Performance of a multigene genomic classifier and clinical parameters in predicting malignancy in a Southeast Asian cohort of patients with cytologically indeterminate thyroid nodules.

BACKGROUND: Most thyroid nodules are benign. It is important to determine the likelihood of malignancy in such nodules to avoid unnecessary surgery. The primary objective of this study was to characterize the genetic landscape and the performance of a multigene genomic classifier in fine-needle aspiration (FNA) biopsies of cytologically indeterminate thyroid nodules in a Southeast Asian cohort. The secondary objective was to assess the predictive contribution of clinical characteristics to thyroid malignancy. METHODS: This prospective, multicenter, blinded study included 132 patients with 134 nodules. Molecular testing (MT) with ThyroSeq v3 was performed on clinical or ex-vivo FNA samples. Centralized pathology review also was performed. RESULTS: Of 134 nodules, consisting of 61% Bethesda category III, 20% category IV, and 19% category V cytology, and 56% were histologically malignant. ThyroSeq yielded negative results in 37.3% of all FNA samples and in 42% of Bethesda category III-IV cytology nodules. Most positive samples had RAS-like (41.7%), followed by BRAF-like (22.6%), and high-risk (17.9%) alterations. Compared with North American patients, the authors observed a higher proportion of RAS-like mutations, specifically NRAS, in Bethesda categories III and IV and more BRAF-like mutations in Bethesda category III. The test had sensitivity, specificity, negative predictive value, and positive predictive value of 89.6%, 73.7%, 84.0%, and 82.1%, respectively. The risk of malignancy was predicted by positive MT and high-suspicion ultrasound characteristics according to American Thyroid Association criteria. CONCLUSIONS: Even in the current Southeast Asian cohort with nodules that had a high pretest cancer probability, MT could lead to potential avoidance of diagnostic surgery in 42% of patients with Bethesda category III-IV nodules. MT positivity was a stronger predictor of malignancy than clinical parameters.

A Multiplex Thyroid-Specific Assay for Quantification of Circulating Thyroid Cell-Free RNA in Plasma of Thyroid Cancer Patients.

BACKGROUND: The standard of care for thyroid cancer management is thyroidectomy and adjuvant radioactive iodine (RAI). There is a paucity of clinical tool that quantifies residual thyroid volume reliably for precise adjuvant RAI dosing. Serum thyroglobulin (TG), tumour marker for thyroid cancer, takes 4 weeks for complete clearance due to its long half-life, and might be undetectable in 12% of structural disease patients. It detects recurrence with a sensitivity of 19-40%, mainly attributed to issue of TG antibody interference with TG immunometric assay. We hypothesise that the quantity of thyroid-specific cell-free RNA (cfRNA) is indicative of amount of thyroid tissues, and that during thyroid surgery, cfRNA levels decrease accordingly. METHODS: We identified 11 biologically significant and highly expressed thyroid-specific targets from Human Protein Atlas and literature. To assess for a fall in thyroid-specific cfRNA level, we recruited 16 patients undergoing thyroid surgery or RAI for malignant or benign thyroid disease, and tracked longitudinal trend of cfRNA. To assess the utility of cfRNA in detecting metastatic thyroid cancer, cfRNA of 11 patients at intermediate to high risk of recurrence was measured during surveillance and at time of clinical recurrence. RESULTS: The multiplex assay was capable of amplifying and quantifying multiple thyroid-specific genes in a single reaction. The selected targets were amplified successfully from RNA extracted directly from the thyroid (positive control), indicating that they were highly expressed within thyroid tissue. These cfRNAs were present in plasma, in amounts quantifiable using qRT-PCR. Four cfRNA transcripts (TPO, GFRA2, IVD, TG) fell post-treatment in more than 50% of cohort. The thyroid peroxidase (TPO) cfRNA fell post-therapy in 63% of cohort by 80%, as early as 1 day post-treatment, supporting the potential role as early indicator of remnant thyroid tissue volume. We demonstrated the clinical relevance of circulating TPO cfRNA by tracking temporal changes in setting of peri-treatment, recurrence, and TG Ab positive state. CONCLUSION: Using a multiplex pre-amplification approach, the TPO cfRNA was a potential biomarker that can track residual thyroid mass. It can be further optimised for quantification of thyroid volume to guide RAI doses and for detection of thyroid cancer recurrence.

