Evaluating Patient-Reported Outcomes in Cushing's Syndrome.

The importance of the patient's perspective on disease has increasingly gained traction among clinical investigators and clinicians. Patient-reported outcomes (PROs) are those which pertain to a patient's health, quality of life, or functional status (associated with health care or treatment) that are reported directly by the patient, without interpretation by a clinician. In this article, we will review PROs as they relate to the signs, symptoms, health-related quality of life, and comorbidities of active Cushing's syndrome (CS), and CS after treatment with surgery, radiotherapy, and medical therapy. We will explore long-term outcomes in the setting of remission, persistence, and recurrence in this population.

Persistent vs Recurrent Cushing's Disease Diagnosed Four Weeks Postpartum.

Background: Cushing's disease (CD) recurrence in pregnancy is thought to be associated with estradiol fluctuations during gestation. CD recurrence in the immediate postpartum period in a patient with a documented dormant disease during pregnancy has never been reported. Case Report. A 30-year-old woman with CD had improvement of her symptoms after transsphenoidal resection (TSA) of her pituitary lesion. She conceived unexpectedly 3 months postsurgery and had no symptoms or biochemical evidence of recurrence during pregnancy. After delivering a healthy boy, she developed CD 4 weeks postpartum and underwent a repeat TSA. Despite repeat TSA, she continued to have elevated cortisol levels that were not well controlled with medical management. She eventually had a bilateral adrenalectomy. Discussion. CD recurrence may be higher in the peripartum period, but the link between pregnancy and CD recurrence and/or persistence is not well studied. Potential mechanisms of CD recurrence in the postpartum period are discussed below. Conclusion: We describe the first report of recurrent CD that was quiescent during pregnancy and diagnosed in the immediate postpartum period. Understanding the risk and mechanisms of CD recurrence in pregnancy allows us to counsel these otherwise healthy, reproductive-age women in the context of additional family planning.

The role of chemotherapy in patients with small cell lung cancer and poor performance status.

BACKGROUND: There are limited data on the role of chemotherapy in patients with small cell lung cancer (SCLC) and poor performance status (PS). METHODS: This was a retrospective analysis of a prospective observational study in patients with SCLC and PS 3 or 4. We recorded the initial therapy, symptom improvement, response rate, overall survival (OS), and the impact of various factors on OS. RESULTS: From June 2010 to August 2019, we enrolled 234 patients; 185 (79%) with PS 3 and 49 (21%) PS 4. Initial therapy was best supportive care (BSC) in 49 patients (21%), standard full dose chemotherapy in 31 (13%), and attenuated chemotherapy in 154 (66%). In 89% patients treated with attenuated chemotherapy, symptom-relief occurred at a median of 3 days (IQR, 1-7). Grade 3 and higher toxicities developed in 60% patients treated with initial attenuated chemotherapy, commonly hyponatremia in 39%, neutropenia in 16%, anemia in 11%, and infection in 10%. Grade 3 and higher toxicities as a result of standard chemotherapy occurred in 89% patients treated with upfront standard full dose chemotherapy compared to 69% of patients who received initial attenuated chemotherapy with subsequent treatment escalation. Overall, there were 6 (2.6%) toxic deaths. The response rate to chemotherapy was 77%. The median OS of the patients who received any chemotherapy was significantly longer at 6 months (95% CI, 4.8-7.2) compared to 1 month (95% CI, 0.4-1.6 months) in patients who were managed with BSC, p < 0.001; hazard ratio, 0.39 (95% CI, 0.27-0.56). The disease stage, lactate dehydrogenase level, and receipt of chemotherapy significantly impacted survival. CONCLUSION: Chemotherapy prolongs survival in patients with SCLC and poor PS. Administering an initial attenuated chemotherapy regimen followed by standard full-dose chemotherapy when the PS improves may lower toxicity and improve tolerance.

Physiologic proteinuria in labor and postpartum: The results of the postpartum proteinuria trial (PoPPy).

