Ipilimumab-induced hypophysitis, a single academic center experience.

BACKGROUND: Immune checkpoint inhibitors, single or in combination, have recently become a cornerstone for the treatment of many malignancies. Ipilimumab, a CTLA-4 inhibitor, was initially FDA approved for treatment of unresectable or metastatic melanoma and subsequently in combination therapy for other cancers. Ipilimumab-induced hypophysitis (IH) risk of development varies in different studies between 0 and 17%. Furthermore, little is known on how to predict which patients will develop IH and its impact on efficacy of Ipilimumab and survival for these patients. Here we reviewed IH and its impact on progression-free survival (PFS) and overall survival (OS). METHODS: Retrospective, IRB- approved review of consecutive 117 melanoma patients who received ipilimumab between 2011 and 2016 was undertaken. Demographic and clinical characteristics, treatment timing and doses, time to progression after therapy, and survival data were reviewed. Patients were predefined in two groups: patients with and without IH. Descriptive statistics were used to summarize the demographic and clinical characteristics of the study sample. All values are shown as means and standard deviation [mean (SD)] unless indicated otherwise. P < 0.05 was considered to be statistically significant. RESULTS: Of the 117 patients, 15 (12.8%) with a median age of 62.1 years developed IH. In the IH cohort, 10 (66.7%) were male and were significantly older than females (median 67.7 vs. 50.8; P = 0.009). This difference was not seen in non-IH group. Male patients with IH were significantly older than males without IH (67.7 vs. 56.4 years, P = 0.020), however this difference was not observed in females. No patient who received prior cancer systemic therapy (0/30) developed IH vs. 17.2% (15/72) without prior therapy developed IH (OR 0.00; 95% CI 0.00 to 0.73, P = 0.011). Between IH and non-IH patients, there was no difference in gender, race, ethnicity, BMI, diabetes or autoimmune disease at baseline, number of administered ipilimumab cycles, presence of primary melanoma lesion, or BRAF status. IH and non-IH patients had a similar median PFS (8.1 vs. 6.8 months, HR = 0.51, 95% CI 0.24 to 1.05 P = 0.062) and OS (53.3 vs. 29.5 months; HR 0.66, 95% CI 0.30 to 1.46; P = 0.307). CONCLUSION: In this study of melanoma patients treated with Ipilimumab, risk of developing IH was high (almost 13%). Older age in men and no prior cancer therapy were associated with IH higher risk. Development of IH was not associated with PFS or OS. Increased use of immune checkpoint inhibitors in the future will impact IH overall risk, thus awareness is needed. Given the lack of reliable identifiable risk factors, close monitoring of signs and symptoms after each therapy cycle is critical for early detection and treatment of hypophysitis.

Clinical outcomes in male patients with lactotroph adenomas who required pituitary surgery: a retrospective single center study.

PURPOSE: Lactotroph adenomas (LA) are the most frequently encountered pituitary tumors. Although more frequently observed in women, LAs in men were recently included in a more aggressive category regardless of histological grading, by the WHO. We aimed to perform a rigorous retrospective review of a single center's pre-operative evaluation, patient characteristics and outcomes of male LAs patients requiring pituitary surgery. METHODS: A retrospective review, over 11 years, of patients who underwent resection of a pituitary adenoma at a single center was conducted. Predictors of persistent disease in male LAs patients along with a comparison to predictors of silent corticotroph adenomas (SCAs) patients who also underwent surgery at the center was also conducted. RESULTS: Thirty-one male patients with LAs were identified. When compared to SCAs patients, LAs male patients were younger (41 vs. 50 years of age, p = 0.01). Men with LAs had more invasive tumors (75% vs. 44.7% p = 0.02). More LAs in men had residual tumor after surgery than patients with SCA (92.6% vs. 42.1%, p < 0.001). Male patients with LAs and patients with SCA had similar rates of requiring additional surgery (28.9% vs. 24.1%, p = NS) and radiation therapy (18.4% vs. 19.4%, p = NS). CONCLUSIONS: High rates of DA resistance, invasive tumors and postoperative residual disease in male patients with LA who required surgery are shown. Surgery improved optic chiasm compression, PRL level and central hypogonadism but, not surprisingly, failed to normalize other pituitary hormones and/or eliminate need for DA therapy.

Novel implantable device to detect cardiac allograft rejection.

