Can thyroid histomorphology identify patients with PTEN hamartoma tumour syndrome?

AIMS: The phosphatase and tensin homologue (PTEN) hamartoma tumour syndrome (PHTS) is a genetic disorder with variable clinical presentation and increased lifetime risk of multiorgan malignancies. The thyroid gland is commonly affected with follicular nodular disease (FND) and follicular cell-derived carcinomas. Histopathological and immunohistochemical assessment of thyroid disease in PHTS is essential to identify patients at-risk. METHODS AND RESULTS: In all, 30 PHTS patients with available thyroidectomy specimen material (2000-2023) and 31 control patients with FND and "adenomatous nodules" were retrieved. Histologic criteria, including the frequency of adenomatous-type nodules versus hyperplastic-type nodules, background and nodular lipomatous metaplasia, chronic lymphocytic thyroiditis, cytoplasmic clearing of follicular cells in nodules, nodule-in-nodule appearance, and spectrum of nuclear atypia between nodules were evaluated in both cohorts and a Thyroid Histomorphologic PHTS Score (THiPS) system was established with a cutoff of 4 points or higher being considered concerning for PHTS. In all, 27 PHTS (90%) and five control (16.1%) cases had THiPS ≥4. A PTEN immunohistochemical stain was evaluated in 25 cases of each cohort and showed nuclear and cytoplasmic loss of expression in all or most of the nodules of 24/25 PHTS cases. In 3/25 control cases, two with THiPS ≥4, had loss of expression in one to multiple nodules. Conventional papillary thyroid carcinomas in PHTS patients retained PTEN cytoplasmic expression. CONCLUSIONS: Our study supports that, although not specific, the finding of multiple histologic features is found more frequently in patients with PHTS compared to the non-PHTS control group. The THiPS system has high sensitivity for thyroid specimens from patients with PHTS.

Progression of Nodular Thyroid Disease in Familial Adenomatous Polyposis Syndrome: Refined Surveillance Recommendations.

BACKGROUND: Patients with familial adenomatous polyposis (FAP) have an increased risk of thyroid nodular disease. Previous studies demonstrated that screening thyroid ultrasound (US) will allow detection of nodules in 38% and thyroid cancer in 2.6% of patients. The aim of this study is to define the value of serial US evaluation at identifying disease progression in patients with FAP. METHODS: Retrospective review from 2008 to 2023 at a single referral center. All patients with FAP and screening thyroid US were included. Patient demographics, initial US characteristics, follow-up regarding the development of new nodules and cancer were assessed using a Kaplan-Meier analysis. RESULTS: A total of 556 patients underwent screening. Fifty percent were male. Median age at first screening was 38 year old. Eighty percent underwent longitudinal follow-up for a median length of 7 years. At initial screening, 169 patients (30%) had nodules. For patients with normal baseline US, 14% developed a nodule overtime. A total of 20 patients (3.6%) were diagnosed with thyroid cancer. The cumulative incidence of initial and subsequent cancer was 4% by 5 years and 6% by 10 years, while the cumulative incidence of thyroid nodules was 40% and 48%, respectively. CONCLUSIONS: Based on the Kaplan-Meier analysis, ongoing longitudinal screening is warranted for patients with FAP as they are prone to thyroid cancer and nodule development overtime even when presenting with a baseline normal US. Additionally, these data demonstrate a slow development of thyroid cancer from a normal US, thus it is reasonable to consider selectively extending the screening interval for this population.

A Multicenter Analysis of the Early Impact of COVID-19 on Junior Resident Operative Case Volume.