Do Ultrasound Patterns and Clinical Parameters Inform the Probability of Thyroid Cancer Predicted by Molecular Testing in Nodules with Indeterminate Cytology?

Background: Molecular testing (MT) is commonly used to refine cancer probability in thyroid nodules with indeterminate cytology. Whether or not ultrasound (US) patterns and clinical parameters can further inform the risk of thyroid cancer in nodules predicted to be positive or negative by MT remains unknown. The aim of this study was to test if clinical parameters, including patient age, sex, nodule size (by US), Bethesda category (III, IV, V), US pattern (American Thyroid Association [ATA] vs. American College of Radiology Thyroid Image Reporting and Data System [TI-RADS] systems), radiation exposure, or family history of thyroid cancer can modify the probability of thyroid cancer or noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) predicted by MT. Methods: We studied 257 thyroid nodules in 232 patients from 10 study centers with indeterminate fine needle aspiration cytology and informative MT results using the ThyroSeq v3 genomic classifier (TSv3). Univariate and multivariate logistic regression was used for data analysis. Results: The presence of cancer/NIFTP was associated with positive TSv3 results (odds ratio 61.39, p < 0.0001). On univariate regression, patient sex, age, and Bethesda category were associated with cancer/NIFTP probability (p < 0.05 for each). Although ATA (p = 0.1211) and TI-RADS (p = 0.1359) US categories demonstrated positive trends, neither was significantly associated with cancer/NIFTP probability. A multivariate regression model incorporating the four most informative non-MT covariates (sex, age, Bethesda category, and ATA US pattern; Model No. 1) yielded a C index of 0.653; R2 = 0.108. When TSv3 was added to Model number 1, the C index increased to 0.888; R2 = 0.572. However, age (p = 0.341), Bethesda category (p = 0.272), and ATA US pattern (p = 0.264) were nonsignificant, and other than TSv3 (p < 0.0001), male sex was the only non-MT parameter that potentially contributed to cancer/NIFTP risk (p = 0.095). The simplest and most efficient clinical model (No. 3) incorporated TSv3 and sex (C index = 0.889; R2 = 0.588). Conclusions: In this multicenter study of thyroid nodules with indeterminate cytology and MT, neither the ATA nor TI-RADS US scoring systems further informed the risk of cancer/NIFTP beyond that predicted by TSv3. Although age and Bethesda category were associated with cancer/NIFTP probability on univariate analysis, in sequential nomograms they provided limited incremental value above the high predictive ability of TSv3. Patient sex may contribute to cancer/NIFTP risk in thyroid nodules with indeterminate cytology.

The Efficacy and Safety of High-Intensity Focused Ultrasound (HIFU) Therapy for Benign Thyroid Nodules-A Single Center Experience from Singapore.

BACKGROUND: High-intensity focused ultrasound (HIFU) is a recent noninvasive technique of treating thyroid nodules. Our study aims to investigate the efficacy and safety of HIFU in treating benign thyroid nodules. METHODS: This is a retrospective analysis of consecutive patients who underwent HIFU of benign thyroid nodules at our institution from July 2017-2018. All procedures were performed by a single surgeon. Patients were evaluated immediately post-procedure, and at subsequent intervals of 1 week, 1 month, 3 months, and 6 months. The primary endpoint was thyroid nodule volume reduction at 6 months posttreatment. Secondary endpoints were post-procedure local complications. RESULTS: Ten patients with 13 thyroid nodules were included. The median follow-up period was 426 days (range 238-573). Mean maximum diameter reduced from 2.6 cm (±0.8) pretreatment to 1.4 cm (±0.7, P < 0.05) 6 months posttreatment. Mean nodule volume reduced from 5.2 cm3 (±4.2) pretreatment to 1.5 cm3 (±1.3, P = 0.01) 6 months posttreatment. Mean volume reduction ratio (VRR) at 6 months posttreatment was 63.2% (±22.5, P < 0.05), with volume reduction of ≥50% in 10 of 13 (76.9%) nodules. Two nodules (15.4%) showed size increases from 4 months posttreatment. No patients experienced local skin burns or hematomas. Mean pain scores were 1.5 (±1.2) immediate post-procedure, 0.8 (±1.5) at 1 week, and 0.6 (±1.2) at 1 month post-procedure, respectively, with no reports of pain beyond 1 month. Only two (20.0%) patients had early, temporary posttreatment voice hoarseness. CONCLUSION: Our study shows HIFU ablation to be efficacious and safe-with significant thyroid nodule volume reductions, and no significant or prolonged local complications.

