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David C Klonoff,1 Brian L Levy,2 Michael J Jaasma,3 Manish Bharara,3 Deborah R Edgar,4 Christian Nasr,5 David L Caraway,3 Erika A Petersen,6 David G Armstrong7 1Diabetes Research Institute, Mills-Peninsula Medical Center, San Mateo, CA, USA; 2New York University Grossman School of Medicine, New York, NY, USA; 3Nevro Corp, Redwood City, CA, USA; 4Commexus Ltd, Dunblane, Scotland, UK; 5Division of Endocrinology, Department of Internal Medicine, The University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA; 6Department of Neurosurgery, University of Arkansas for Medical Sciences, Little Rock, AR, USA; 7Department of Surgery, Keck School of Medicine of University of Southern California, Los Angeles, CA, USACorrespondence: David C Klonoff, Diabetes Research Institute, Mills-Peninsula Medical Center, 100 South San Mateo Drive, Room 1165, San Mateo, CA, 94401, USA, Tel +1650-218-1142, Email dklonoff@diabetestechnology.orgPurpose: The recent SENZA-PDN study showed that high-frequency (10kHz) spinal cord stimulation (SCS) provided significant, durable pain relief for individuals with painful diabetic neuropathy (PDN), along with secondary benefits, including improved sleep quality and HRQoL. Given that metabolic factors and chronic neuropathic pain are related, we evaluated potential secondary effects of 10kHz SCS on hemoglobin A1c (HbA1c) and weight in SENZA-PDN participants with type 2 diabetes (T2D).Patients and Methods: This analysis included 144 participants with T2D and lower limb pain due to PDN who received 10kHz SCS during the SENZA-PDN study. Changes in HbA1c, weight, pain intensity, and sleep were evaluated over 24 months, with participants stratified according to preimplantation HbA1c (> 7% and > 8%) and body mass index (BMI; ≥ 30 and ≥ 35 kg/m2).Results: At 24 months, participants with preimplantation HbA1c > 7% and > 8% achieved clinically meaningful and statistically significant mean reductions in HbA1c of 0.5% (P = 0.031) and 1.1% (P = 0.004), respectively. Additionally, we observed a significant mean weight loss of 3.1 kg (P = 0.003) across all study participants. In subgroups with BMI ≥ 30 and ≥ 35 kg/m2, weight reductions at 24 months were 4.1 kg (P = 0.001) and 5.4 kg (P = 0.005), respectively. These reductions were accompanied by a mean pain reduction of 79.8% and a mean decrease in pain interference with sleep of 65.2% at 24 months across all cohorts.Conclusion: This is the first study of SCS to demonstrate long-term, significant, and clinically meaningful reductions in HbA1c and weight in study participants with PDN and T2D, particularly among those with elevated preimplantation HbA1c and BMI. Although the mechanism for these improvements has yet to be established, the results suggest possible direct and indirect metabolic benefits with 10kHz SCS in addition to durable pain relief.Trial Registration: ClincalTrials.gov Identifier, NCT03228420.Keywords: diabetic peripheral neuropathy, painful diabetic neuropathy, spinal cord stimulation, neuromodulation, neuropathic pain

Background: Medulloblastoma is the most common malignant brain tumor in children. This entity in adulthood is rare. The aim of our study is to evaluate therapeutic results and prognostic factors of adult medulloblastoma treated at our institute with post-operative radiotherapy., Methods: We retrospectively reviewed a cohort of 55 patients with medulloblastoma who underwent radiation in the department of radiation oncology of institute Salah Azaiz (Tunis) over a 18-year period (1994-2012)., Results: The surgery was total or subtotal resection in 73% of cases. Forty-eight patients received radiotherapy to the entire craniospinal axis as part of the curative treatment. The median interval from surgery to the initiation of radiotherapy was 83 days. Etoposide-cisplatin chemotherapy was only performed in metastatic patients ( n  = 4). The 5-years and 10-years overall survival rates were respectively 53 and 34%. The dose of radiotherapy to the craniospinal axis was a prognostic factor. The 5-years and 10-years event-free-survival rates were 64 and 41%. Reduction in the dose of radiotherapy to the craniospinal axis and fourth ventricular floor involvement were correlated with a worse event-free survival., Conclusion: Our results, compared to those of the literature, conclude that the reduction in the dose of radiotherapy to the craniospinal axis (<34 Gy) in the standard risk group of adult medulloblastoma could not be done without chemotherapy. In the high-risk group of adult medulloblastoma, radiotherapy to the cerebrospinal axis at the dose of 36 Gy with chemotherapy, is required for disease control.