INTRODUCTION: Institutions have reported decreases in operative volume due to COVID-19. Junior residents have fewer opportunities for operative experience and COVID-19 further jeopardizes their operative exposure. This study quantifies the impact of the COVID-19 pandemic on resident operative exposure using resident case logs focusing on junior residents and categorizes the response of surgical residency programs to the COVID-19 pandemic. MATERIALS AND METHODS: A retrospective multicenter cohort study was conducted; 276,481 case logs were collected from 407 general surgery residents of 18 participating institutions, spanning 2016-2020. Characteristics of each institution and program changes in response to COVID-19 were collected via surveys. RESULTS: Senior residents performed 117 more cases than junior residents each year (P < 0.001). Prior to the pandemic, senior resident case volume increased each year (38 per year, 95% confidence interval 2.9-74.9) while junior resident case volume remained stagnant (95% confidence interval 13.7-22.0). Early in the COVID-19 pandemic, junior residents reported on average 11% fewer cases when compared to the three prior academic years (P = 0.001). The largest decreases in cases were those with higher resident autonomy (Surgeon Jr, P = 0.03). The greatest impact of COVID-19 on junior resident case volume was in community-based medical centers (246 prepandemic versus 216 during pandemic, P = 0.009) and institutions which reached Stage 3 Program Pandemic Status (P = 0.01). CONCLUSIONS: Residents reported a significant decrease in operative volume during the 2019 academic year, disproportionately impacting junior residents. The long-term consequences of COVID-19 on junior surgical trainee competence and ability to reach cases requirements are yet unknown but are unlikely to be negligible.

Bilateral exploration in primary hyperparathyroidism: Double adenoma distribution and biochemical patterns over two decades.

BACKGROUND: We investigated if anatomic patterns of abnormal parathyroid glands have ch anged for primary hyperparathyroidism (pHPT) as atypical biochemical presentation (normohormonal and normocalcemic) has increased. METHODS: Retrospective review of patients with pHPT who underwent routine bilateral neck exploration. RESULTS: 2762 patients were included. The "late" cohort (2014-2020) exhibited lower preoperative calcium (10.8 vs 11.1 â€‹mg/dL; P â€‹= â€‹0.001) and PTH levels (101 vs. 146 â€‹pg/mL; P â€‹= â€‹0.001) compared to the "early" cohort (2000-2006). Patients with atypical biochemical profiles increased from 25.5% to 31.3% (P â€‹< â€‹0.001). The prevalence of single adenoma (SA) decreased (66.1% vs 58.9%, P â€‹= â€‹0.02) while the proportion of double adenoma (DA) increased (17.3% vs. 22.6%, P â€‹< â€‹0.01). Upper parathyroid adenoma(s) remained the most common finding for SA and DA in both time points. CONCLUSIONS: Despite changes in patient characteristics, single upper adenoma and bilateral double upper adenomas remain the most common findings for patients with pHPT.

Longitudinal Analysis of Cancer Risk in Children and Adults With Germline PTEN Variants.

Importance: Identifying hereditary cancer predisposition facilitates high-risk organ-specific cancer surveillance and prevention. In PTEN hamartoma tumor syndrome (PHTS), longitudinal studies remain lacking, and there are insufficient data on cancers in children and young adults, as well as individuals with neurodevelopmental disorders (NDD). Objective: To evaluate lifetime cancer risks, including second malignant neoplasms (SMN), among patients with PHTS. Design, Setting, and Participants: Prospective longitudinal cohort study (September 1, 2005, through January 6, 2022). General population risks from the Surveillance, Epidemiology, and End Results database. Patients with PHTS, molecularly defined as carrying germline PTEN variants, were accrued from community and academic medical centers throughout North America, South America, Europe, Australia, and Asia. Data were analyzed from July 2022 to February 2023. Exposures: Review of physical and electronic medical records, and follow-up through clinical visits or telephone interviews. Main Outcomes and Measures: Lifetime cancer risks in PHTS relative to the general population. Results: A total of 7302 patients were prospectively accrued, 701 of whom had germline PTEN variants (median [IQR] age at consent, 38 [12-52] years; 413 female patients [59%]). Longitudinal follow-up data could be obtained for 260 patients (37%), with a median (IQR) follow-up of 4 (2-8) years. Of the 701 patients, 341 (49%) received at least 1 cancer diagnosis, with 144 (42%) of those having SMN. The study found significantly elevated lifetime risks for breast (91%), endometrial (48%), thyroid (33%), kidney (30%), and colorectal cancers (17%), as well as melanoma (5%). Cancer diagnoses were also observed in children and young adults with PHTS (15%) and in patients with PHTS with neurodevelopmental disorders (11%). Elevated risks (P < .001) of thyroid (age-adjusted standardized incidence ratios [SIR], 32.1; 95% CI, 26.0-39.0), kidney (SIR, 26.5; 95% CI, 18.8-36.3), endometrial (SIR, 26.0; 95% CI, 19.5-34.1), breast (SIR, 20.3; 95% CI, 17.3-23.7), and colorectal (SIR, 7.9; 95% CI, 5.2-11.7) cancers, and melanoma (SIR, 6.3; 95% CI, 3.5-10.5) were observed. Of the 341 patients with PHTS with cancer, 51 (15%) had 1 or more cancers diagnosed at age 29 years or younger, and 16 (31.4%) of those developed SMN at final follow-up. Twenty-three patients with PHTS with NDD and cancer were identified, with 5 (22%) having developed SMN at final follow-up. Individuals with PHTS and NDD showed higher lifetime cancer risks compared with individuals with PHTS but without NDD (hazard ratio, 2.7; 95% CI, 1.7-4.2; P < .001). Conclusions and Relevance: This cohort study found consistently elevated lifetime cancer risks in PHTS. Organ-specific surveillance should continue in patients with PHTS. Additional study is required to ascertain elevated cancer risks in patients with PHTS with NDD.

