Ricardo Correa

Carney Complex: an update

Carney complex (CNC) is a rare autosomal dominant syndrome, characterized by pigmented lesions of the skin and mucosa, cardiac, cutaneous and other myxomas and multiple endocrine tumors. The disease is caused by inactivating mutations or large deletions of the PRKAR1A gene located at 17q22-24 coding for the regulatory subunit type I alpha of protein kinase A (PKA) gene. Most recently, components of the complex have been associated with defects of other PKA subunits, such as the catalytic subunits PRKACA (adrenal hyperplasia) and PRKACB (pigmented spots, myxomas, pituitary adenomas). In this report, we review CNC, its clinical features, diagnosis, treatment and molecular etiology, including PRKAR1A mutations and the newest on PRKACA and PRKACB defects especially as they pertain to adrenal tumors and Cushings syndrome.

Promotion of Wellness and Mental Health Awareness Among Physicians in Training: Perspective of a National, Multispecialty Panel of Residents and Fellows

BACKGROUND Physicians in training are at high risk for depression, and physicians in practice have a substantially elevated risk of suicide compared to the general population. The graduate medical education community is currently mobilizing efforts to improve resident wellness. OBJECTIVE We sought to provide a trainee perspective on current resources to support resident wellness and resources that need to be developed to ensure an optimal learning environment. METHODS The ACGME Council of Review Committee Residents, a 29-member multispecialty group of residents and fellows, conducted an appreciative inquiry exercise to (1) identify existing resources to address resident wellness; (2) envision the ideal learning environment to promote wellness; and (3) determine how the existing infrastructure could be modified to approach the ideal. The information was aggregated to identify consensus themes from group discussion. RESULTS National policy on resident wellness should (1) increase awareness of the stress of residency and destigmatize depression in trainees; (2) develop systems to identify and treat depression in trainees in a confidential way to reduce barriers to accessing help; (3) enhance mentoring by senior peers and faculty; (4) promote a supportive culture; and (5) encourage additional study of the problem to deepen our understanding of the issue. CONCLUSIONS A multispecialty, national panel of trainees identified actionable goals to broaden efforts in programs and sponsoring institutions to promote resident wellness and mental health awareness. Engagement of all stakeholders within the graduate medical education community will be critical to developing a comprehensive solution to this important issue.

Somatic USP8 Gene Mutations Are a Common Cause of Pediatric Cushing Disease

Context: Somatic mutations in the ubiquitin-specific protease 8 (USP8) gene have been recently identified as the most common genetic alteration in patients with Cushing disease (CD). However, the frequency of these mutations in the pediatric population has not been extensively assessed. Objective: We investigated the status of the USP8 gene at the somatic level in a cohort of pediatric patients with corticotroph adenomas. Design and Methods: The USP8 gene was fully sequenced in both germline and tumor DNA samples from 42 pediatric patients with CD. Clinical, biochemical, and imaging data were compared between patients with and without somatic USP8 mutations. Results: Five different USP8 mutations (three missense, one frameshift, and one in-frame deletion) were identified in 13 patients (31%), all of them located in exon 14 at the previously described mutational hotspot, affecting the 14-3-3 binding motif of the protein. Patients with somatic mutations were older at disease presentation [mean 5.1 ± 2.1 standard deviation (SD) vs 13.1 ± 3.6 years, P = 0.03]. Levels of urinary free cortisol, midnight serum cortisol, and adrenocorticotropic hormone, as well as tumor size and frequency of invasion of the cavernous sinus, were not significantly different between the two groups. However, patients harboring somatic USP8 mutations had a higher likelihood of recurrence compared with patients without mutations (46.2% vs 10.3%, P = 0.009). Conclusion: Somatic USP8 gene mutations are a common cause of pediatric CD. Patients harboring a somatic mutation had a higher likelihood of tumor recurrence, highlighting the potential importance of this molecular defect for the disease prognosis and the development of targeted therapeutic options.