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., (© 2023 The Authors. The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Importance: Survival outcomes for anaplastic thyroid cancer (ATC), the most aggressive subtype of thyroid cancers, have remained poor. However, targeted therapies and immunotherapies present new opportunities for treatment of this disease. Evaluations of survival outcomes over time with new multimodal therapies are needed for optimizing treatment plans., Objective: To evaluate the association of treatment strategies and tumor characteristics with overall survival (OS) among patients with ATC., Design, Setting, and Participants: This retrospective case series study evaluated the survival outcomes stratified by treatment strategies and tumor characteristics among patients with ATC treated at a tertiary level academic institution from January 1, 2000, to December 31, 2021. Demographic, tumor, treatment, and outcome characteristics were analyzed. Kaplan-Meier method and log rank test modeled OS by treatment type and tumor characteristics. Data were analyzed in May 2022., Main Outcomes and Measures: Overall survival (OS)., Results: The study cohort comprised 97 patients with biopsy-proven ATC (median [range] age at diagnosis, 70 [38-93] years; 60 (62%) female and 85 [88%] White individuals; 59 [61%] never smokers). At ATC diagnosis, 18 (19%) patients had stage IVA, 19 (20%) had stage IVB, and 53 (55%) had stage IVC disease. BRAF status was assessed in 38 patients; 18 (47%) had BRAF-V600E variations and 20 (53%), BRAF wild type. Treatment during clinical course included surgery for 44 (45%) patients; chemotherapy, 41 (43%); definitive or adjuvant radiation therapy, 34 (RT; 35%); and targeted therapy, 28 (29%). Median OS for the total cohort was 6.5 (95% CI, 4.3-10.0) months. Inferior OS was found in patients who did not receive surgery (hazard ratio [HR], 2.12; 95% CI, 1.35-3.34; reference, received surgery), chemotherapy (HR, 3.28; 95% CI, 1.99-5.39; reference, received chemotherapy), and definitive or adjuvant RT (HR, 2.47; 95% CI, 1.52-4.02; reference, received definitive/adjuvant RT). On multivariable analysis, age at diagnosis (HR, 1.03; 95% CI, 1.01-1.06), tumor stage IVC (HR, 2.65; 95% CI, 1.35-5.18), and absence of definitive or adjuvant RT (HR, 1.90; 95% CI, 1.01-3.59) were associated with worse OS., Conclusions and Relevance: This retrospective single-institution study found that lower tumor stage, younger age, and the ability to receive definitive or adjuvant RT were associated with improved OS in patients with ATC.

Background: Burnout among medical students has always been a major concern., Objective: To evaluate changes in the prevalence rates of burnout among Lebanese pre-final and final year medical students while taking into consideration the impact of coronavirus 2019 (COVID-19) on both the academical and clinical experiences., Methods: This is a multi-centered, survey-based, cross-sectional study conducted in October 2021. The Copenhagen Burnout Inventory questionnaire was used on 120 medical students from three different medical schools in Lebanon., Results: The overall burnout prevalence was 40.01%. When further dividing it into domains, 39.36% of students had personal burnout, 41.52% had work-related burnout, and 39.16% had pandemic-related burnout. Theoretical learning and clinical training were reported to be affected in respectively 66.70% and 71.70%. However, only 10.00% of the students have regretted choosing medicine and 67.50% felt comfortable to get to the next academic level., Conclusion: High levels of burnout were reported among pre-final and final year medical students with a subsequent negative impact on their academic life and clinical training. Medical schools should start adopting a conscious view of how to guide medical students in finding adequate coping mechanisms during these times of crisis.