Utilizing Dynamic Risk Stratification in Patients With Tall Cell Variant Papillary Thyroid Cancer.

OBJECTIVES: Tall cell variant (TCV) papillary thyroid cancer (PTC) is a subtype of PTC associated with aggressive tumor behavior, advanced stage, and higher rates of recurrence and mortality. The present study aimed to test an established dynamic risk stratification tool in the TCV population, with the goal of better predicting the postoperative course of these patients. STUDY DESIGN: Retrospective chart review. METHODS: A total of 94 patients with TCV who underwent total thyroidectomy with radioactive iodine ablation were retrospectively reviewed from 1998 through 2020. Biochemical, structural, and overall response to treatment was determined for each patient, based on postoperative thyroglobulin levels and imaging findings. Primary outcomes were locoregional and distant recurrence, presence of disease at final follow-up, need for additional intervention, and disease-specific mortality. RESULTS: Patients with TCV who were stratified as having an excellent overall response to treatment had lower rates of locoregional recurrence than indeterminate, biochemical incomplete, and structural incomplete responses (2.0%, 33.3%, 55.0%, and 85.7% at 5 years respectively, p < 0.001). The same was true for distant recurrence as well (2.0%, 9.0%, 35.1%, and 42.9%, p < 0.001). An excellent response was also associated with lower rates of presence of disease at final follow-up, need for additional intervention, and disease-specific mortality. CONCLUSIONS: Although TCV is an aggressive subtype associated with worse clinical outcomes than classical PTC, patients with an excellent overall response to treatment have significantly improved outcomes when compared to indeterminate, biochemical incomplete, and structural incomplete responses. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:2430-2438, 2023.

Development and Progression of Thyroid Disease in PTEN Hamartoma Tumor Syndrome: Refined Surveillance Recommendations.

Background: PTEN hamartoma tumor syndrome (PHTS) is associated with a high prevalence and early onset of differentiated thyroid cancer and benign thyroid disease. However, a consensus on the time of initiation and frequency of thyroid cancer surveillance has not yet been reached. Most commonly, guidelines recommend annual thyroid ultrasounds, but vary widely in the time of initiation, ranging from shortly after birth to 18 years of age. Minimal data are available on the development and progression of thyroid disease over time in this population. This study aimed to target this knowledge gap by investigating the time to develop thyroid nodules and thyroid cancer from an initial ultrasound in 76 PHTS patients. Methods: The electronic records of 281 prospectively accrued PHTS patients were retrospectively reviewed between 2005 and 2021, and 76 patients were identified as having at least two thyroid ultrasounds. Time-to-event analyses were performed, determining the probability of developing thyroid nodules and thyroid cancer over time. Results: We demonstrated that PHTS patients with an initial thyroid ultrasound without nodules (n = 41) had >90% likelihood of remaining free of a clinically actionable nodule at 3 years and an 85% likelihood at 6 years. None of these patients developed thyroid cancer over the entire follow-up period (mean 4.6 years). In patients with a clinically nonactionable nodule, defined as not meeting criteria for fine needle aspiration or thyroidectomy (n = 14), we demonstrated that 80% will not have an actionable nodule at 3 years, and none developed thyroid cancer over the entire follow-up period. Conclusions: Our observations suggest stratifying surveillance intervals based on thyroid ultrasound result, and support extending surveillance intervals in PHTS patients without nodules on ultrasound to 3-5 years, and patients with clinically nonactionable nodules to 2-3 years, in contrast to the current recommendation of annual ultrasounds. This change in practice would decrease the burden of frequent ultrasounds, especially in young children and adolescents who are more likely to have a normal or nonactionable ultrasound result.