BACKGROUND: Allograft rejection remains the nemesis of solid organ transplantation. Soul Mate is a novel implantable wireless data transmission system that analyzes 9 intramyocardial electrogram parameters recorded from 4 or 6 configurations of 2 or 3 epicardial leads to detect allograft rejection. This study determined the ability of the Soul Mate to detect early rejection of transplanted hearts. METHODS AND RESULTS: Five dogs underwent heterotopic cervical heart transplantation and simultaneous implantation of the Soul Mate's Cardiac Rejection Monitoring Device. Dogs were initially immunosuppressed, but subsequent drug discontinuation allowed allograft rejection to appear. Allograft biopsies were performed at regular intervals to determine rejection grade, which was compared to a calculated rejection score determined as percent change from baseline of values for each intramyocardial electrogram. There was significant correlation between the biopsy results and the evolution of 5 parameters. The strongest correlation (r=0.939; P<0.001) was obtained using the "general median" parameter from 4 configurations, assessed 1 day before the biopsy, with a sensitivity of 85.7% and a specificity of 100% compared to the myocardial biopsy results. CONCLUSIONS: The Soul Mate allograft rejection monitoring system accurately detected transplanted heart rejection in a canine model noninvasively with continuous sampling. This proof-of-concept study suggests that the Soul Mate could be used to more intensely and more frequently monitor cardiac allografts for rejection.

In vivo evaluation of zirconia ceramic in the DexAide right ventricular assist device journal bearing.

Zirconia is a ceramic with material properties ideal for journal bearing applications. The purpose of this study was to evaluate the use of zirconium oxide (zirconia) as a blood journal bearing material in the DexAide right ventricular assist device. Zirconia ceramic was used instead of titanium to manufacture the DexAide stator housing without changing the stator geometry or the remaining pump hardware components. Pump hydraulic performance, journal bearing reliability, biocompatibility, and motor efficiency data of the zirconia stator were evaluated in six chronic bovine experiments for 14-91 days and compared with data from chronic experiments using the titanium stator. Pump performance data including average in vivo pump flows and speeds using a zirconia stator showed no statistically significant difference to the average values for 16 prior titanium stator in vivo studies, with the exception of a 19% reduction in power consumption. Indices of hemolysis were comparable for both stator types. Results of coagulation assays and platelet aggregation tests for the zirconia stator implants showed no device-induced increase in platelet activation. Postexplant evaluation of the zirconia journal bearing surfaces showed no biologic deposition in any of the implants. In conclusion, zirconia ceramic can be used as a hemocompatible material to improve motor efficiency while maintaining hydraulic performance in a blood journal bearing application.

A texting-based blood pressure surveillance intervention.

The authors examined whether using home BP measurements collected via a custom-built bi-directional-texting platform incorporated into patients' electronic medical records would lead to treatment calibration and improved BP management. Patients were randomized to either the intervention group and collected home measurements based on reminders and reported via bi-directional texting, or to the control group, with home BP measurement reporting via standard practice (eg, phone, electronic medical record portal) and instructed to return 7 morning and 7 evening BP measurements. Outcomes included number of BP measurements submitted, the number of medication changes, reduction in BP, and BP control. 72% of the intervention group submitted at least 14 readings, compared with 45% of the control group. BP control improved in both groups. However, the authors found no statistically significant difference in BP or the number of BP-medication changes at 1, 3, or 6 months compared with the control group.

Updates in Diagnosis and Treatment of Acromegaly.

Acromegaly is a rare disease, caused largely by a growth hormone (GH) pituitary adenoma. Incidence is higher than previously thought. Due to increased morbidity and mortality, if not appropriately treated, early diagnosis efforts are essential. Screening is recommended for all patients with clinical features of GH excess. There is increased knowledge that classical diagnostic criteria no longer apply to all, and some patients can have GH excess with normal GH response to glucose. Treatment is multifactorial and personalised therapy is advised.

Diabetes as an increasingly common comorbidity among patient hospitalizations for tuberculosis in the USA.