Screening for GPR101 defects in pediatric pituitary corticotropinomas

Cushing disease (CD) in children is caused by adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas. Germline or somatic mutations in genes such as MEN1, CDKIs, AIP, and USP8 have been identified in pediatric CD, but the genetic defects in a significant percentage of cases are still unknown. We investigated the orphan G protein-coupled receptor GPR101, a gene known to be involved in somatotropinomas, for its possible involvement in corticotropinomas. We performed GPR101 sequencing, expression analyses by RT-qPCR and immunostaining, and functional studies (cell proliferation, pituitary hormones secretion, and cAMP measurement) in a series of patients with sporadic CD secondary to ACTH-secreting adenomas in whom we had peripheral and tumor DNA (N=36). No increased GPR101 expression was observed in tumors compared to normal pituitary (NP) tissues, nor did we find a correlation between GPR101 and ACTH expression levels. Sequence analysis revealed a very rare germline heterozygous GPR101 variant (p.G31S) in one patient with CD. Overexpression of the p.G31S variant did not lead to increased growth and proliferation, although modest effects on cAMP signaling were seen. GPR101 is not overexpressed in ACTH-secreting tumors compared to NPs. A rare germline GPR101 variant was found in one patient with CD but in vitro studies did not support a consistent pathogenic effect. GPR101 is unlikely to be involved in the pathogenesis of CD.

Castleman Disease: A Rare Condition with Endocrine Manifestations

Castleman disease (CD) most commonly affects lymphoid tissues in the thorax, abdomen, pelvis, and neck. Extralymphatic tissues, such as lacrimal glands, lung, pancreas, larynx, parotid, meninges, and even muscles, have also been reported as sites. The etiology is unknown and its incidence has not been reported in the literature. Castleman disease can be classified clinically into a unicentric or multicentric form, depending on the number of lymph nodes involved, and histologically into a hyaline vascular variant, plasma cell, mixed cellular, or plasmablastic variant. The disease has a predominantly inflammatory background, reflected in high levels of vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6). The role of cytokines in CD explains the clinical presentation. The clinical scenario varies widely, based mainly on the histologic type. Unicentric CD usually presents without symptomatology, whereas multicentric manifests with fatigue, abdominal or thoracic pain, cytopenias, and/or B- symptoms (10% weight loss in the last six months, nocturnal diaphoresis, and fever). The endocrinopathy has a wide range of manifestations, affecting either the pituitary or other target organs. Achieving the diagnosis is complicated and there is no laboratory or imaging pathognomonic for this disease. The gold standard is an excisional biopsy from an affected lymph node. The treatment depends on the type of CD. Unicentric CD has a good response to excisional surgery. However, in multicentric CD (MCD), surgery may provide transient relief of symptoms but with a rebound effect, so it is not considered a good method. The use of chemotherapy, monoclonal antibodies, glucocorticoids, and thalidomide has shown some improvement in MCD.

Recurrent Thrombotic Thrombocytopenic Purpura-Like Syndrome as a Paraneoplastic Phenomenon in Malignant Peritoneal Mesothelioma: A Case Report and Review of the Literature

We report the case of an African American male with no significant past medical history presenting with recurrent, rapidly relapsing episodes of thrombotic thrombocytopenic purpura (TTP) despite aggressive treatment with several lines of treatment. Incidentally, these episodes were associated with severe abdominal pain which eventually developed into acute abdomen and prompted exploratory laparotomy, revealing diffuse carcinomatosis with a tumor located on the left pelvis that was encasing the distal sigmoid colon. Pathology made a final diagnosis of peritoneal mesothelioma. TTP-like syndrome (TTP-LS) has been described as a paraneoplastic phenomenon in several malignancies but never before in the setting of malignant mesothelioma. Paraneoplastic TTP-like syndrome has historically been associated with a dismal prognosis and particular clinical and laboratory abnormalities described in this paper. It is of utmost importance to make a prompt determination whether TTP is idiopathic or secondary to an underlying condition because of significant differences in their prognosis, treatment, and response. This paper also reviews the current literature regarding this challenging condition.

