Extended Pharmacokinetics Improve Site-Specific Prodrug Activation Using Radiation.

Radiotherapy is commonly used to treat cancer, and localized energy deposited by radiotherapy has the potential to chemically uncage prodrugs; however, it has been challenging to demonstrate prodrug activation that is both sustained and truly localized to tumors without affecting off-target tissues. To address this, we developed a series of novel phenyl-azide-caged, radiation-activated chemotherapy drug-conjugates alongside a computational framework for understanding corresponding pharmacokinetic and pharmacodynamic (PK/PD) behaviors. We especially focused on an albumin-bound prodrug of monomethyl auristatin E (MMAE) and found it blocked tumor growth in mice, delivered a 130-fold greater amount of activated drug to irradiated tumor versus unirradiated tissue, was 7.

Single-cell analysis reveals context-dependent, cell-level selection of mtDNA.

Heteroplasmy occurs when wild-type and mutant mitochondrial DNA (mtDNA) molecules co-exist in single cells. Heteroplasmy levels change dynamically in development, disease and ageing, but it is unclear whether these shifts are caused by selection or drift, and whether they occur at the level of cells or intracellularly. Here we investigate heteroplasmy dynamics in dividing cells by combining precise mtDNA base editing (DdCBE) with a new method, SCI-LITE (single-cell combinatorial indexing leveraged to interrogate targeted expression), which tracks single-cell heteroplasmy with ultra-high throughput.

Epigenetic profiling reveals key genes and cis-regulatory networks specific to human parathyroids.

In all terrestrial vertebrates, the parathyroid glands are critical regulators of calcium homeostasis and the sole source of parathyroid hormone (PTH). Hyperparathyroidism and hypoparathyroidism are clinically important disorders affecting multiple organs. However, our knowledge regarding regulatory mechanisms governing the parathyroids has remained limited.

History of Thyroid Surgery in the Last Century.

Before the 20th century, thyroid surgery was regarded as "horrid butchery" such that no honest and sensible surgeon would ever engage in it. Yet, by the mid-20th century, thyroidectomy had become a respected, life-saving, safe, and increasingly practiced operation. From Kocher to Wells and onward into the 21st century, the evolution of thyroid surgery has continued, enhanced by the integration of endocrinology, genetics, immunology, physiology, technology, training, and multidisciplinary care.

Modeling the tumor microenvironment of anaplastic thyroid cancer: an orthotopic tumor model in C57BL/6 mice.

Introduction: Securing a well-established mouse model is important in identifying and validating new therapeutic targets for immuno-oncology. The C57BL/6 mouse is one of the most fully characterised immune system of any animal and provides powerful platform for immuno-oncology discovery. An orthotopic tumor model has been established using TBP3743 (murine anaplastic thyroid cancer [ATC]) cells in B6129SF1 hybrid mice, this model has limited data on tumor immunology than C57BL/6 inbred mice.

Implementation of a New Surgeon Onboarding Program in an Academic-affiliated Community Hospital.

Best practices in onboarding are well-established, but surgeons frequently receive suboptimal introductions to new practice settings. At the same time, increasing regionalization of surgical programs and strategic alignments between academic and community hospitals have increased the demand for surgeons to practice at multiple sites with variable resources and institutional cultures. In response to this growing problem, we developed and implemented a surgeon onboarding program in an academic-affiliated community hospital.

Thyroid Cancers Exhibit Oncogene-Enhanced Macropinocytosis that Is Restrained by IGF1R and Promote Albumin-Drug Conjugate Response.

Purpose: Oncogene-driven macropinocytosis fuels nutrient scavenging in some cancer types, yet whether this occurs in thyroid cancers with prominent MAPK-ERK and PI3K pathway mutations remains unclear. We hypothesized that understanding links between thyroid cancer signaling and macropinocytosis might uncover new therapeutic strategies.

Experimental Design: Macropinocytosis was assessed across cells derived from papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), non-malignant follicular thyroid, and aggressive anaplastic thyroid cancer (ATC), by imaging fluorescent dextran and serum albumin.

Effectors Enabling Adaptation to Mitochondrial Complex I Loss in Hürthle Cell Carcinoma.