Predictors of survival outcome following radical gastrectomy for gastric cancer.

BACKGROUND: Radical surgery with adjuvant therapy is now the standard treatment for locally advanced gastric cancer. However, the best regimen for adjuvant therapy remains controversial. We aim to determine the predictors of survival outcome of gastric cancer patients who underwent curative surgery with or without adjuvant therapy in our institution. METHODS: All patients who received surgery for gastric cancer from years 2000 to 2015 were studied using a prospective gastric cancer database at the National University Hospital, Singapore. RESULTS: A total of 405 patients underwent radical gastrectomy with curative intent. Seventy-eight percent received extended lymphadenectomy (≥D1). R0 resection was achieved in 377 patients (93%) with 30-day mortality rate of 1.7%. There was no significant difference in the complication rate between D1 and extended lymphadenectomy group. One hundred and forty-five patients (36%) received adjuvant therapy. With a median follow-up of 5.9 years, the 5-year disease-free survival for stage I to IV patients were 78%, 58%, 27% and 9%, respectively. Among the 141 patients with known recurrences, the first site of recurrence was 38% distant, 24% locoregional, 20% peritoneal and the rest were multiple sites. Stage of disease, adjuvant therapy, extent of lymphadenectomy, post-operative complication and approach of surgery were independent risk factors for long-term survival. CONCLUSIONS: Stage of disease, adjuvant therapy, extent of lymphadenectomy, post-operative complication and approach of surgery are significant predictors for long-term survival. Adequate and safe surgery to allow adjuvant therapy should be the goal of all surgeons for our gastric cancer patients.

Predictors of thyroxine replacement following hemithyroidectomy in a south east Asian cohort.

BACKGROUND: Thyroxine replacement following a hemithyroidectomy is not commonly discussed during consent for the procedure as the risk of hypothyroidism is perceived to be low. METHODS: Retrospective review of 901 patients who underwent hemithyroidectomy at a tertiary referral institution during the period January 2000 to December 2015. The main outcome studied was the overall incidence of hypothyroidism and the associated risk factors. RESULTS: Hypothyroidism developed in 123 (13%) patients and 94 patients (10%) required hormone supplementation over a mean follow up of 21 months (range 1-168 months). Preoperative TSH of more than 2.5 was seen in 38 of 123 (31%) of patients. Presence of diffuse thyroiditis was the only independent risk factor on multivariate analysis (P = 0.002) found to be associated with the development of hypothyroidism. CONCLUSION: After thyroid lobectomy, approximately one in 10 patients requiring thyroid hormone treatment for hypothyroidism. Presence of diffuse thyroiditis is a significant risk factor for hypothyroidism.

Subclassification of Bethesda Atypical and Follicular Neoplasm Categories According to Nuclear and Architectural Atypia Improves Discrimination of Thyroid Malignancy Risk.

