Citations

1044 Background: Trastuzumab is well-demonstrated to be associated with cardiotoxicity (typically reduced ejection fraction), most commonly in patients who also receive anthracycline. The vascular effects of trastuzumab and anthracycline are understudied; we aimed to compare change in endothelial function during and after trastuzumab and to assess how anthracycline receipt affects this. Methods: This is an observational prospective study of women with newly diagnosed HER2-positive breast cancer. All participants underwent baseline evaluation of endothelial function testing by use of the EndoPAT2000 device approximately every three months over the subsequent 18 months after the initiation of HER2-directed therapy +/- anthracycline. The primary endpoint was change in endothelial function over time using the reactive hyperemia index (RHI). Framingham Risk Score (FRS) and lower RHI are both known to be independent predictors of future cardiovascular events in the general population. RHI deterioration was defined as a 20% reduction from baseline RHI to any available follow-up RHI assessment. Univariate analyses assessed if age, FRS, baseline RHI, and RHI deterioration differed between recipients and non-recipients of anthracycline using the Wilcoxon test. A multivariate logistic model evaluated FRS, age, and anthracycline receipt as possible independent predictors of RHI deterioration. Results: Among 38 eligible patients who consented and completed baseline assessments in addition to at least one follow-up assessment, 17 (45%) subsequently received anthracycline. 145 total follow-up RHI assessments were available overall (5 per patient on average). There were no differences between recipients and non-recipients of anthracyclines with regard to age [mean 49 years (SD 12) vs 53 years (SD 11); p=0.25], baseline FRS [mean 1.0 (SD 1.0) vs 1.5 (SD 1.4); p= 0.28] or baseline RHI [mean 2.4 (SD 0.6) vs 2.1 (SD 0.7); p=0.09]. RHI deterioration was more common for anthracycline recipients (mean 43% vs 21%; p=0.004), and in the multivariate model, anthracycline use was the only independent predictor of RHI deterioration (odds ratio: 2.8; 95% confidence interval: 1.35-6.07; p=0.006). Conclusions: This study suggests that endothelial dysfunction is more common after combined anthracycline and HER2-directed therapy than after HER2-directed therapy alone. RHI should be further studied as a possible early biomarker of cardiovascular toxicity in patients receiving treatment for breast cancer.

Abstract Older patients often have multiple medical issues which predisposes them to complications of polypharmacy and medication interactions. We present a case of an 89-year-old female who presented to the emergency department after a fall. An electrocardiogram (ECG) showed a junctional bradycardia with a ventricular rate of 50 beats per minute (BPM). Her magnesium was 3.5 mg/dl (1.7–2.3 mg/dl). She had recently increased her milk of magnesia use for constipation. Pertinent other medications included verapamil 280 mg daily. On admission 2 grams of calcium gluconate IV were administered and the verapamil was held. An ECG the next morning showed sinus rhythm with a ventricular rate of 76 BPM.

Abstract Background In the classic description of perilunate injuries, the short radiolunate ligament (SRL) remains intact. Objective This study was aimed to determine the occurrence of SRL disruptions with perilunate injuries and review the clinical and radiographic outcomes after surgical management. Patients and Methods A retrospective review was conducted for patients who sustained a perilunate injury and a concomitant disruption of the SRL at a single–level-1 trauma center between January 2013 and January 2017. Patients with the combined injury pattern were compared with those with perilunate injury alone without SRL injury during the study period. Outcome measures included pain scores (visual analogue score), wrist and forearm range of motion, patient's return to their former occupation, and multiple radiographic parameters. Results Twenty-seven patients were treated operatively for a perilunate injury. Eight of these patients (30%) were found to have associated disruption of the SRL. When compared with patients with perilunate injury alone, these patients had a lower rate of return to work (57% [4 of 7] vs. 92% [12 of 13]), a significantly longer mean length of time to return to work (5.9 vs. 3.8 months), and a higher rate of associated upper extremity injury (75% [3 of 8] vs. 16% [3 of 19]. Conclusion Combined SRL disruption and perilunate dislocation or fracture dislocation represent a high-energy variant from the classic description of a perilunate injury. A heightened awareness for this combined injury pattern should be maintained when treating patients with perilunate injuries. Level of Evidence This is a Level III, prognostic study.

