Young and resilient: Unraveling papillary thyroid cancer outcomes in males under 40.

BACKGROUND: While males present with more adverse clinicopathologic features in papillary thyroid carcinoma (PTC), younger age has previously been shown to be a favorable prognostic factor. We examined the combined effect of male sex and young age on PTC outcomes. METHODS: We conducted a retrospective analysis of a prospectively maintained database of thyroid cancer surgery patients (2000-2020) at a single quaternary care institution. We included papillary thyroid carcinoma cases and excluded those with prior cancer-related thyroid surgery. We examined demographics, cancer stage, surgical outcomes, and complications by age and sex, analyzing groups below and above the age of 40 years. RESULTS: A total of 680 patients with PTC were included. Females constituted 68% (age ≥40 years: 44% and <40 years: 24%) and males 32% (≥40 years: 24% and <40 years: 8%). A significant difference (p < 0.001) of N1 disease distribution was found between the groups. N1a metastasis was greater in patients younger than 40 regardless of sex ((M < 40 (15%), F < 40 (15%), M ≥ 40 (12%), and F ≥ 40 (9%)). While, M < 40 had greater N1b metastasis (36%) than all other groups (M ≥ 40 (28%), F < 40 (22%), and F ≥ 40 (10%)). There was no significant difference in the distribution of T stages between groups. Groups showed no differences in 30-day outcomes, recurrence at 1 year, reoperation, mortality, nerve injury, or hypocalcemia. CONCLUSIONS: Young males with PTC face increased occurrence of nodal metastasis yet experience similar recurrence rates as their female and older counterparts. Subgroup analysis underscores the predictive role of sex and age in advanced PTC cases.

The overtreatment of papillary thyroid microcarcinoma in the community.

INTRODUCTION: Total thyroidectomy is the traditional primary approach for papillary thyroid cancer. However, recent evidence supports conservative management for low-risk tumors like papillary thyroid microcarcinomas (PTMCs). This study explores the adoption of these practices in our community, using a cancer database to analyze treatment strategies. METHODS: A retrospective review of a 1433-patient institutional database identified 258 â€‹PTMC cases. Outcomes, including 30-day mortality, reoperation rate, postoperative hypocalcemia, and recurrent laryngeal nerve (RLN) injury, were assessed. RESULTS: Of PTMC patients, 63.4% underwent total thyroidectomy, with higher rates of RLN injury (8.8% vs. 2.3%) and hypocalcemia (12.4% vs. 0.0%) compared to lobectomy. Non-endocrine surgeons had higher postoperative radioactive iodine administration rates (28.6% vs. 6.1%). Subgroup analysis revealed a shift in total thyroidectomy rates based on tumor size and surgery period. CONCLUSION: Our community favors total thyroidectomy for PTMC, despite associated complications. Enhanced awareness and adherence to PTMC best practice guidelines are warranted.

Preclinical safety evaluation of continuous UV-A lighting in an operative setting.

BACKGROUND: Germicidal ultraviolet (UV-C) light has been shown as an effective modality for disinfection in laboratory settings and in the operative room. Traditionally, short-wavelength UV-C devices, which have previously been shown to cause DNA damage, are utilized only for disinfection in pre- and post-operative settings and are not continuously active during operations. Continuous use of intraoperative UV light has potential to decrease pathogens and subsequent surgical site infections (SSIs), which arise in approximately 5-15% of operative cases. SSIs are a significant determinant of patient morbidity, readmission rates, and overall cost. Therefore, a method of UV light disinfection with a low risk of DNA damage is needed so that greater antimicrobial protection can be afforded to patients during the entirety of their surgical procedures. A new disinfection device that harnesses longer-wavelength UV-A light to disinfect the surgical field throughout the entirety of the procedure, including pre- and post-operation has been developed. METHODS: This study aimed to determine if UV-A light administered intraoperatively was safe, as defined by the minimal presence of DNA damage and safe amounts of reflection upon medical personnel. Using in vitro models, we examined the differential impacts of UV-C and UV-A light on DNA damage and repair pathways. In a murine model, we looked at the production of DNA damage photoproduction in relation to UV-A versus UV-C exposure. RESULTS: Our results show UV-A light does not induce a significant amount of DNA damage at the cellular or tissue level. Furthermore, a preclinical porcine study showed that surgical personnel were exposed to safe levels of UV-A irradiance from an overhead UV-A light used during an operation. The amount of UV-A transmitted through surgical personal protective equipment (PPE) also remained within safe levels. CONCLUSIONS: In conclusion, we found that UV-A may be safe for intraoperative use.

Faulty Metabolism: A Potential Instigator of an Aggressive Phenotype in Cdk5-dependent Medullary Thyroid Carcinoma.