BACKGROUND: Although The Bethesda System for Reporting Thyroid Cytopathology has provided clinicians with a standardized classification scheme for the diagnosis of thyroid fine-needle aspiration cytology (FNAC) specimens, the indeterminate categories of Bethesda III (B3)-atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS)-and Bethesda IV (B4)-follicular neoplasm/suspicious for follicular neoplasm (FN/SFN)-continue to pose challenges with regards to ideal diagnostic and therapeutic management. Having previously demonstrated the presence of nuclear atypia as a high-risk subgroup in B3, the objective of this study was to evaluate the malignancy rates in the B4 subgroup with nuclear atypia. METHODS: A retrospective review of all thyroid FNACs diagnosed as B4 (FN/SFN) between 2008 and 2015 was conducted at a tertiary referral center in Singapore. Data on patient demographics, sonographic features, and final histological diagnosis were collected. This was compared to data from a previous analysis on all nodules diagnosed as B3 (AUS/FLUS) over a similar period. RESULTS: A total of 137/309 (44.3%) and 88/111 (79.3%) FNACs diagnosed as B3 and B4, respectively, underwent surgical excision yielding final histopathological diagnoses. The malignancy rate of B4 was 31/88 (35.2%) compared to B3, which was 37/137 (27.0%). Subclassification based on the presence of architectural versus nuclear atypia showed significantly higher malignancy rates in B4 nodules with nuclear atypia (21.8% vs. 57.6%; p < 0.01). These findings corroborate previous results within the B3 category (malignancy rate of 14.7% vs. 36.8%; p < 0.01). The only sonographic features predictive of malignancy were the presence of macrocalcifications in B4 compared to irregularity of margins in B3. CONCLUSION: The presence of nuclear atypia identifies subgroups with significant differential malignancy risks within both the B3 and B4 categories. This supports the notion that subclassification is a useful risk stratification tool that can guide diagnostic and therapeutic management of indeterminate thyroid nodules with heterogenous risk profiles.

Thyroid cytology-nuclear versus architectural atypia within the "Atypia of undetermined significance/follicular lesion of undetermined significance" Bethesda category have significantly different rates of malignancy.

BACKGROUND: The Bethesda System for Reporting Thyroid Cytopathology is the most widely used classification system for the reporting of thyroid fine-needle aspiration cytology (FNAC) specimens. However, the "atypical" category ("atypia of undetermined significance" [AUS] or "follicular lesion of undetermined significance" [FLUS]) continues to cause diagnostic and therapeutic dilemmas. The objectives of this study were to describe the differential malignancy rates of FNACs diagnosed as AUS/FLUS based on nuclear or architectural atypia and to assess the significance of demographic and ultrasonographic features in predicting malignancy in this category. METHODS: A retrospective review was performed of all thyroid FNACs between 2008 and 2014 that were diagnosed as AUS/FLUS at a tertiary referral center in Singapore. Patient demographics, preoperative ultrasonographic features, and follow-up data were collected and correlated with the final histopathologic diagnosis in resected cases. RESULTS: In total, 309 thyroid nodules were diagnosed as AUS/FLUS, and 137 (44%) were surgically excised. Final histology yielded 37 (27%) malignancies. The malignancy rate for nodules that featured nuclear atypia was significantly higher at 36.8% than the rate for nodules that had only architectural atypia at 14.7% (P < .01). After up to 3 repeat FNACs, 67.1% of cases had a more definitive diagnosis. The only predictive sonographic finding for malignancy was irregular margins (P < .01). CONCLUSIONS: The disparity between malignancy risks within the Bethesda "atypical" category suggests that cytologic (nuclear) atypia is significantly more predictive of malignancy than architectural atypia. This supports the substratification of patients according to risk and a corresponding management approach within this category. A sonographic finding of irregular margins is also predictive for malignancy. Cancer Cytopathol 2017;125:245-256. © 2016 American Cancer Society.

Is preoperative withdrawal of aspirin necessary in patients undergoing elective inguinal hernia repair?

BACKGROUND: Antiplatelets such as aspirin are widely used to reduce thrombotic events in patients with various cardiovascular comorbidities. Continuing aspirin through noncardiac surgery has been shown to reduce risk of major adverse cardiac events (MACE) but may lead to higher bleeding complications. Inguinal hernia repair is a commonly performed surgical procedure among such patients, but no guideline exists regarding perioperative use of aspirin. OBJECTIVE: We aim to investigate the safety profile of aspirin continuation in the perioperative period in patients undergoing elective primary inguinal hernia repair. METHODS: All patients who underwent elective primary inguinal hernia repair from 2008 to 2015 and were on aspirin preoperatively were identified. The patients were divided into two groups: those who continued aspirin through the morning of the operation and those who were advised to stop aspirin therapy 3-7 days prior to operation. All patients underwent either open Lichtenstein mesh repair or laparoscopic total extra-peritoneal mesh repair. Outcomes measured include intraoperative blood loss, operative time, bleeding complications, wound site complications and MACE. RESULTS: Among 1841 patients who underwent elective primary inguinal hernia mesh repair, 142 (7.7 %) patients were on preoperative aspirin. Fifty-seven patients underwent laparoscopic repair, while 85 underwent open mesh repair. Twenty-seven out of fifty-seven (47.3 %) from the laparoscopic group and 55/85 (64.7 %) from the open group were instructed to stop aspirin (p = 0.040). There were no significant differences between those who stopped aspirin and those who continued in terms of intraoperative blood loss and operative timing. Immediate postoperative bleeding complications and follow-up wound complications were also similar between the two groups. Overall, there were no MACE among those who underwent laparoscopic repair. Three MACE were recorded in the open group (2 stopped vs. 1 continued; p = 0.943). There was no perioperative mortality. CONCLUSION: Continuation of aspirin is safe and should be preferred in patients with higher cardiovascular risk.