Comparison of mechanical cardiopulmonary support strategies during lung transplantation.

INTRODUCTION: Lung transplantation outcomes are influenced by the intraoperative mechanical cardiopulmonary support strategy used. This surgery was historically done either on cardiopulmonary bypass (CPB) or off pump. Recently, there has been increased interest in intraoperative support with veno-arterial (VA) or veno-venous (VV) extracorporeal membrane oxygenation (ECMO). However, there is a lack of consensus on the relative risks, benefits and indications for each intraoperative support strategy. AREAS COVERED: This review includes information from cohort studies, case-control studies, and case series that compare morbidity and/or mortality of two or more intraoperative cardiopulmonary support strategies during lung transplantation. EXPERT OPINION: The optimal strategy for intraoperative cardiopulmonary support during lung transplantation remains an area of debate. Current data suggest that off pump is associated with better outcomes and could be considered whenever feasible. ECMO is generally associated with preferable outcomes to CPB, but the data supporting this association is not robust. Interestingly, whether CPB is unplanned or prolonged might influence outcomes more than the use of CPB itself. These observations can help guide surgical teams in their approach for intraoperative mechanical support strategy during lung transplantation and should serve as the basis for further investigations.

Immunopathogenesis and biomarkers of recurrent atrial fibrillation following ablation therapy in patients with preexisting atrial fibrillation.

INTRODUCTION: Recurrent atrial fibrillation (RAF) following ablation therapy occurs in about 50% of patients. The pathogenesis of RAF is unknown, but is believed to be driven by atrial remodeling in the setting of background inflammation. Structural, electrophysiological and mechanical remodeling has been associated with atrial fibrillation (AF). Inflammation and fibrotic remodeling are the major factors perpetuating AF, as mediators released from the atrial tissues and cardiomyocytes due to mechanical and surgical injury could initiate the inflammatory process. In this article, we have critically reviewed the key mediators that may serve as potential biomarkers to predict RAF. Areas covered: Damage associated molecular patterns, heat shock proteins, inflammatory cytokines, non-inflammatory markers, markers of inflammatory cell activity, and markers of collagen deposition and metabolism are evaluated as potential biomarkers with molecular treatment options in RAF. Expert commentary: Establishing biomarkers to predict RAF could be useful in reducing morbidity and mortality. Investigations into the role of DAMPs participating in a sterile immune response may provide greater insight into the pathogenesis of RAF. Markers evaluating immune cell activity, collagen deposition, and levels of heat shock proteins show the greatest promise as potential biomarkers to predict RAF and develop novel therapies.

Mechanisms, diagnosis, and treatment of heart failure with preserved ejection fraction and diastolic dysfunction.

INTRODUCTION: Heart failure with preserved ejection fraction (HFpEF) continues to be a major challenge for clinicians. Many crucial aspects of the syndrome remain unclear, including the exact pathophysiology, early diagnosis, and treatment. Patients with HFpEF are often asymptomatic late into the disease process, and treatment with medications commonly used in heart failure with reduced ejection fraction (HFrEF) has not been proven to be beneficial. In addition, the confusion of similar terms with HFpEF, such as diastolic heart failure, and diastolic dysfunction (DD), has led to a misunderstanding of the true scope of HFpEF. Areas covered: In this review, authors highlight the differences in terminology and critically review the current knowledge on the underlying mechanisms, diagnosis, and latest treatment strategies of HFpEF. Expert commentary: While significant advances have been made in the understanding of HFpEF, the definitive diagnosis of HFpEF continues to be difficult. The development of improved and standardized methods for detecting DD has shown promise in identifying early HFpEF. However, even with early detection, there are few treatment options shown to provide mortality benefit warranting further investigation.