The urine protein to creatinine ratio (PC) is a sensitive and specific means of diagnosing preeclampsia in the antepartum period, but the 0.3 g protein per gram of creatinine threshold may be non-specific postpartum due to physiologic proteinuria after delivery. The objective of this study was to examine the reliability of PC in labor and postpartum and to determine if PC is affected by mode of delivery. This is the first study of its kind to examine physiologic proteinuria by catheterized PC in individual patients before and after delivery. This single-center prospective cohort study included two groups: term uncomplicated nulliparous patients in labor with epidural analgesia and patients for scheduled repeat cesarean deliveries. Patients with hypertension, antepartum proteinuria, renal disease, gross hematuria, or evidence of infection were excluded. Catheterized pre- and post-delivery urine PC were compared using paired t-tests. 27 and 40 patients were included in the vaginal and cesarean delivery groups, respectively. 52% of the vaginal delivery and 58% of the cesarean delivery groups were positive for proteinuria at the 0.3 g protein per g creatinine threshold. Pre- and post-delivery specimens were significantly different in the vaginal (mean difference 0.28, p = 0.05) and cesarean (mean difference 0.25, p < 0.01) delivery groups. The conclusions reached included the finding that PC measurements are unreliable in the immediate postpartum period regardless of mode of delivery, and utilizing the 0.3 threshold to diagnose preeclampsia in close proximity to delivery would contribute to increased false positive tests.

Vasa Previa: Prenatal Diagnosis and Outcomes: Thirty-five Cases From a Single Maternal-Fetal Medicine Practice.

OBJECTIVES: To assess the accuracy and effectiveness of routine screening for vasa previa, to describe our experience, and to assess factors that contribute to missed cases of vasa previa. METHODS: A retrospective descriptive study of all cases of vasa previa from a single maternal-fetal medicine service between 2009 and 2017 was performed. Ultrasound findings and obstetric and neonatal outcomes were reviewed and analyzed. RESULTS: Thirty-five cases of vasa previa were identified. Most cases (33 of 35 [94.3%]) were diagnosed antenatally. All 33 cases that followed our screening protocol were diagnosed antenatally and had favorable outcomes. Two cases that did not follow our protocol were not diagnosed antenatally and were delivered emergently. The mean gestational age ± SD at delivery of antenatally diagnosed cases was 34.9 ± 1.69 weeks. All neonates survived. CONCLUSIONS: Routine ultrasound screening for vasa previa using American Institute of Ultrasound in Medicine criteria will almost universally lead to good outcomes and prevent perinatal mortality.

Is preeclampsia an independent predictor of diastolic dysfunction? A retrospective cohort study.

OBJECTIVE: To determine if preeclampsia is an independent predictor of diastolic dysfunction and what factors among patients with preeclampsia are associated with diastolic dysfunction. METHODS: This is a retrospective cohort study of patients who delivered between 2008 and 2013 at a single institution who had a maternal echocardiogram during their pregnancy or within 5months of delivery. Patients with structural heart disease, ejection fraction less than 45%, pulmonary embolus, or age over 45years were excluded. Medical records were reviewed for medical and obstetric complications and echocardiogram findings. Demographic characteristics and rate of diastolic dysfunction were compared between patients with preeclampsia and without preeclampsia. Multivariate logistic regression was performed controlling for age, ethnicity, gestational age at delivery, diabetes, preeclampsia, intrauterine growth restriction (IUGR), antihypertensive use and magnesium sulfate administration. RESULTS: Sixty-six patients were identified, of which 39 (59%) had preeclampsia. Past history of preeclampsia, IUGR in the current pregnancy, antihypertensive use and magnesium sulfate use were higher in the preeclampsia group. Fifteen patients (39%) in the preeclampsia group were African-American compared to 2 (3%) in the control group (p<0.01). Seventeen (44%) of the patients with preeclampsia were found to have diastolic dysfunction compared to 3 (11%) controls (OR=6.18, 95% CI 1.59,24.02; p=0.006). Logistic regression analysis did not reveal other independent predictors of diastolic dysfunction. In the patients with preeclampsia, history of preeclampsia with severe features and IUGR were not associated with diastolic dysfunction. CONCLUSIONS: Our study supports previous findings that preeclampsia is associated with diastolic dysfunction.

Neurite sprouting and synapse deterioration in the aging Caenorhabditis elegans nervous system.