Outcomes of parathyroidectomy in renal hyperparathyroidism in patients with No access to renal transplantation in Singapore.

BACKGROUND: Total parathyroidectomy with autotransplantation (TPTX + AT) and subtotal parathyroidectomy (SPTX) are considered standard surgical treatments for refractory renal hyperparathyroidism. However, there is little data available comparing their outcomes in an area with poor access to renal transplant and calcimimetics. METHODS: Patients with renal hyperparathyroidism who underwent TPTX + AT and SPTX in a tertiary institution from 2006 to 2013 were studied. Patient characteristics, pre- and post-operative biochemical marker levels, and outcomes including recurrence rates, post-operative morbidity and mortality were analysed. RESULTS: 87 patients underwent parathyroidectomy for renal hyperthyroidism. Transplant patients were excluded in this study. 81 patients were on long-term dialysis, with a median time of 7 years from initiation of haemodialysis to parathyroidectomy. 57 patients (70.4%) underwent TPTX + AT while 24 (29.6%) underwent SPTX. Post-operatively, there was significant decrease in parathyroid hormone (PTH), calcium and phosphate levels in both groups. PTH and phosphate levels were significantly lowered with TPTX compared to SPTX (p = 0.004, 0.003). Symptomatic hypocalcaemia was seen in both groups. In a median follow-up of 4 years, 11 patients developed biochemical recurrence, with a median time of 29 months to recurrence. Median PTH at recurrence was 67.1 pmol/L. Rate of recurrence was higher in patients who underwent SPTX (20.8% vs 10.5%), with a shorter median time to recurrence (median 62.1 vs 81.3 months). 2 patients required resection of the autograft. Cohort mortality was 11 patients (13.4%), with 3 deaths secondary to cardiovascular events. CONCLUSION: Total parathyroidectomy with autoimplantation is superior to subtotal parathyroidectomy in the short to intermediate term.

Training improves laparoscopic tasks performance and decreases operator workload.

BACKGROUND: It has been postulated that increased operator workload during task performance may increase fatigue and surgical errors. The National Aeronautics and Space Administration-Task Load Index (NASA-TLX) is a validated tool for self-assessment for workload. Our study aims to assess the relationship of workload and performance of novices in simulated laparoscopic tasks of different complexity levels before and after training. METHODS: Forty-seven novices without prior laparoscopic experience were recruited in a trial to investigate whether training improves task performance as well as mental workload. The participants were tested on three standard tasks (ring transfer, precision cutting and intracorporeal suturing) in increasing complexity based on the Fundamentals of Laparoscopic Surgery (FLS) curriculum. Following a period of training and rest, participants were tested again. Test scores were computed from time taken and time penalties for precision errors. Test scores and NASA-TLX scores were recorded pre- and post-training and analysed using paired t tests. One-way repeated measures ANOVA was used to analyse differences in NASA-TLX scores between the three tasks. RESULTS: NASA-TLX score was lowest with ring transfer and highest with intracorporeal suturing. This was statistically significant in both pre-training (p < 0.001) and post-training (p < 0.001). NASA-TLX scores mirror the changes in test scores for the three tasks. Workload scores decreased significantly after training for all three tasks (ring transfer = 2.93, p < 0.001, precision cutting = 3.74, p < 0.001, intracorporeal suturing = 2.98, p < 0.001). CONCLUSION: NASA-TLX score is an accurate reflection of the complexity of simulated laparoscopic tasks in the FLS curriculum. This also correlates with the relationship of test scores between the three tasks. Simulation training improves both performance score and workload score across the tasks.