The genomic and transcriptomic landscape of anaplastic thyroid cancer: implications for therapy.

BACKGROUND: Anaplastic thyroid carcinoma is the most undifferentiated form of thyroid cancer and one of the deadliest of all adult solid malignancies. Here we report the first genomic and transcriptomic profile of anaplastic thyroid cancer including those of several unique cell lines and outline novel potential drivers of malignancy and targets of therapy. METHODS: We describe whole genomic and transcriptomic profiles of 1 primary anaplastic thyroid tumor and 3 authenticated cell lines. Those profiles augmented by the transcriptomes of 4 additional and unique cell lines were compared to 58 pairs of papillary thyroid carcinoma and matched normal tissue transcriptomes from The Cancer Genome Atlas study. RESULTS: The most prevalent mutations were those of TP53 and BRAF; repeated alterations of the epigenetic machinery such as frame-shift deletions of HDAC10 and EP300, loss of SMARCA2 and fusions of MECP2, BCL11A and SS18 were observed. Sequence data displayed aneuploidy and large regions of copy loss and gain in all genomes. Common regions of gain were however evident encompassing chromosomes 5p and 20q. We found novel anaplastic gene fusions including MKRN1-BRAF, FGFR2-OGDH and SS18-SLC5A11, all expressed in-frame fusions involving a known proto-oncogene. Comparison of the anaplastic thyroid cancer expression datasets with the papillary thyroid cancer and normal thyroid tissue transcriptomes suggested several known drug targets such as FGFRs, VEGFRs, KIT and RET to have lower expression levels in anaplastic specimens compared with both papillary thyroid cancers and normal tissues, confirming the observed lack of response to therapies targeting these pathways. Further integrative data analysis identified the mTOR signaling pathway as a potential therapeutic target in this disease. CONCLUSIONS: Anaplastic thyroid carcinoma possessed heterogeneous and unique profiles revealing the significance of detailed molecular profiling of individual tumors and the treatment of each as a unique entity; the cell line sequence data promises to facilitate the more accurate and intentional drug screening studies for anaplastic thyroid cancer.

Complete genomic landscape of a recurring sporadic parathyroid carcinoma.

Parathyroid carcinoma is a rare endocrine malignancy with an estimated incidence of less than 1 per million population. Excessive secretion of parathyroid hormone, extremely high serum calcium level, and the deleterious effects of hypercalcaemia are the clinical manifestations of the disease. Up to 60% of patients develop multiple disease recurrences and although long-term survival is possible with palliative surgery, permanent remission is rarely achieved. Molecular drivers of sporadic parathyroid carcinoma have remained largely unknown. Previous studies, mostly based on familial cases of the disease, suggested potential roles for the tumour suppressor MEN1 and proto-oncogene RET in benign parathyroid tumourigenesis, while the tumour suppressor HRPT2 and proto-oncogene CCND1 may also act as drivers in parathyroid cancer. Here, we report the complete genomic analysis of a sporadic and recurring parathyroid carcinoma. Mutational landscapes of the primary and recurrent tumour specimens were analysed using high-throughput sequencing technologies. Such molecular profiling allowed for identification of somatic mutations never previously identified in this malignancy. These included single nucleotide point mutations in well-characterized cancer genes such as mTOR, MLL2, CDKN2C, and PIK3CA. Comparison of acquired mutations in patient-matched primary and recurrent tumours revealed loss of PIK3CA activating mutation during the evolution of the tumour from the primary to the recurrence. Structural variations leading to gene fusions and regions of copy loss and gain were identified at a single-base resolution. Loss of the short arm of chromosome 1, along with somatic missense and truncating mutations in CDKN2C and THRAP3, respectively, provides new evidence for the potential role of these genes as tumour suppressors in parathyroid cancer. The key somatic mutations identified in this study can serve as novel diagnostic markers as well as therapeutic targets.

The influence of papillary features on the risk of malignancy in thyroid nodules diagnosed as atypia of undetermined significance or follicular lesion of undetermined significance.