Abstract Context Appropriate management of adrenal insufficiency (AI) in pregnancy can be challenging due to the rarity of the disease and lack of evidence-based recommendations to guide glucocorticoid and mineralocorticoid dosage adjustment. Objective Multicenter survey on current clinical approaches in managing AI during pregnancy. Design Retrospective anonymized data collection from 19 international centers from 2013 to 2019. Setting and Patients 128 pregnancies in 113 women with different causes of AI: Addison disease (44%), secondary AI (25%), congenital adrenal hyperplasia (25%), and acquired AI due to bilateral adrenalectomy (6%). Results Hydrocortisone (HC) was the most commonly used glucocorticoid in 83% (97/117) of pregnancies. Glucocorticoid dosage was increased at any time during pregnancy in 73/128 (57%) of cases. In these cases, the difference in the daily dose of HC equivalent between baseline and the third trimester was 8.6 ± 5.4 (range 1-30) mg. Fludrocortisone dosage was increased in fewer cases (7/54 during the first trimester, 9/64 during the second trimester, and 9/62 cases during the third trimester). Overall, an adrenal crisis was reported in 9/128 (7%) pregnancies. Cesarean section was the most frequent mode of delivery at 58% (69/118). Fetal complications were reported in 3/120 (3%) and minor maternal complications in 15/120 (13%) pregnancies without fatal outcomes. Conclusions This survey confirms good maternal and fetal outcome in women with AI managed in specialized endocrine centers. An emphasis on careful endocrine follow-up and repeated patient education is likely to have reduced the risk of adrenal crisis and resulted in positive outcomes.

Abstract Context Clinical applications of genomic assessment of thyroid cancers are rapidly evolving. Objectives, Design, and Setting We studied tumor samples from patients with imminently threatening and rare thyroid cancers to identify genomic alterations that might correlate with outcomes and/or be productively therapeutically targetable. Patient Context Progressive and metastatic, and/or rare, thyroid cancers were studied, 2012 to 2016, at Mayo Clinic sites. Intervention The intervention was Foundation One tumor interrogation. Main Outcome Measures Main outcome measures included genomic alterations, patient characteristics, and overall survival. Results Samples from 55 patients were evaluated: 20 anaplastic thyroid cancers (ATCs) (36%), 25 radioactive iodine–refractory differentiated thyroid cancers (DTCs)/poorly differentiated thyroid cancers (PDTCs) (45%; 14 papillary thyroid cancer [PTCs], 6 PDTCs, 5 Hürthle cell cancers), 8 medullary thyroid cancers (MTCs) (15%), and 2 others (a spindle epithelial tumor with thymus-like differentiation, and a primary thyroid sarcoma). Overall, 72% of DTCs, 79% of ATCs, and 75% of MTCs were deemed to have potentially productively targetable alterations. The most commonly encountered mutation was of TERT promoter (56% of DTCs, 68% of ATCs)—but this is not presently targetable. Targetable BRAFV600E mutations were found in 40% of DTCs/PDTCs (83% of PTCs) and 32% of ATCs; of MTCs, 75% had targetable RET mutations, and 25% HRAS mutations. Of patient tumors with nonmutated BRAFV600E, 53% of DTC/PDTCs and 69% of ATCs had other potentially productively targetable mutations. Genomic alterations in our series of poor prognosis metastatic DTC/PDTCs also closely resembled those seen in ATC. Conclusions Whereas genomic interrogation of favorable prognosis thyroid cancer seems ill advised, potentially productively targetable mutations were demonstrated in the majority of tumors from patients with metastatic thyroid cancers requiring systemic therapy, suggesting a rationale for the selective application of this technology.

Abstract Patients with chronic lymphocytic leukemia (CLL) are characterized by monoclonal expansion of CD5+CD23+CD27+CD19+κ/λ+ B lymphocytes and are clinically noted to have profound immune suppression. In these patients, it has been recently shown that a subset of B cells possesses regulatory functions and secretes high levels of interleukin 10 (IL-10). Our investigation identified that CLL cells with a CD19+CD24+CD38hi immunophenotype (B regulatory cell [Breg]–like CLL cells) produce high amounts of IL-10 and transforming growth factor β (TGF-β) and are capable of transforming naive T helper cells into CD4+CD25+FoxP3+ T regulatory cells (Tregs) in an IL-10/TGF-β-dependent manner. A strong correlation between the percentage of CD38+ CLL cells and Tregs was observed. CD38hi Tregs comprised more than 50% of Tregs in peripheral blood mononuclear cells (PBMCs) in patients with CLL. Anti-CD38 targeting agents resulted in lethality of both Breg-like CLL and Treg cells via apoptosis. Ex vivo, use of anti-CD38 monoclonal antibody (mAb) therapy was associated with a reduction in IL-10 and CLL patient-derived Tregs, but an increase in interferon-γ and proliferation of cytotoxic CD8+ T cells with an activated phenotype, which showed an improved ability to lyse patient-autologous CLL cells. Finally, effects of anti-CD38 mAb therapy were validated in a CLL–patient-derived xenograft model in vivo, which showed decreased percentage of Bregs, Tregs, and PD1+CD38hiCD8+ T cells, but increased Th17 and CD8+ T cells (vs vehicle). Altogether, our results demonstrate that targeting CD38 in CLL can modulate the tumor microenvironment; skewing T-cell populations from an immunosuppressive to immune-reactive milieu, thus promoting immune reconstitution for enhanced anti-CLL response.