Mechanistic modeling of cancers such as Medullary Thyroid Carcinoma (MTC) to emulate patient-specific phenotypes is challenging. The discovery of potential diagnostic markers and druggable targets in MTC urgently requires clinically relevant animal models. Here we established orthotopic mouse models of MTC driven by aberrantly active Cdk5 using cell-specific promoters. Each of the two models elicits distinct growth differences that recapitulate the less or more aggressive forms of human tumors. The comparative mutational and transcriptomic landscape of tumors revealed significant alterations in mitotic cell cycle processes coupled with the slow-growing tumor phenotype. Conversely, perturbation in metabolic pathways emerged as critical for aggressive tumor growth. Moreover, an overlapping mutational profile was identified between mouse and human tumors. Gene prioritization revealed putative downstream effectors of Cdk5 which may contribute to the slow and aggressive growth in the mouse MTC models. In addition, Cdk5/p25 phosphorylation sites identified as biomarkers for Cdk5-driven neuroendocrine tumors (NETs) were detected in both slow and rapid onset models and were also histologically present in human MTC. Thus, this study directly relates mouse and human MTC models and uncovers vulnerable pathways potentially responsible for differential tumor growth rates. Functional validation of our findings may lead to better prediction of patient-specific personalized combinational therapies.

The Association of Socioeconomic Factors and Well-Differentiated Thyroid Cancer.

INTRODUCTION: Well-differentiated thyroid cancer (WDTC) is the most common thyroid malignancy, and the worldwide incidence is increasing. Early stage disease is curable with surgery. We hypothesized that patients who live at greater distances from health care institutions or have complicating socioeconomic barriers may present with more advanced diseases and have worse outcomes. METHODS: The National Cancer Database (NCDB) was used to identify patients who were diagnosed with WDTC between 2004 and 2018. Race, ethnicity, insurance status, income status, and distance from residence to health care clinic of diagnosis (great circle distance [GCD]) were analyzed with respect to the severity of disease at presentation (stage) and outcomes. Binary logistic regression and Cox regression were used to determine associations between socioeconomic variables and tumor stage or survival. RESULTS: The Hispanic (OR: 1.49, CI: 1.45-1.54, P < 0.001) and Asian (OR: 1.49, CI: 1.43-1.55, P < 0.001) populations had higher odds of developing an advanced disease when compared to the White population separately. Patients without insurance displayed higher odds of developing an advanced disease at diagnosis compared to those with insurance (OR: 1.39, CI: 1.31-1.47, P < 0.001). Adjusted-Cox regression analysis of survival revealed that Black patients had detrimental survival outcomes when compared to White patients (HR: 1.24, P < 0.001), and patients with private insurance had improved survival outcomes when compared to those without insurance (HR: 0.58, P < 0.001). CONCLUSIONS: Hispanic and Asian patients were found to be more likely to present with an advanced disease but also displayed greater overall survival when compared to the White population. The Black population, patients without insurance, and patients with lower income status exhibited worse survival outcomes.

Under-Representation of Racial Groups in Genomics Studies of Gastroenteropancreatic Neuroendocrine Neoplasms.

Not all populations are poised to benefit from advancing genomics in gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN), as genomics have focused on White patients. This study aimed to evaluate racial populations represented in genomic studies of GEP-NENs and to provide evidence of differential genomic findings between racial groups in GEP-NENs. Manuscripts analyzing DNA, RNA, or DNA methylation in GEP-NENs were queried using PUBMED and EMBASE. NIH race/ethnicity term frequency was then determined by Natural Language Processing, followed by manual evaluation of tumor types and subjects by racial group. IHC of institutional tissue micro-arrays and analysis of AACR GENIE data analyzed was performed to determine mutational differences between Black and White pancreatic NEN (pNEN) patients. 313 manuscripts conducted the requisite genomic analyses, 16 of which included subject race data. Race data were included in 13/184 DNA, 4/107 RNA, and 1/54 DNA Methylation analyses. These studies included 89% White subjects (n = 2032), 5.8% Asian subjects (n = 132), 4.0% "Other" subjects (n = 93), and 1.2% Black subjects (n = 27). No Native American/Alaska Native, Native Hawaiian/Pacific Islander, or ethnically Hispanic/Latinx subjects were represented. There were significant differences in MEN1 mutations among Black and White patients in immunohistochemical (13:40) and GENIE data (24:268 patients per group, respectively), with 9 additional genes differentially mutated in the GENIE dataset. Genomic sequencing data for GEP-NENs is almost racially homogenous. Differences in pNEN genomics may exist between racial groups, highlighting a need for diversity in future genomic analyses of GEP-NENs to understand the putative influence of interracial genomic variation on GEP-NEN prevention, diagnosis, and therapy. Significance: There is little diversity in genomic studies of GEP-NENs, which may exhibit clinically impactful variation in their tumor biology among racial groups. Improved diversity in such studies is imperative for understanding this variation and its potential impacts on disease prevention, diagnosis, therapeutic targeting, and clinical outcomes.