Caenorhabditis elegans is a powerful model for analysis of the conserved mechanisms that modulate healthy aging. In the aging nematode nervous system, neuronal death and/or detectable loss of processes are not readily apparent, but because dendrite restructuring and loss of synaptic integrity are hypothesized to contribute to human brain decline and dysfunction, we combined fluorescence microscopy and electron microscopy (EM) to screen at high resolution for nervous system changes. We report two major components of morphological change in the aging C. elegans nervous system: (1) accumulation of novel outgrowths from specific neurons, and (2) physical decline in synaptic integrity. Novel outgrowth phenotypes, including branching from the main dendrite or new growth from somata, appear at a high frequency in some aging neurons, but not all. Mitochondria are often associated with age-associated branch sites. Lowered insulin signaling confers some maintenance of ALM and PLM neuron structural integrity into old age, and both DAF-16/FOXO and heat shock factor transcription factor HSF-1 exert neuroprotective functions. hsf-1 can act cell autonomously in this capacity. EM evaluation in synapse-rich regions reveals a striking decline in synaptic vesicle numbers and a diminution of presynaptic density size. Interestingly, old animals that maintain locomotory prowess exhibit less synaptic decline than same-age decrepit animals, suggesting that synaptic integrity correlates with locomotory healthspan. Our data reveal similarities between the aging C. elegans nervous system and mammalian brain, suggesting conserved neuronal responses to age. Dissection of neuronal aging mechanisms in C. elegans may thus influence the development of brain healthspan-extending therapies.

Transradial approach for stenting of vertebrobasilar stenosis: a feasibility study.

BACKGROUND: Endovascular intervention of vertebrobasilar stenosis is a relatively new but alternative modality of management, supported by very few studies and case reports. Femoral approach has been used in all. The purpose of present study is to evaluate feasibility of the radial artery as an alternative approach for vertebral artery stenting (VAS) and basilar artery stenting (BAS). METHODS: Forty-seven patients (mean age 70 +/- 5, 38 male) underwent VAS and BAS. VAS was offered in 42 and BAS was offered in five patients. All the patients were symptomatic having stenosis greater than 75%. The target vertebral artery (VA) was cannulated using a 6Fr Internal Mammary Artery (IMA) guide catheter using ipsilateral radial approach. 0.014'' floppy tip coronary guide wire was advanced and parked across the culprit stenosis. Pre dilation was done using a 2 x 12 mm(2) or a 2.5 x 12 mm(2) PTCA catheter and balloon mounted 2.5 x 13 mm(2) or 3 x 13 mm(2) bare metal stent was deployed using 8-10 atm pressure for all chronic lesions. For acute occlusions, the procedure was divided in two stages. In first stage, the lesion was dilated using PTCA catheter (1.5 x 12 mm(2)) at 4-6 atm pressure just to establish the distal flow. After 24 hr, the patient was brought back and the culprit lesion was stented using 8-10 atm pressure. The procedure was staged to prevent hyperperfusion brain injury. RESULTS: VAS was successful in 42/42 (100%) patients. BAS was successful in five out of five (100%) patients. However, three patients had transient periprocedural stroke which recovered completely within 6 hr and one patient developed intracerebral hemorrhage (ICH) who died after 24 hr. Hyper perfusion brain injury was the cause for ICH. CONCLUSION: VAS and BAS using the transradial approach appear to be safe, technically feasible, and reproducible. Technical ease of cannulation of vertebral artery with IMA guide catheter using ipsilateral transradial approach should make it more convenient when compared with femoral approach.

Effect of a single course of isotretinoin therapy on bone mineral density in adolescent patients with severe, recalcitrant, nodular acne.