Importance: Tall cell morphology (TCM) is a rare and aggressive variant of papillary thyroid carcinoma (PTC) that has been associated with poor outcomes; however, the risk factors for worse survival are not well characterized., Objective: To identify prognostic factors associated with cancer recurrence and death in patients with PTC-TCM., Design, Setting, and Participants: All patients treated for PTC-TCM at a single tertiary-level academic health care institution from January 1, 1997, through July 31, 2018, were included. Tall cell variant (TCV) was defined as PTC with TCM of 30% or more; and tall cell features (TCF) was defined as PTC with TCM of less than 30%. Patients with other coexisting histologic findings and/or nonsurgical management were excluded. Clinicopathologic features associated with worse outcomes were identified using Kaplan-Meier and Cox proportional-hazards model. Data were analyzed from March 1, 2018, to August 15, 2018., Main Outcomes and Measures: Locoregional recurrence-free survival (LRRFS), distant recurrence-free survival (DRFS), and overall survival (OS) after surgery., Results: A total of 365 patients (median [range] age, 51.8 [15.9-91.6] years; 242 [66.3%] female) with PTC-TCM (TCV, 32%; TCF, 68%) were evaluable. Total thyroidectomy was performed in 336 (92%) patients; 19 (5.2%) received radiotherapy; and 15 (4.1%) received radioactive iodine. Clinical features were pT3 or T4, 65%; node-positive, 53%; and positive surgical margins, 24%. LRRFS at 1-, 3-, 5-, and 10-year was 95%, 87%, 82%, and 73%, respectively. On multivariable analysis, male sex and age were not independent predictors of inferior 5-year LRRFS, whereas positive surgical margins (HR, 3.5; 95% CI, 2.0-6.3), positive lymph nodes (HR, 2.8; 95% CI, 1.4-5.8), and primary tumor size of 3 cm or more (HR, 3.3; 95% CI, 1.4-7.8) were strongly associated with worse LRRFS. Age 55 years or older (HR, 3.2; 95% CI, 1.5-7.0), male sex (HR 4.5; 95% CI, 2.1-10.0), positive surgical margins (HR, 2.7; 95% CI, 1.2-6.0), nodal positivity (HR, 3.1; 95% CI, 1.3-7.7), tumor diameter of 1.5 cm or more (HR, 20.6; 95% CI, 2.8-152.1), and TCV vs TCF (HR, 3.1; 95% CI, 1.5-6.7) were associated with worse DRFS. Male sex (HR, 3.1; 95% 1.4-6.8) and tumor diameter of 1.5 cm or more (HR, 2.8; 95% CI, 1.0-7.4) were associated with worse OS. A findings-based nomogram was constructed to predict 10-year LRRFS (C index, 0.8)., Conclusions and Relevance: This retrospective cohort study found that in patients with PTC-TCM, positive surgical margins, node positive disease, and tumor size of 3 cm or more were risk factors for worse LRRFS. Intensified locoregional therapy, including adjuvant radiation, may be considered for treating these patients.

Background: Interpretation of Hürthle cell-predominant cytologies (HCP) is very challenging as a majority is diagnosed as indeterminate. Prior studies have reported various cytologic features to help distinguish non-neoplastic (NN) from neoplastic and malignant lesions but had contradicting results. Our aim was to identify risk factors predictive of neoplasm and/or malignancy by correlating cytologic features with clinical and ultrasound findings., Methods: Sixty-nine HCP cases with surgical follow-up were identified, including 35 NN, 20 adenomas, and 14 carcinomas. Ultrasound data were recorded utilizing Thyroid Imaging Reporting and Data System (TI-RADS) and American Thyroid Association (ATA) scoring systems. Sixteen cytologic criteria were evaluated and semi-quantitatively scored. Data were assessed by univariable, multivariable and stepwise logistic regression analysis; and statistical significance achieved at P-value <0.05., Results: On univariable analysis, significant predictors of neoplasm were high cellularity, isolated single cells, absent colloid, non-uniform HC population (anisonucleosis), larger nodule size, and higher ATA score. Large-cell dysplasia and transgressing blood vessels were not found to be significant factors. Multivariable analysis identified a combination of four risk factors (high cellularity, anisonucleosis, absent colloid, and size ≥2.9 cm) that was associated with neoplasm in 10/11 patients. None of 15 patients with zero or 1 out of 4 risk factors had malignancy or neoplasm on follow-up. This model also significantly outperformed ATA and TI-RADS scoring systems., Conclusion: In the absence of four or three risk factors, the model excluded malignancy and neoplasm in all patients. The presence of all four factors predicted neoplasm and malignancy in 91% and 46% of cases, respectively., (© 2022 The Authors. Diagnostic Cytopathology published by Wiley Periodicals LLC.)