Unlabelled: Oncocytic (Hürthle cell) carcinoma of the thyroid (HCC) is genetically characterized by complex I mitochondrial DNA mutations and widespread chromosomal losses. Here, we utilize RNA sequencing and metabolomics to identify candidate molecular effectors activated by these genetic drivers. We find glutathione biosynthesis, amino acid metabolism, mitochondrial unfolded protein response, and lipid peroxide scavenging to be increased in HCC.

Do Resident Coaching Programs Benefit their Coaches? Impact of a Professional Development Coaching Program on The Coaches.

Background: Coaching has been shown to decrease physician burnout; however, coachee outcomes have been the focus. We report the impact of coaching on women-identifying surgeons who participated as coaches in a 9-month virtual program.

Methods: A coaching program was implemented in the Association of Women Surgeons (AWS) to determine the effects of coaching on well-being and burnout from 2018 to 2020.

Radiation Cleaved Drug-Conjugate Linkers Enable Local Payload Release.

Conjugation of therapeutic payloads to biologics including antibodies and albumin can enhance the selectively of drug delivery to solid tumors. However, achieving activity in tumors while avoiding healthy tissues remains a challenge, and payload activity in off-target tissues can cause toxicity for many such drug-conjugates. Here, we address this issue by presenting a drug-conjugate linker strategy that releases an active therapeutic payload upon exposure to ionizing radiation.

Impact of a Virtual Professional Development Coaching Program on the Professional Fulfillment and Well-Being of Women Surgery Residents: A Randomized Controlled Trial.

Objective: Evaluate the effect of a virtual coaching program offered to women surgery residents in a surgical society.

Background: Randomized controlled experiments evaluating the effect of coaching on trainee well-being and burnout is lacking.

Methods: Women surgery residents in the Association of Women Surgeons were recruited to participate in a randomized controlled trial of the effects of a virtual coaching program on trainee well-being.

Overcoming differential tumor penetration of BRAF inhibitors using computationally guided combination therapy.

BRAF-targeted kinase inhibitors (KIs) are used to treat malignancies including BRAF-mutant non-small cell lung cancer, colorectal cancer, anaplastic thyroid cancer, and, most prominently, melanoma. However, KI selection criteria in patients remain unclear, as are pharmacokinetic/pharmacodynamic (PK/PD) mechanisms that may limit context-dependent efficacy and differentiate related drugs. To address this issue, we imaged mouse models of BRAF-mutant cancers, fluorescent KI tracers, and unlabeled drug to calibrate in silico spatial PK/PD models.

Deciphering albumin-directed drug delivery by imaging.

Albumin is the most abundant plasma protein, exhibits extended circulating half-life, and its properties have long been exploited for diagnostics and therapies. Many drugs intrinsically bind albumin or have been designed to do so, yet questions remain about true rate limiting factors that govern albumin-based transport and their pharmacological impacts, particularly in advanced solid cancers. Imaging techniques have been central to quantifying - at a molecular and single-cell level - the impact of mechanisms such as phagocytic immune cell signaling, FcRn-mediated recycling, oncogene-driven macropinocytosis, and albumin-drug interactions on spatial albumin deposition and related pharmacology.

American Association of Clinical Endocrinology And Associazione Medici Endocrinologi Thyroid Nodule Algorithmic Tool.

Objective: The first edition of the American Association of Clinical Endocrinology/American College of Endocrinology/Associazione Medici Endocrinologi Guidelines for the Diagnosis and Management of Thyroid Nodules was published in 2006 and updated in 2010 and 2016. The American Association of Clinical Endocrinology/American College of Endocrinology/Associazione Medici Endocrinologi multidisciplinary thyroid nodules task force was charged with developing a novel interactive electronic algorithmic tool to evaluate thyroid nodules.

Methods: The Thyroid Nodule App (termed TNAPP) was based on the updated 2016 clinical practice guideline recommendations while incorporating recent scientific evidence and avoiding unnecessary diagnostic procedures and surgical overtreatment.

Survival After Adrenalectomy for Metastatic Lung Cancer.

Background: Adrenal metastasectomy is associated with increased survival in non-small cell lung cancer (NSCLC) with isolated adrenal metastases. Although clinical use of adrenal metastasectomy has expanded, indications remain poorly defined. The aim of this study was to evaluate the clinical benefit of adrenal metastasectomy for all lung cancer subtypes.