Immune Thrombocytopenic Purpura and Gastritis by H. pylori Associated With Type 1 Diabetes Mellitus

We present the 15th case reported worldwide and 3rd case reported in Latin America of immune thrombocytopenic purpura associated with Type 1 diabetes mellitus in Scopus, MEDLINE, and SciELO. An 11-year-old male patient of mixed ethnicity with immune thrombocytopenic purpura, Type 1 diabetes mellitus, and gastritis due to H. pylori presented to the emergency room with petechiae, ecchymosis, and gingival and conjunctival bleeding that had been worsening for the past three months. The patient had a body mass index of 18.85 kg/m2 (P75). A biochemical analysis showed 1×109 platelets/L, increased prothrombin time, increased partial thromboplastin time, and an HbA1C of 7.84% on admission. He was prescribed a single dose of intravenous methylprednisolone 750 mg in 100 mL of NaCl and daily oral 50 mg prednisolone, with intravenous 250 mg tranexamic acid every eight hours. The patient’s glycemic control was continued with the administration of insulin glargine (30 units every 24 hours) and prandial insulin glulisine (five to eight units per meal). Before admission, the patient was on a prescribed treatment of sitagliptin 50 mg and metformin 850 mg, but this was suspended in the emergency room. For the eradication of H. pylori he was prescribed amoxicillin 500 mg every eight hours, oral clarithromycin 335 mg every 12 hours, and IV omeprazole 40 mg. After 15 days, he showed disease resolution and he was discharged to his home with orders to follow-up with pediatrics, hematology, and endocrinology services. The first-line treatment for immune thrombocytopenic purpura patients with active bleeding and a platelet count < 30,000 platelets/μl is the administration of corticosteroids and inmunoglobulin.

The 2017 ACGME Common Work Hour Standards: Promoting Physician Learning and Professional Development in a Safe, Humane Environment

Kim J. Burchiel, MD, FACS Rowen K. Zetterman, MD Kenneth M. Ludmerer, MD Ingrid Philibert, PhD, MBA Timothy P. Brigham, MDiv, PhD Kathy Malloy, BA James A. Arrighi, MD Stanley W. Ashley, MD Jessica L. Bienstock, MD, MPH Peter J. Carek, MD, MS, CAQSM, FAAFP, DABFM Ricardo Correa, MD David A. Forstein, DO Robert R. Gaiser, MD Jeffrey P. Gold, MD George A. Keepers, MD Benjamin C. Kennedy, MD Lynne M. Kirk, MD Anai Kothari, MD Lorrie A. Langdale, MD Philip H. Shayne, MD Steven C. Stain, MD Suzanne K. Woods, MD Claudia Wyatt-Johnson, BA, MA Thomas J. Nasca, MD, MACP

The Importance of Writing and Publishing Case Reports During Medical Training

Case reports are valuable resources of unusual information that may lead to new research and advances in clinical practice. Many journals and medical databases recognize the time-honored importance of case reports as a valuable source of new ideas and information in clinical medicine. There are published editorials available on the continued importance of open-access case reports in our modern information-flowing world. Writing case reports is an academic duty with an artistic element. Unfortunately, few physicians-in-training receive formal education on what constitutes a publishable case report. This article emphasizes that the medical education community, specially the graduate medical education community, should be aware of the importance of writing and publishing good quality case reports.

S61– Transnational collaboration in developing ADAPTE clinical guidelines and use of GRADE when making recommendations: Experiences from Costa Rica, Panama and Guatemala

tional databases, 2910 from national databases, 443 from guidelines clearinghouses, and 600 from hand searching. Almost 1000 potential producers belonging to the macro, meso, and micro level of the health system were identified. They were located mainly in Spain (417), in Argentina (368), and in Brazil (214). Among all pCPGs that were retrieved in international databases, 348 out of 1283 were finally considered CPGs. They were mostly produced in Spain (189), followed by Brazil (73), Argentina (26), Mexico (23), and Portugal (20). The relation between pCPGs and final considered CPGs when applying selection criteria in Medline, EMBASE, and Lilacs was 39%, 48%, and 8%, respectively. DISCUSSION (CONCLUSION): Iberoamerican countries’ production of CPGs is distributed among different sources of information. Although existing platforms or clearinghouses have been put in place, such as Guiasalud in Spain, there is still a need for building capacities in other countries and considering a unique CPG clearinghouse in Spanish. TARGET AUDIENCE(S): 1. Guideline developer 2. Guideline implementer 3. Developer of guideline-based products 4. Quality improvement manager/facilitator 5. Medical educator 6. Health care policy analyst/policymaker 7. Health insurance payers and purchasers 8. Medical providers and executives 9. Allied health professionals 10. Nurses