Cdk5 drives formation of heterogeneous pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous population of neoplasms that arise from hormone-secreting islet cells of the pancreas and have increased markedly in incidence over the past four decades. Non-functional PanNETs, which occur more frequently than hormone-secreting tumors, are often not diagnosed until later stages of tumor development and have poorer prognoses. Development of successful therapeutics for PanNETs has been slow, partially due to a lack of diverse animal models for pre-clinical testing. Here, we report development of an inducible, conditional mouse model of PanNETs by using a bi-transgenic system for regulated expression of the aberrant activator of Cdk5, p25, specifically in ß-islet cells. This model produces a heterogeneous population of PanNETs that includes a subgroup of well-differentiated, non-functional tumors. Production of these tumors demonstrates the causative potential of aberrantly active Cdk5 for generation of PanNETs. Further, we show that human PanNETs express Cdk5 pathway components, are dependent on Cdk5 for growth, and share genetic and transcriptional overlap with the INS-p25OE model. The utility of this model is enhanced by the ability to form tumor-derived allografts. This new model of PanNETs will facilitate molecular delineation of Cdk5-dependent PanNETs and the development of new targeted therapeutics.

Wide Provider Variation in Cost for Thyroidectomy: Potential Benefits of Standardizing Practice?

OBJECTIVE(S): Identifying provider variation in surgical costs could control rising healthcare expenditure and deliver cost-effective care. While these efforts have mostly focused on complex and expensive operations, provider-level variation in costs of thyroidectomy has not been well examined. METHODS: We retrospectively evaluated 921 consecutive total thyroidectomies performed by 14 surgeons at our institution between September 2011 and July 2016. Data were extracted from the Change Healthcare Performance Analytics Program. RESULTS: Mean patient age was 47.4 ± 0.5 y, 81% were females, 64.7% were Caucasians, and 18.8% were outpatients. The number of thyroidectomies performed by the 14 surgeons ranged from 4 to 597 (mean = 66). The mean costs per provider varied widely from $4,293 to $15,529 (P < 0.001). The mean length of stay was 1d ± .03 with wide variation among providers (0-6 d). Providers whose hospital cost exceeded the institutional mean demonstrated significantly higher anesthesia fees and lab costs (P < 0.001). CONCLUSIONS: We found substantial variation in hospital cost among providers for thyroidectomy despite practicing in the same academic institution, with some surgeons spending 3x more for the same operation. Implementing institutional standards of practice could reduce variation and the costs of surgical care.

A single institution experience with papillary thyroid cancer: Are outcomes better at comprehensive cancer centers?

INTRODUCTION: Papillary thyroid cancer (PTC) is the most common form of thyroid cancer. Although the survival rate is excellent, recurrence is as high as 20%. The mainstay of therapy is thyroidectomy and lymph node dissection based on risk factors. Data from other cancers suggest that surgical outcomes are most optimal at comprehensive cancer centers. We hypothesize that patients with PTC who had their initial operation at a comprehensive cancer center would have a better oncologic outcome. METHODS: We utilized an IRB-approved cancer care registry database of patients with thyroid cancer who were seen at our institution between 2000 and 2018. Patient records were updated with cancer-specific outcomes including recurrence and need for re-intervention. Clinical and surgical outcomes were then compared between patients who had their initial operation at a comprehensive cancer center (CCC group, n = 503) versus those who did not (non-CCC group, n = 72). RESULTS: Mean patient age was 49 ± 16 years and 70% were female. Average tumor size was 1.6 ± 1.6 cm. There was no difference in tumor size, age, gender or race between groups. Pre-operative ultrasound was more frequently performed at the CCC (89%) than at non-CCC's (51%, p < 0.001). CCC patients were more likely to undergo initial total thyroidectomies compared to non-CCC patients (76% vs. 21%, p < 0.001). Positive surgical margins were more frequently found in patients at non-CCC's (19%) than at the CCC (9.7%, p = 0.016). Finally, CCC patients had a significantly lower cancer recurrence rate (5.0% vs. 37.5%, p < 0.001). Therefore, the need for additional cancer operations was much greater in patients who had initial thyroid surgery at non-CCC (31.9% vs. 1.4%, p < 0.001). CONCLUSIONS: Patients with PTC who have their initial thyroidectomy at non-CCC have higher recurrence rates, higher rates of positive tumor margins on pathology, and increased need for additional operations. These data suggest that patients who have their initial procedure at a CCC for PTC have better long-term outcomes.