Four-dimensional computed tomography (4D-CT) for preoperative parathyroid localization: A good study but are we using it?

Background: Four-dimensional computed tomography (4D-CT) scan to localize abnormal parathyroid glands is diagnostically superior to ultrasound (US) and sestamibi. The implementation of 4D-CT imaging is unknown.

Methods: The Collaborative Endocrine Surgery Quality Improvement Program (CESQIP) database from 2014 to 2018 was utilized.

American Association of Clinical Endocrinology And Associazione Medici Endocrinologi Thyroid Nodule Algorithmic Tool.

Objective: The first edition of the American Association of Clinical Endocrinology/American College of Endocrinology/Associazione Medici Endocrinologi Guidelines for the Diagnosis and Management of Thyroid Nodules was published in 2006 and updated in 2010 and 2016. The American Association of Clinical Endocrinology/American College of Endocrinology/Associazione Medici Endocrinologi multidisciplinary thyroid nodules task force was charged with developing a novel interactive electronic algorithmic tool to evaluate thyroid nodules.

Methods: The Thyroid Nodule App (termed TNAPP) was based on the updated 2016 clinical practice guideline recommendations while incorporating recent scientific evidence and avoiding unnecessary diagnostic procedures and surgical overtreatment.

Therapeutically reprogrammed nutrient signalling enhances nanoparticulate albumin bound drug uptake and efficacy in KRAS-mutant cancer.

Nanoparticulate albumin bound paclitaxel (nab-paclitaxel, nab-PTX) is among the most widely prescribed nanomedicines in clinical use, yet it remains unclear how nanoformulation affects nab-PTX behaviour in the tumour microenvironment. Here, we quantified the biodistribution of the albumin carrier and its chemotherapeutic payload in optically cleared tumours of genetically engineered mouse models, and compared the behaviour of nab-PTX with other clinically relevant nanoparticles. We found that nab-PTX uptake is profoundly and distinctly affected by cancer-cell autonomous RAS signalling, and RAS/RAF/MEK/ERK inhibition blocked its selective delivery and efficacy.

h-Index and Academic Rank by Gender Among Breast Surgery Fellowship Faculty.

Gender disparities in academic promotion and leadership are well documented. Scholarly impact is essential for promotion. The Hirsch-index (h-index) is a measure of impact using number of publications and citations.

Representation of women plenary speakers at the American Academy of Neurology Annual Meeting.

Objective: To determine whether women have been equitably represented among plenary speakers at the American Academy of Neurology (AAN) Annual Meeting by counting and categorizing speakers and comparing outcomes to AAN membership and US neurology workforce data.

Methods: Lists of plenary speakers between 1958 and 2019 (62 years) were obtained from the AAN. The primary outcome measures were numbers and proportions of men and women in aggregate and among physicians.

Detecting Immune Response to Therapies Targeting PDL1 and BRAF by Using Ferumoxytol MRI and Macrin in Anaplastic Thyroid Cancer.

Background Anaplastic thyroid cancer (ATC) is aggressive with a poor prognosis, partly because of the immunosuppressive microenvironment created by tumor-associated macrophages (TAMs). Purpose To understand the relationship between TAM infiltration, tumor vascularization, and corresponding drug delivery by using ferumoxytol-enhanced MRI and macrin in an ATC mouse model. Materials and Methods ATC tumors were generated in 6-8-week-old female B6129SF1/J mice through intrathyroid injection to model orthotopic tumors, or intravenously to model hematogenous metastasis, and prospectively enrolled randomly into treatment cohorts ( = 94 total; August 1, 2018, to January 15, 2020).

Adrenalectomy for Secondary Malignancy: Patients, Outcomes, and Indications.

Objective: The goal of this study was to examine a multi-institutional experience with adrenal metastases to describe survival outcomes and identify subpopulations who benefit from adrenal metastasectomy.

Background: Adrenalectomy for metastatic disease is well-described, although indications and outcomes are incompletely defined.

Methods: A retrospective cohort study was performed of patients undergoing adrenalectomy for secondary malignancy (2002-2015) at 6 institutions.