BACKGROUND: The objective of this study was to the assess the risk of malignancy in thyroid lesions that were diagnosed as AUS/FLUS when using a novel cytology subclassification system that is based on the presence or absence of papillary features. METHODS: AUS/FLUS case cytology was re-reviewed and subclassified into minor or major concern groups based upon the absence or presence of papillary features, respectively. The risk of malignancy (ROM) was calculated and compared between the two groups. Inter-pathologist agreement in case subclassification was also measured. RESULTS: The minor concern group had a 12.6% associated ROM, while the major concern group had a significantly higher ROM (58.4%), (P < 0.001). Based on 108 cases, the inter-pathologist agreement in case subclassification was 79%, and the κ value was 0.47. CONCLUSIONS: The identification of papillary features significantly increases the ROM in thyroid lesions with an AUS/FLUS diagnosis.

Hospital-based opioid treatment: Expanding and sustaining the model in Texas.

This Brief Report includes follow-up data about the sustainability and expansion of the Buprenorphine Team (B-Team), a hospital-based opioid treatment (HBOT) program. Between September 2018 and January 2023, the B-Team started 398 patients with opioid-use disorder (OUD) on buprenorphine therapy and coordinated outpatient care for 353 patients before discharge. Two-hundred and forty-nine of these patients were scheduled for follow-up at our partner addiction treatment clinic. Retention rates at our partner clinic remain relatively high: 73 patients (36% of eligible patients) continued to attend appointments between 6 and 12 months, and 40 of 180 patients (22%) who have been discharged from the hospital for at least 1 year continued to attend appointments. This model has been adopted at three additional Texas hospitals, resulting in rapid growth: 1037 patients were started on buprenorphine across these four sites during 2021-2022. Our longitudinal results support HBOT as an effective model for treating patients with OUD.

Hemithyroidectomy is the preferred initial operative approach for an indeterminate fine needle aspiration biopsy diagnosis.

BACKGROUND: Fine needle aspiration biopsy represents the critical initial diagnostic test used for evaluation of thyroid nodules. Our objectives were to determine the cytological distribution, the utility of clinicopathologic characteristics for predicting malignancy and the true proportion of cancer among individuals who presented with indeterminate cytology and had undergone thyroid surgery for suspicion of cancer. METHODS: We retrospectively reviewed 1040 consecutive primary thyroid operations carried out over an 8-year period at a tertiary care endocrine referral centre. Follicular neoplasm (FN), Hürthle cell neoplasm (HN), neoplasms suspicious for but not diagnostic of papillary carcinoma (IP) and neoplasms with cellular atypia (IA) were reviewed. RESULTS: In all, 380 individuals presented with cytologically indeterminate thyroid nodules. Of these, 252 (66%) patients had FN, 47 (12%) HN, 44 (12%) IP, 26 (7%) IA and 11 (4%) had mixed diagnoses. Biopsied lesions were found to be malignant on pathological evaluation in 102 (27%) patients: 49 (19%) with FN, 11 (23%) HN, 28 (64%) IP and 9 (35%) with IA. Hemithyroidectomy was adequate definitive treatment in 196 of 225 (87%) patients with FN and 39 of 42 (93%) with HN. Significant associations with a cancer diagnosis were identified for smaller tumour size in patients with FN (p = 0.004) and right thyroid lobe location in patients with IP (p = 0.012), although these factors were nonsignificant in the corrected analyses for multiple comparisons. CONCLUSION: In a review of the experience at a Canadian centre, 4 operations were carried out to identify each cancer, and hemithyroidectomy was the optimal initial and definitive surgical approach for most patients.

Subcutaneous transplantation of human thyroid tissue into a pre-vascularized Cell Pouch™ device in a Mus musculus model: Evidence of viability and function for thyroid transplantation.

This study aimed to investigate the survival and efficacy indicators of human thyroid tissue transplantation into a retrievable, prevascularized implanted Sernova Corp Cell Pouch™ (CP) device. Thyroid tissue from human donors was transplanted subcutaneously into the pre-implanted CP device or into the subcutaneous (SC) space alone as a control in a nude Mus musculus model. Transplanted M. musculus were monitored for human serum thyroglobulin (TG) levels for 3 months until the transplants were removed for histological assessment. Human thyroid tissue survived and continued to produce TG in transplanted nude M. musculus in the CP, with no adverse events. CP transplants exhibited more persistent and robust production of human TG than tissue placed in the SC space alone from 3 to 13 weeks post transplantation. Fresh thyroid transplants had better survival and function compared to cryopreserved transplants. Thyroid transplant viability correlated with TG levels at 3 months post-transplant (p = 0.03). Immunofluorescence staining of transplants for TG and TPO localized in thyroid follicles. Human thyroid tissue transplanted into the subcutaneously implanted pre-vascularized CP in nude M. musculus survived and continued to produce robust and persistent human TG and warrants further investigation as a treatment for postoperative hypothyroidism.