Background: Painful diabetic neuropathy (PDN) is one of the major complications of diabetes mellitus. It is often debilitating and refractory to pharmaceutical therapies. Our goal was to systematically review and evaluate the strength of evidence of interventional management options for PDN and make evidence-based recommendations for clinical practice., Methods: We searched PubMed, Scopus, Google Scholar, and Cochrane Llibrary and systematically reviewed all types of clinical studies on interventional management modalities for PDN., Results: We identified and analyzed 10 relevant randomized clinical trials (RCTs), 8 systematic reviews/meta-analyses, and 5 observational studies of interventional modalities for PDN using pain as primary outcome. We assessed the risk of bias in grading of evidence and found that there is moderate to strong evidence to support the use of dorsal column spinal cord stimulation (SCS) in treating PDN in the lower extremities (evidence level: 1B+), while studies investigating its efficacy in the upper extremities are lacking. Evidence exists that acupuncture and injection of botulinum toxin-A provide relief in pain or muscle cramps due to PDN with minimal side effects (2B+/1B+). Similar level of evidence supports surgical decompression of lower limb peripheral nerves in patients with intractable PDN and superimposed nerve compression (2B±/1B+). Evidence for sympathetic blocks or neurolysis and dorsal root ganglion (DRG) stimulation is limited to case series (2C+)., Conclusions: Moderate to strong evidence exists to support the use of SCS in managing lower extremity pain in patients who have failed conventional medical management for PDN. Acupuncture or injection of botulinum toxin-A can be considered as an adjunctive therapy for PDN. Surgical decompression of peripheral nerves may be considered in patients with PDN superimposed with nerve compression. High-quality studies are warranted to further evaluate the safety, efficacy, and cost-effectiveness of interventional therapies for PDN., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 International Anesthesia Research Society.)

Background and Aim: Poorly differentiated thyroid cancer (PDTC) is a rare but aggressive subtype of thyroid cancer that portends a poor prognosis. There remains a paucity of literature on PDTC outcomes. The aim of our study was to evaluate outcomes of PDTC in our tertiary care facility., Patients and Methods: We identified all histologically confirmed PDTC cases from 1997-2018 treated at our Institution and collected data points in an IRB-approved registry. We then conducted a retrospective study to assess outcomes and identified factors associated with inferior outcomes., Results: Twenty-three patients were identified with a median age at diagnosis of 60 years (range=39-89 years). Nineteen (83%) underwent total thyroidectomy. Eight (42%) patients had lymph node dissections and 2 (11%) underwent adjuvant radiation. Thirteen (68%) patients were treated with radioactive iodine (RAI). Those who underwent total thyroidectomy had a median overall survival (mOS) of 88 months, 5 year-OS of 56%, 5 year-local recurrence-free survival (LRFS) of 45%, and 5 year-distant recurrence-free survival (DRFS) of 36%. T4 disease had worse mOS (14 vs. 87 m, p=0.0082), and 5 year-LRFS rate (12 vs. 74%, p=0.0312) compared to T1-3. N0 disease had an improved mOS (172 vs. 32 m, p=0.0013), 5 year-LRFS rate (63 vs. 17%, p=0.0033), and 5 year-DRFS (57 vs. 0%, p=0.0252). Eight out of 23 patients (35%) were alive at last follow-up, with a median of 68 months (range=20-214). The most common cause of death was distant recurrence (73%). Six patients received systemic therapy with various tyrosine kinase inhibitors with a median duration on treatment of 7 months (range=1-30 months)., Conclusion: Advanced T and N stage were factors associated with significantly inferior outcomes. While select patients benefited with systemic treatment, it remains unclear if intensified locoregional therapy should be considered in patients with PDTC., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Li-Fraumeni syndrome (LFS) is a rare autosomal hereditary predisposition to multiples cancers, mainly affecting young individuals. It is characterized by a broad tumor spectrum. To our best knowledge, only one Tunisian study with a confirmed LFS was published., Methods: Our study focused on the clinical, histopathological and genetic results of two patients with rare tumor phenotype and tried to establish genotype-phenotype correlation. The clinical diagnosis was based on Chompret-Bonaiti criteria relative to LFS. Molecular study was assessed using Sanger sequencing of the hotspot germline variants of TP53 gene., Results: We report 2 Tunisian families fulfilling the clinical criteria of Chompret-Bonaiti. The tumor phenotype was bilateral breast cancer (BC) in 27-year-old woman and multiple tumors for the second proband, with an onset age of 14, 35 and 36 yo for osteosarcoma, BC and esophageal cancer respectively. Each of them had a rare histological type of breast cancer associated with LFS, phyllode tumor and intralobular carcinoma. Both patients had cancer family history. The molecular study showed deleterious heterozygous germline TP53 variants in each index case: The first had a well-known hotspot missense variation c.742C>T p.(R248W) with a rare histological association, explaining genotype phenotype correlation. The second case had a nonsense variation c.159G>A p.(W53*), rare worldwide, extending the phenotype spectrum in LFS. Immunohistochemistry study in tumor samples confirmed the lack of p53 protein expression., Conclusions: Conclusively, germline TP53 testing is primordial in patients with a family history suggestive of LFS for clinical practice avoiding genotoxic treatments and adapting the surveillance. National database in LFS listing clinical and mutational data is important to set, particularly for variants rarely reported worldwide. Experience from different countries must be integrated to harmonize global protocols for cancer surveillance in LFS., (© 2022. The Author(s).)