BACKGROUND: Adverse changes in bone have been reported for patients undergoing high-dose, long-term (several years) isotretinoin therapy for disorders of cornification. The effect of short-term (4-5 months) therapy at the lower dose recommended for acne on bone development in younger, growing adolescent (12-17 years) patients has not been well studied. OBJECTIVE: The purpose of the study was to evaluate the effect of a standard, single course of isotretinoin (Accutane) therapy on bone mineral density (BMD) of the lumbar spine and hip in adolescents ages 12 to 17 years with severe, recalcitrant, nodular acne. METHODS: In this open-label, multicenter study, 217 adolescents (81 girls) with severe, recalcitrant, nodular acne were enrolled and treated with isotretinoin twice daily with food at the recommended total dose of approximately 1 mg/kg for 16 to 20 weeks. BMD in the lumbar spine and hip was measured at baseline and at the end of therapy by dual energy radiograph absorptiometry. RESULTS: There was no clinically significant mean change in BMD measured at the lumbar spine (+1.4%, range: -4.9% to +12.3%) or total hip (-0.26%, range: -11.3% to +15.0%). Hyperostosis was not observed in any patient. Typical efficacy expected in the treatment of acne was observed. CONCLUSIONS: A 16- to 20-week course of isotretinoin treatment at the recommended dose for severe acne has no clinically significant effect on lumbar spine and total hip BMD in the adolescent (12-17 years) population.

Echinacea purpurea for prevention of experimental rhinovirus colds.

A randomized, double-blind, placebo-controlled clinical trial was conducted to evaluate the ability of Echinacea purpurea to prevent infection with rhinovirus type 39 (RV-39). Forty-eight previously healthy adults received echinacea or placebo, 2.5 mL 3 times per day, for 7 days before and 7 days after intranasal inoculation with RV-39. Symptoms were assessed to evaluate clinical illness. Viral culture and serologic studies were performed to evaluate the presence of rhinovirus infection. A total of 92% of echinacea recipients and 95% of placebo recipients were infected. Colds developed in 58% of echinacea recipients and 82% of placebo recipients (P=.114, by Fisher's exact test). Administration of echinacea before and after exposure to rhinovirus did not decrease the rate of infection; however, because of the small sample size, statistical hypothesis testing had relatively poor power to detect statistically significant differences in the frequency and severity of illness.

The effect of isotretinoin on the pharmacokinetics and pharmacodynamics of ethinyl estradiol and norethindrone.

BACKGROUND: Isotretinoin is a known teratogen, and when it is prescribed to women of childbearing potential, 2 forms of contraception must be used, commonly including hormonal contraception. Although isotretinoin and estradiol are metabolized largely by cytochrome P450 (CYP) 3A4 and glucuronidation, the potential for clinical drug interaction, with subsequent pharmacodynamic impact, has not been evaluated. METHODS: We enrolled 26 healthy women who were to receive isotretinoin for the treatment of severe, recalcitrant nodular acne and who were taking or planning to take oral contraceptives. The pharmacokinetics of ethinyl estradiol and norethindrone (INN, norethisterone) (the components of Ortho Novum 7/7/7; Ortho-McNeil Pharmaceutical, Inc, Raritan, NJ) and pharmacodynamic assessments of oral contraceptive effectiveness (concentrations of serum progesterone, luteinizing hormone, and follicle-stimulating hormone) were determined on days 6 and 20 of 2 separate oral contraceptive cycles, before and during isotretinoin treatment. RESULTS: The addition of isotretinoin to the oral contraceptive regimen resulted in small and inconsistent, although statistically significant (P <.04), decreases in the concentrations of both ethinyl estradiol (9% decrease in area under the plasma concentration-time curve from time 0 to 24 hours after the dose on day 6) and norethindrone (11% decrease in maximum plasma concentration on day 20). Isotretinoin did not cause any statistically significant increases in pharmacodynamic markers, although a majority of women had increases in these measures. Although there was no correlation between isotretinoin (or metabolite) levels and oral contraceptive levels (P >.05), there was a correlation between progesterone level and oral contraceptive levels (P <.05). Variability was large for both pharmacokinetic measures (median coefficients of variation of 44%-69% [for each time point within a study period]) and pharmacodynamic measures (median coefficients of variation of 64%-114%). One woman in each study phase, one before and one during isotretinoin treatment, had a progesterone elevation consistent with possible ovulation. No serious or unexpected adverse events were observed. CONCLUSIONS: The small reduction in ethinyl estradiol and norethindrone levels associated with isotretinoin was not associated with any pharmacodynamic changes in our study. The combination of the teratogenic risk of isotretinoin and the large variability of and correlation between oral contraceptive levels and pharmacodynamic measures, however, strongly reinforces the necessity of additional contraceptive methods during concomitant administration of these drugs.