Diagnostic utility of galectin-3 in thyroid cancer.

Galectin-3 (Gal-3), which has received significant recent attention for its utility as a diagnostic marker for thyroid cancer, represents the most well-studied molecular candidate for thyroid cancer diagnosis. Gal-3 is a protein that binds to beta-galactosidase residues on cell surface glycoproteins and has also been identified in the cytoplasmic and nuclear compartment. This marker has been implicated in regulation of normal cellular proliferation and apoptosis, as well as malignant transformation and the metastasis of cancer cells. We here present a mechanistic review of Gal-3 and its role in cancer development and progression. Gal-3 expression studies in thyroid tissue and cytologic tumor specimens and their methodological considerations are also discussed in this article. Despite great variance in their methodology, the majority of immunohistochemical studies found that Gal-3 was differentially expressed in thyroid carcinoma compared with benign and normal thyroid specimens, suggesting that Gal-3 is a good diagnostic marker for thyroid cancer. Recent studies have also demonstrated improved methodological reliability. On the other hand, Gal-3 genomic expression studies have shown inconsistent results for diagnostic utility and are not recommended. Overall, the development of Gal-3 as a diagnostic marker for thyroid cancer represents a promising avenue for future study, and its clinical application could significantly reduce the number of diagnostic thyroid operations performed for cases of indeterminant fine needle aspiration biopsy cytology, and thus positively impact the current management of thyroid nodular disease.

Detection and management of hypothyroidism following thyroid lobectomy: evaluation of a clinical algorithm.

BACKGROUND: The objectives of this study were to determine: (1) the incidence permanent hypothyroidism after thyroid lobectomy (TL), (2) whether asymptomatic patients with mildly elevated thyrotropin (TSH) levels can be managed without thyroid hormone replacement, and (3) if the degree of lymphocytic infiltration (LI) and germinal center (GC) formation in the resected thyroid lobe correlates with the development of post-TL hypothyroidism. METHODS: Subjects undergoing TL between January 2006 and January 2008 at 2 centers were enrolled in the study and thyroid function was followed prospectively based on a previously published algorithm. The histology of each resected thyroid lobe was examined, and the degree of LI and GC was quantified. RESULTS: The study cohort consisted of 117 patients. Early postoperative TSH levels were significantly increased over preoperative levels (P < .001). TSH measured at 6 months to 1 year postoperatively, while still significantly increased over preoperative levels (P < .001), was also significantly reduced (P = .006) compared with early postoperative levels. Of the patients who presented with early postoperative hypothyroidism, 69.2% recovered to normal levels without intervention. The overall incidence of early postoperative hypothyroidism was 21.6%, and permanent hypothyroidism was 7.8%. A high degree of LI and GC correlated with a significantly higher mean TSH level (P = .003). CONCLUSIONS: The incidence of hypothyroidism following TL is low, and a significant proportion of individuals who become biochemically hypothyroid will demonstrate only a transient elevation in their TSH levels. As well, individuals with LI, or GC formation, within their resected thyroid lobe may be at increased risk for post-TL hypothyroidism.

Hospital Buprenorphine Program for Opioid Use Disorder Is Associated With Increased Inpatient and Outpatient Addiction Treatment.

Despite evidence that medications for patients with opioid use disorder (OUD) reduce mortality and improve engagement in outpatient addiction treatment, these life-saving medications are underutilized in the hospital setting. This study reports the outcomes of the B-Team (Buprenorphine-Team), a hospitalist-led interprofessional program created to identify hospitalized patients with OUD, initiate buprenorphine in the inpatient setting, and provide bridge prescription and access to outpatient treatment programs. During the first 2 years of the program, the B-Team administered buprenorphine therapy to 132 patients in the inpatient setting; 110 (83%) of these patients were bridged to an outpatient program. Of these patients, 65 patients (59%) were seen at their first outpatient appointment; 42 (38%) attended at least one subsequent appointment 1 to 3 months after discharge from the hospital; 29 (26%) attended at least one subsequent appointment between 3 and 6 months after discharge; and 24 (22%) attended at least one subsequent appointment after 6 months. This model is potentially replicable at other hospitals because it does not require dedicated addiction medicine expertise.

