary of progress in the approach of patients with hypothyroidism that exhibit residual symptoms despite treatment.MethodsWe reviewed the current literature and here we focused on the mechanisms leading to a deficiency of T3 in some LT4-treated patients, the role of residual thyroid tissue and the rationale for combination therapy with LT4 + liothyronine (LT3).ResultsA score of clinical trials comparing therapy with LT4 versus LT4 + LT3 concluded that both are safe and equally effective (neither is superior); however, these trials failed to recruit a sufficiently large number of patients with residual symptoms. New clinical trials that considered LT4-treated symptomatic patients revealed that such patients benefit from and prefer therapy containing LT4 + LT3; desiccated thyroid extract has also been used with similar results. A practical approach to patients with residual symptoms and on initiation of combination therapy with LT4 + LT3 is provided.ConclusionA recent joint statement of the American, British, and European Thyroid Associations recommends that a trial with combination therapy be offered to patients with hypothyroidism that do not fully benefit from therapy with LT4.