Ex Vivo Modeling of Human Neuroendocrine Tumors in Tissue Surrogates.

Few models exist for studying neuroendocrine tumors (NETs), and there are mounting concerns that the currently available array of cell lines is not representative of NET biology. The lack of stable patient-derived NET xenograft models further limits the scientific community's ability to make conclusions about NETs and their response to therapy in patients. To address these limitations, we propose the use of an ex vivo 3D flow-perfusion bioreactor system for culturing and studying patient-derived NET surrogates. Herein, we demonstrate the utility of the bioreactor system for culturing NET surrogates and provide methods for evaluating the efficacy of therapeutic agents on human NET cell line xenograft constructs and patient-derived NET surrogates. We also demonstrate that patient-derived NET tissues can be propagated using the bioreactor system and investigate the near-infrared (NIR) dye IR-783 for its use in monitoring their status within the bioreactor. The results indicate that the bioreactor system and similar 3D culture models may be valuable tools for culturing patient-derived NETs and monitoring their response to therapy ex vivo.

A growth model of neuroendocrine tumor surrogates and the efficacy of a novel somatostatin-receptor-guided antibody-drug conjugate: Perspectives on clinical response?

BACKGROUND: As patient-derived xenografts and other preclinical models of neuroendocrine tumors for testing personalized therapeutics are lacking, we have developed a perfused, 3D bioreactor model to culture tumor surrogates from patient-derived neuroendocrine tumors. This work evaluates the duration of surrogate culture and surrogate response to a novel antibody-drug conjugate. METHODS: Twenty-seven patient-derived neuroendocrine tumors were cultured. Histologic sections of a pancreatic neuroendocrine tumor xenograft (BON-1) tumor were assessed for SSTR2 expression before tumor implantation into 2 bioreactors. One surrogate was treated with an antibody-drug conjugate composed of an anti-mitotic Monomethyl auristatin-E linked to a somatostatin receptor 2 antibody. Viability and therapeutic response were assessed by pre-imaging incubation with IR-783 and the RealTime-Glo AnnexinV Apoptosis and Necrosis Assay (Promega Corporation, Madison, WI) over 6 days. A primary human pancreatic neuroendocrine tumor was evaluated similarly. RESULTS: Mean surrogate growth duration was 34.8 days. Treated BON-1 surrogates exhibited less proliferation (1.2 vs 1.9-fold) and greater apoptosis (1.5 vs 1.1-fold) than controls, whereas treated patient-derived neuroendocrine tumor bioreactors exhibited greater degrees of apoptosis (13- vs 9-fold) and necrosis (2.5- vs 1.6-fold). CONCLUSION: Patient-derived neuroendocrine tumor surrogates can be cultured reliably within the bioreactor. This model can be used to evaluate the efficacy of antibody-guided chemotherapy ex vivo and may be useful for predicting clinical responses.

Novel small RNA (sRNA) landscape of the starvation-stress response transcriptome of Salmonella enterica serovar typhimurium.

Small RNAs (sRNAs) are short (∼50-200 nucleotides) noncoding RNAs that regulate cellular activities across bacteria. Salmonella enterica starved of a carbon-energy (C) source experience a host of genetic and physiological changes broadly referred to as the starvation-stress response (SSR). In an attempt to identify novel sRNAs contributing to SSR control, we grew log-phase, 5-h C-starved and 24-h C-starved cultures of the virulent Salmonella enterica subspecies enterica serovar Typhimurium strain SL1344 and comprehensively sequenced their small RNA transcriptomes. Strikingly, after employing a novel strategy for sRNA discovery based on identifying dynamic transcripts arising from "gene-empty" regions, we identify 58 wholly undescribed Salmonella sRNA genes potentially regulating SSR averaging an ∼1,000-fold change in expression between log-phase and C-starved cells. Importantly, the expressions of individual sRNA loci were confirmed by both comprehensive transcriptome analyses and northern blotting of select candidates. Of note, we find 43 candidate sRNAs share significant sequence identity to characterized sRNAs in other bacteria, and ∼70% of our sRNAs likely assume characteristic sRNA structural conformations. In addition, we find 53 of our 58 candidate sRNAs either overlap neighboring mRNA loci or share significant sequence complementarity to mRNAs transcribed elsewhere in the SL1344 genome strongly suggesting they regulate the expression of transcripts via antisense base-pairing. Finally, in addition to this work resulting in the identification of 58 entirely novel Salmonella enterica genes likely participating in the SSR, we also find evidence suggesting that sRNAs are significantly more prevalent than currently appreciated and that Salmonella sRNAs may actually number in the thousands.