The development and implementation of a "B-Team" (buprenorphine team) to treat hospitalized patients with opioid use disorder.

IMPLEMENTATION INSIGHTS.

Lymphoepithelial cysts of the pancreas: the use of endoscopic ultrasound-guided fine-needle aspiration in diagnosis.

Lymphoepithelial cysts (LECs) are rare non-neoplastic lesions that can appear as a complex cyst or a mass in the pancreas. Cytology from endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) can be helpful in making a diagnosis with the aim of avoiding unnecessary surgical resection. A case involving a 51-year-old woman with lower abdominal pain who was found to have a multiloculated cystic lesion at the junction of the pancreatic body and tail is described. Cytology from EUS-FNA was consistent with a pancreatic LEC. The lesion was managed conservatively and follow-up imaging of the cyst over the following two years was unchanged. The patient remains clinically well. Cytology from EUS-FNA can help distinguish LECs from cystic neoplasms, thus preventing radical surgical resection of this benign pancreatic cyst.

Colorectal Cancer Detection Based on Deep Learning.

INTRODUCTION: The initial point in the diagnostic workup of solid tumors remains manual, with the assessment of hematoxylin and eosin (H&E)-stained tissue sections by microscopy. This is a labor-intensive step that requires attention to detail. In addition, diagnoses are influenced by an individual pathologist's knowledge and experience and may not always be reproducible between pathologists. METHODS: We introduce a deep learning-based method in colorectal cancer detection and segmentation from digitized H&E-stained histology slides. RESULTS: In this study, we demonstrate that this neural network approach produces median accuracy of 99.9% for normal slides and 94.8% for cancer slides compared to pathologist-based diagnosis on H&E-stained slides digitized from clinical samples. CONCLUSION: Given that our approach has very high accuracy on normal slides, use of neural network algorithms may provide a screening approach to save pathologist time in identifying tumor regions. We suggest that this new method may be a powerful assistant for colorectal cancer diagnostics.

Limited clinical utility of intraoperative frozen section during parathyroidectomy for treatment of primary hyperparathyroidism.

BACKGROUND: This study's objective was to evaluate the utility of intraoperative frozen section (IFS) performed during parathyroidectomy for treatment of primary hyperparathyroidism (PHP), and to identify patients for whom it is most helpful. METHODS: A retrospective chart review was carried out for all patients who underwent parathyroidectomy for treatment of PHP between January 2013 and June 2018. RESULTS: 262 patients made up the final study population. Overall, IFS provided information that influenced the operative plan in 46 patients (17.6%). IFS altered the operative plan in 10.2% of cases that were correctly preoperatively localized, and in 41.5% of cases that were either incorrectly or not preoperatively localized. CONCLUSIONS: IFS did not provide information that influenced the operative plan during parathyroidectomy for treatment of PHP for the majority of patients. Patients that present with normal PTH and hypercalcemia, or those who do not localize preoperatively, are most likely to benefit from IFS.

Fixation Effects on Variant Calling in a Clinical Resequencing Panel.

Formalin fixation is the standard method for the preservation of tissue for diagnostic purposes, including pathologic review and molecular assays. However, this method is known to cause artifacts that can affect the accuracy of molecular genetic test results. We assessed the applicability of alternative fixatives to determine whether these perform significantly better on next-generation sequencing assays, and whether adequate morphology is retained for primary diagnosis, in a prospective study using a clinical-grade, laboratory-developed targeted resequencing assay. Several parameters relating to sequencing quality and variant calling were examined and quantified in tumor and normal colon epithelial tissues. We identified an alternative fixative that suppresses many formalin-related artifacts while retaining adequate morphology for pathologic review.

The presence of papillary features in thyroid nodules diagnosed as atypia of undetermined significance or follicular lesion of undetermined significance increases cancer risk and should influence treatment.