OBJECTIVE: Diabetes is a risk factor for active tuberculosis (TB). The purpose of this paper was to estimate the risk of hospitalization for TB with and without a secondary diagnosis of diabetes in groups with different ethnic backgrounds. RESEARCH DESIGN AND METHODS: We used the Nationwide Inpatient Sample from 1998 to 2011, identifying all patients with a primary diagnosis of TB and/or a secondary diagnosis of diabetes (type 1 or type 2) or HIV. Next, we performed logistic regression to investigate the association of diabetes status, HIV status, and race (and the interaction of diabetes and race) with the risk of hospitalization with a primary diagnosis of TB. We also included a time covariate, to determine whether potential risk factors changed during the study period. RESULTS: Controlling for HIV status, diabetes did not increase the odds of TB in white and black patients. However, in Hispanic and Asian/Pacific Islander patients, diabetes increased the odds of TB by a factor of 1.7 (95% CI 1.51 to 1.83). Asian/Pacific Islanders who had diabetes but not HIV experienced 26.4 (95% CI 23.1 to 30.1) times the odds of TB relative to the white males without diabetes or HIV. In addition, the percent of TB cases that belong to these high-risk groups (Asian/Pacific Islander/Hispanic diabetics) has more than doubled from 4.6% in 1998 to 9.6% in 2011. CONCLUSIONS: In specific demographic groups, diabetes was a strong risk factor for hospital admissions for TB.

A pilot study for inducing chronic heart failure in calves by means of oral monensin.

INTRODUCTION: Heart failure remains a major cause of mortality in the United States, despite advancing technologies, newer methods of treatment, and novel devices. To evaluate such novel devices, a large-animal model of chronic heart failure is critical in carrying out preclinical animal studies. METHODS: We evaluated the efficacy of oral monensin in inducing stable heart failure in five Jersey calves. Various doses of monensin were administered. Hemodynamics, pressure-volume loops, echocardiographic measurements, extent of tissue perfusion, and histopathologic data were recorded before and after induction of heart failure. RESULTS: Responses were variable in the animals. One experiment showed a significant decrease in cardiac output within one week, associated with simultaneous increases in left atrial pressure, central venous pressure, and mean pulmonary artery pressure. Left ventricular pressure-volume loops showed that the slope of the end-systolic pressure-volume relation decreased markedly between the baseline and terminal study, suggesting a decrease in contractility. Echocardiographic studies indicated a decrease in ejection fraction. Histopathologic analysis in cardiac tissue showed extensive fibrosis and necrosis. CONCLUSION: We demonstrated the feasibility of inducing and maintaining severe yet stable heart failure for up to 3 weeks in a calf model by administration of oral monensin.

Median sternotomy approach for chronic bovine experiments.

Lateral thoracotomy is the traditional surgical approach for preclinical animal testing of various ventricular assist devices. Median sternotomy, however, is regarded from a functional standpoint as the most appropriate approach for cardiac surgical procedures, particularly for device implantation. The purpose of this study was to evaluate the outcomes of performing a median sternotomy in chronic bovine studies. Three chronic studies using the sternotomy approach were performed. Surgical access was compared to the lateral thoracotomy approach used in three other animal experiments. Postoperative speed of recovery, pain management, sternotomy incision, and monitoring line exit site healing and infection were also evaluated. With sternotomy, better surgical access to all cardiac chambers and great vessels and more room for device placement were achieved. The recovery time was similar to that using the lateral thoracotomy approach, with no additional difficulties observed in standing or recumbency and no need for increased pain management. At the time of autopsy, the sternum was well healed without any sign of infection. In conclusion, these studies showed that a median sternotomy can be used successfully for chronic bovine studies. This approach will be used for our future biventricular assist device implantation surgeries.

Development of DexAide right ventricular assist device: update II.

The DexAide right ventricular assist device (RVAD) is a magnetically and hydrodynamically levitated implantable centrifugal pump. Recent progress includes 1) redesign of the inflow/outflow conduits, which yielded two successful 3-month experiments, 2) development of alternative journal bearing materials, and 3) completion of an 18-month duration of in vitro endurance testing. Verification testing of the RVAD electronics has been completed, and a prototype biventricular assist device (BVAD) system has been tested. Acute DexAide/CorAide BVAD implantations via median sternotomy in two calves documented BVAD control algorithms and anatomical fit. A drug-induced chronic calf heart failure model, currently under development in our laboratory, resulted in a successful BVAD implantation in a calf with heart failure. Our future plans are to complete in vitro and in vivo validation of alternative bearing materials, perform preclinical DexAide in vivo and in vitro reliability studies, and obtain Food and Drug Administration (FDA) approval for an Investigational Device Exemption to conduct a clinical pilot study. In conclusion, two successful 3 month in vivo experiments and an 18-month in vitro endurance test were completed. After final bearing material selection, the DexAide design will be "frozen" so that preclinical systems can be manufactured. BVAD experiments using a chronic heart failure model are in progress.