AbstractObjectiveComprehensive data about patients with bilateral pheochromocytoma are limited. We aimed to describe the clinical presentation, genetic analysis, treatment and outcomes of patients with bilateral pheochromocytoma.DesignA retrospective study at a tertiary care centre.PatientsAll patients with bilateral pheochromocytoma evaluated at Mayo Clinic in Rochester, Minnesota between January 1951 and December 2015.MeasurementsTumour size, genetic testing, plasma/urine metanephrines and catecholamines.ResultsA total of 94 patients (51% women) were diagnosed with bilateral pheochromocytoma at a median age at first presentation of 31 years (range, 4‐70). Bilateral disease was noted in 8.0% of pheochromocytoma patient overall and 37.5% of patients 18 years of younger. Most patients presented with synchronous tumours (80%). Median time to metachronous tumours was 4.5 years (range, 1‐38). Genetic disease was identified in 75 (80%) patients, including MEN 2A (42.6%), VHL (19.1%), MEN 2B (9.6%) and NF1 (8.5%). Excess catecholamines were present in 97% of patients. Patients with synchronous pheochromocytoma commonly underwent simultaneous bilateral adrenalectomy (99%), and 18 (24%) had cortical‐sparing surgery. Multicentric tumours were reported in 23 of 77 (30%) patients with available data. Recurrent disease was found in 9.6% of patients, and 8.5% developed metastatic disease. Median follow‐up was 8.5 years. At the study conclusion, 4 patients had died due to pheochromocytoma or adrenalectomy.ConclusionsBilateral pheochromocytoma occurred in 7.0% of adults with pheochromocytoma and 37.5% of paediatric patients. Genetic disease was identified in 80% of patients, predominantly MEN2A. Multicentric tumours were common, but most were still cured following adrenalectomy.

Abstract Myelolipoma is the second most common adrenal tumor. Yet, systematic approach to these tumors remains poorly defined. Thus, we aimed to describe natural history of myelolipoma and to identify predictors of tumor growth and need for surgery. We conducted a retrospective longitudinal follow-up study of consecutive patients with myelolipoma. A total of 321 myelolipomas (median size, 2.3 cm [range, 0.5-18.0]) were diagnosed in 305 patients at median age of 63 years (25-87). Most myelolipomas were discovered incidentally (86.6%), whereas others were discovered on imaging done for cancer staging (8.8%) or during workup of mass effect symptoms (4.6%). Median duration of follow-up was 54 months (range, 0.03-267). Compared with myelolipomas <6 cm, tumors ≥6 cm were more likely to be right-sided (59% vs 41%, P=0.02), bilateral (21% vs 3%, P <.0001), cause mass effects symptoms (32% vs 0%, P<.0001), have radiographic hemorrhagic changes (14% vs 1%, P<.0001), and undergo adrenalectomy (52% vs 5%, P<.0001). There was no difference in sex or age at diagnosis between the groups. Hemorrhagic changes were noted in 9 (3.0%) patients with median tumor size of 7.0 cm (range, 1.8-18.0). Concomitant adrenal hormone excess was diagnosed in 12/126 (9.5%) patients. Primary aldosteronism was noted in 9 patients: due to concomitant ipsilateral (n=3) or contralateral adrenocortical adenoma (n=3), or bilateral idiopathic adrenal hyperplasia (n=3). Autonomous cortisol excess was noted in 3 patients: due to concomitant contralateral (n=2) or ipsilateral adrenocortical adenoma (n=1). Of 162 patients with ≥6 months of imaging follow-up, tumor size change ranged from -10 to 115 mm (median, 0 mm) and tumor growth rate ranged from -5.6 to 140 mm/year (median, 0 mm/year). Tumor growth ≥1.0 cm (n=26, 16.0%) was associated with larger initial tumor size (3.6 vs 2.3 cm, P=0.02) and hemorrhagic changes on imaging (12% vs 2%, P=0.007), compared with <1 cm size change. Myelolipomas with ≥1.0 cm growth were more likely to undergo adrenalectomy (35% vs 8%, P<.0001). Among 37 (12%) patients that underwent adrenalectomy for myelolipoma, surgical indications included: large tumor size/tumor growth (32%), diagnostic surgery (27%), mass effect symptoms (14%), concomitant ipsilateral tumor leading to hormonal excess (11%), acute hemorrhage (8%), and concomitant resection during non-adrenal surgery (8%). In conclusion, most myelolipomas are discovered incidentally, whereas myelolipomas ≥6 are more likely to cause mass effect symptoms, have radiographic hemorrhagic changes, and more commonly undergo resection. Hormonal excess is rare and is usually attributed to concomitant adrenocortical adenoma or hyperplasia. Tumor growth ≥1.0 cm is associated with larger myelolipoma and presence of hemorrhagic changes. Surgical resection should be considered in symptomatic patients with large tumors, evidence of hemorrhage, or tumor growth.