BACKGROUND: The objective of this study was to evaluate the influence of papillary features on risk of malignancy (ROM) within the Atypia of Undetermined Significance or Follicular Lesion of Undetermined Significance (AUS-FLUS) Bethesda System for Reporting Thyroid Cytopathology (BSRTC) diagnostic category. METHODS: A Retrospective review of cases with an AUS-FLUS diagnosis that underwent a thyroidectomy was carried out, and cases were subcategorized based upon the presence of papillary features. RESULTS: For the entire study population there were 93 (22%) of 427 FNAB specimens that had an AUS-FLUS diagnosis, and a 32% associated ROM. Papillary features were identified in 44 FNAB specimens (47% of the AUS-FLUS cases or 10% of the entire study population), and when present had a 45% ROM. The 49 FNAB specimens (53%) that did not exhibit papillary features had a significantly lower ROM (20%) than those that did have papillary features (p = 0.0069). CONCLUSIONS: The presence of papillary features in a thyroid FNAB with an AUS-FLUS diagnosis is common, and is associated with a higher ROM than is currently suggested by the BSRTC.

Characteristics of Patients with Colonic Polyps Requiring Segmental Resection.

Background: It is unclear if the availability of new techniques for removal of large colonic polyps has affected the use of segmental colon resection. We sought to evaluate the characteristics of polyps undergoing surgical resection, including involvement of therapeutic gastroenterologists (TG). Methods: 484 patients had a colonic resection; 165 (34%) were identified from the pathology database with polyp, adenoma, or mass in the clinical history field; these charts were reviewed. Results: 128 patients (mean age 68 yrs, 72% male) were included. The mean polyp size was 2.9 cm (0.4 cm-12.0 cm). Adenocarcinoma was diagnosed in 50 (39.1%). 97 (75.8%) patients had a polyp that was felt to be unresectable by EMR, and 31 (24.2%) underwent successful EMR followed by surgery for adenocarcinoma (n = 29). The indication for surgery in those with unresectable polyps was variable and was not clearly documented in 51 (52.6%); only 17 of these patients (17.5%) had a TG involved. Conclusion: A high proportion of polyps managed by segmental resection did not contain adenocarcinoma. This data suggests that even in a tertiary care center where advanced endoscopic techniques are easily available, they are not always utilized. Educational endeavors to ensure that ideal pathways of intervention are utilized require implementation.

Increased Cancer Risk in Younger Patients with Thyroid Nodules Diagnosed as Atypia of Undetermined Significance.

BACKGROUND: The objective of this study was to determine if patient age and/or gender significantly alter the risk of thyroid malignancy in the Bethesda System for Reporting Thyroid Cytopathology (BSRTC) diagnostic categories. METHODS: A retrospective review of 291 sequential patients that underwent thyroid nodule fine needle aspiration biopsy (FNAB) and subsequent surgery at a single center was carried out. Cases were grouped according to age (55 years and older versus younger than 55 years) and gender. The cancer risk was calculated for each BSRTC diagnostic group. A p-value <0.05 was not considered statistically significant. RESULTS: The study population was composed of 291 patients (227 females and 64 males). Histopathology diagnosed cancer in 113 cases (39%). The cancer risk was significantly increased in cases with a BSRTC diagnosis of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) in patients younger than 55 years of age (36.8% vs 7.4%, p=0.0082). CONCLUSIONS: Though thyroid cancer was significantly more common in males (p=0.021), gender did not significantly influence specific BRSTC diagnostic category cancer risk estimation. A BSRTC AUS/FLUS diagnosis is associated with an increased cancer risk in younger patients.

Characterization of the human thyroid epigenome.

The thyroid gland, necessary for normal human growth and development, functions as an essential regulator of metabolism by the production and secretion of appropriate levels of thyroid hormone. However, assessment of abnormal thyroid function may be challenging suggesting a more fundamental understanding of normal function is needed. One way to characterize normal gland function is to study the epigenome and resulting transcriptome within its constituent cells. This study generates the first published reference epigenomes for human thyroid from four individuals using ChIP-seq and RNA-seq. We profiled six histone modifications (H3K4me1, H3K4me3, H3K27ac, H3K36me3, H3K9me3, H3K27me3), identified chromatin states using a hidden Markov model, produced a novel quantitative metric for model selection and established epigenomic maps of 19 chromatin states. We found that epigenetic features characterizing promoters and transcription elongation tend to be more consistent than regions characterizing enhancers or Polycomb-repressed regions and that epigenetically active genes consistent across all epigenomes tend to have higher expression than those not marked as epigenetically active in all epigenomes. We also identified a set of 18 genes epigenetically active and consistently expressed in the thyroid that are likely highly relevant to thyroid function. Altogether, these epigenomes represent a powerful resource to develop a deeper understanding of the underlying molecular biology of thyroid function and provide contextual information of thyroid and human epigenomic data for comparison and integration into future studies.