Abstract Neuroendocrine tumors (NET) represent up to 0.5% of all new cancers and can be functional or non-functional. Epidemiologic data on NET in Mexico is very limited. To delineate the clinical characteristics of patients with functional NET at a tertiary national referral center in Mexico we performed a retrospective cohort study (January 1987-June 2019). The target study population was adults with functional NET with biochemical and histopathological confirmation. Results: 126 patients with functional NET were included in this study. The median follow-up was 47.4 months (IQR 10.8 to 93.7). Most were female (64.3%). The mean age at diagnosis was 46.3 ± 14.48 years. The most frequent insulinomas (59.5%), followed by (12.7%) carcinoid tumors, gastrinomas (11.1%), ACTHomas (10.3%), VIPomas (2.4%) glucagonomas (2.4%) and PPomas (1.6%). Nineteen subjects (15.1%) had genetic syndromes, mainly MEN1 (89.5%); and 8.7% had other neoplasms, most frequently non-functional gastrointestinal (GI) carcinoids (36.3%) and thyroid cancer (18.8%). The median duration of symptoms prior to diagnosis was 24 months (IQR 7.75 to 48). The most common locations were, the GI tract (86.5%), whereas 7.1% were outside the GI tract and 6.4% were of unknown primary origin. Functional NETs outside GI tract were localized primarily in lungs (66.6%). Functional pancreatic NETs occurred more commonly in the tail (39.6%). 24.6% had locoregional or distant metastasis during follow-up. The most frequent metastatic sites were liver (86.5%), regional lymph nodes (59.8%) and bone (13.5%). The most common treatment was surgery (87.3%, with 13.6% ≥2), followed by 18.3% somatostatin receptor analogues and 11.1% cytotoxic chemotherapy. Most subjects (73%) had complete remission with first line therapy, but 14.1% had recurrence at a median of 50.7 months (IQR 15.4 to 97.6). Subjects with an incomplete remission progressed after a median of 14.85 months (IQR 10 to 38.9). Conclusions: The clinical characteristics of functional NET treated at a tertiary center in Mexico are similar to those in other population and geographic locations described in the literature.

Background: Peripherally inserted central catheters and centrally inserted central catheters have numerous benefits but can be associated with risks. This meta-analysis compared central catheters for relevant clinical outcomes using recent studies more likely to coincide with practice guidelines. Methods: Several databases, Ovid MEDLINE, Embase, and EBM Reviews were searched for articles (2006–2018) that compared central catheters. Analyses were limited to peer-reviewed studies comparing peripherally inserted central catheters to centrally inserted central catheters for deep vein thrombosis and/or central line–associated bloodstream infections. Subgroup, sensitivity analyses, and patient-reported measures were included. Risk ratios, incidence rate ratios, and weighted event risks were reported. Study quality assessment was conducted using Newcastle–Ottawa and Cochrane Risk of Bias scales. Results: Of 4609 screened abstracts, 31 studies were included in these meta-analyses. Across studies, peripherally inserted central catheters were protective for central line–associated bloodstream infection (incidence rate ratio = 0.52, 95% confidence interval: 0.30–0.92), with consistent results across subgroups. Peripherally inserted central catheters were associated with an increased risk of deep vein thrombosis (risk ratio = 2.08, 95% confidence interval: 1.47–2.94); however, smaller diameter and single-lumen peripherally inserted central catheters were no longer associated with increased risk. The absolute risk of deep vein thrombosis was calculated to 2.3% and 3.9% for smaller diameter peripherally inserted central catheters and centrally inserted central catheters, respectively. On average, peripherally inserted central catheter patients had 11.6 more catheter days than centrally inserted central catheter patients ( p = 0.064). Patient outcomes favored peripherally inserted central catheters. Conclusion: When adhering to best practices, this study demonstrated that concerns related to peripherally inserted central catheters and deep vein thrombosis risk are minimized. Dramatic changes to clinical practice over the last 10 years have helped to address past issues with central catheters and complication risk. Given the lower rate of complications when following current guidelines, clinicians should prioritize central line choice based on patient therapeutic needs, rather than fear of complications. Future research should continue to consider contemporary literature over antiquated data, such that it recognizes the implications of best practices in modern central catheterization.