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Background: Thyroid carcinoma >4 cm in size is staged as T3a. The current American Thyroid Association guidelines recommend subtotal/total thyroidectomy and consideration for postoperative radioactive iodine (RAI) treatment for these tumors. In this retrospective cohort study, we aimed to explore the clinical course of large encapsulated thyroid carcinoma without other risk factors. Methods: Eighty-eight patients with large (>4 cm) encapsulated well-differentiated thyroid carcinoma resected between 1995 and 2021 were included in this retrospective cohort study. Exclusion criteria were tall cell variant, any extent of vascular invasion, extrathyroidal extension (microscopic or gross), high-grade histology, noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), infiltrative tumors, positive resection margin, and cases with follow-up <1 year. The primary outcomes are risk of nodal metastasis at the initial resection, disease-free survival (DFS), and disease-specific survival (DSS). Results: The tumor histotype was follicular carcinoma (n = 18, 21%), oncocytic (Hurthle cell) carcinoma (n = 8, 9%), and papillary thyroid carcinoma (PTC; n = 62, 70%). Among PTC, 38 were encapsulated follicular variant, 20 classic type, and 4 solid variant. Four cases had extensive capsular invasion (CI), 61 (69%) had focal CI, whereas 23 did not have CI. Thirty-two cases (36%) were treated with lobectomy/hemithyroidectomy alone, and 55 patients (62%) did not receive RAI. Five patients had nodal metastasis at the time of primary resection, all of whom had classic-type PTC. The median follow-up period was 4.8 years (interquartile range: 3.2–9.7 years). No recurrence, being local, regional, or distant, was observed in the entire cohort, including those patients treated with lobectomy alone without RAI. The 10-year DFS and DSS were 100%, respectively. Conclusion: Large intrathyroidal encapsulated well-differentiated thyroid carcinoma without vascular invasion follow an extremely indolent clinical course with negligible risk of recurrence. Lobectomy alone without RAI may be the appropriate treatment strategy for this selected group of patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Smoking is the commonest cause of oral cavity squamous cell carcinoma (OC-SCC), but the cause of OC-SCC in nonsmokers is unknown. Our primary goal was to use metagenomic shotgun sequencing (MSS) to directly define the taxonomic composition and functional potential of oral metagenome in nonsmokers with OC-SCC. We found three bacterial phyla, one genus, and one species were enriched in OC-SCC while two phyla, five genera, and 18 species were enriched in controls. Pathways related to metabolism of flavin, biotin, thiamine, heme, sugars, fatty acids, peptidoglycans, and tRNA were more abundant in OC-SCC while those related to metabolism of nucleotides and essential amino acids were more abundant in controls. The MSS method achieved similar results to the commonly used 16S rRNA gene survey in compositional differentiation but differed greatly from prediction using 16S rRNA genes in functional differentiation of microbiomes in OC-SCC and controls. Objectives: Smoking is the commonest cause of oral cavity squamous cell carcinoma (OC-SCC), but the etiology of OC-SCC in nonsmokers is unknown. Our primary goal was to use metagenomic shotgun sequencing (MSS) to define the taxonomic composition and functional potential of oral metagenome in nonsmokers with OC-SCC. Methods: We conducted a case–control study with 42 OC-SCC case and 45 control nonsmokers. MSS was performed on DNA extracted from mouthwash samples. Taxonomic analysis and pathway analysis were done using MetaPhlAn2 and HUMAnN2, respectively. Statistical difference was determined using the Mann–Whitney test controlling false discovery rate. Results: There was no significant difference in age, sex, race, or alcohol consumption between OC-SCC and control patients. There was a significant difference in beta diversity between OC-SCC and controls. At the phylum level, Bacteroidetes and Synergistetes were overly represented in OC-SCC while Actinobacteria and Firmicutes were overly represented in controls. At the genus level, Fusobacterium was overly represented in OC-SCC compared with controls, while Corynebacterium, Streptococcus, Actinomyces, Cryptobacterium, and Selenomonas were overly represented in controls. Bacterial pathway analysis identified overrepresentation in OC-SCC of pathways related to metabolism of flavin, biotin, thiamin, heme, sugars, fatty acids, peptidoglycans, and tRNA and overrepresentation of nucleotides and essential amino acids in controls. Conclusions: The oral microbiome in nonsmoker patients with OC-SCC is significantly different from that of nonsmoker control patients in taxonomic compositions and functional potentials. Our study's MSS findings matched with previous 16S-based methods in taxonomic differentiation but varied greatly in functional differentiation of microbiomes in OC-SCC and controls. [ABSTRACT FROM AUTHOR]

Paragangliomas are rare neuroendocrine tumors that can be found from the skull base to the pelvis. Head and neck paragangliomas have been historically treated with surgery. However, surgical resection adds risk of injury to vascular structures and cranial nerves that can lead to morbidity such as hoarseness, dysarthria, dysphagia, or aspiration. Recently, improved understanding of the behavior of these tumors and increasing experience in non-surgical treatments, such as observation and radiation therapy, have changed the paradigms of management of this entity. Multiple series now show a trend toward a more conservative management, with a higher percentage of patients being observed or treated with radiotherapy. Several factors should be taken into consideration when deciding the most appropriate treatment for head and neck paragangliomas, starting by differentiating carotid body tumors from non-carotid body tumors. In general, surgical resection is normally recommended for carotid body tumors as the complications from treatment are usually minimal. In contrast, for non-carotid body tumors, surgery is often associated with significant functional impairment due to cranial nerve paralysis. As such, non-surgical treatment is now usually recommended for this subset of head and neck paragangliomas. In young patients with no comorbidities and a small to medium carotid body tumors, surgery should be considered. Moreover, surgery should be offered for secreting tumors, malignant tumors, tumors with rapid growth or increase in symptomatology, and when radiotherapy cannot be performed. Conversely, conservative management with active surveillance or radiotherapy can be offered in the remaining cases in order to avoid unnecessary morbidity while still providing acceptable tumor control. [ABSTRACT FROM AUTHOR]

The article focuses on Hürthle cell carcinomas (HCCs) display two exceptional genotypes: near-homoplasmic mutation of mitochondrial DNA (mtDNA) and genome-wide loss of heterozygosity (gLOH). It mentions mtDNA mutations and profound depletion of citrate pools are common in HCC and other thyroid malignancies, suggesting that thyroid cancers are broadly equipped to survive tricarboxylic acid cycle impairment.

The aim of this study was to carry out a case control study comparing the HPV genome in patients with oral cavity squamous cell carcinoma (OC-SCC) to normal patients using metagenomic shotgun sequencing. We recruited 50 OC-SCC cases which were then matched with a control patient by age, gender, race, smoking status and alcohol status. DNA was extracted from oral wash samples from all patients and whole genome shotgun sequencing performed. The raw sequence data was cleaned, reads aligned with the human genome (GRCH38), nonhuman reads identified and then HPV genotypes identified using HPViewer. In the 50 patients with OC-SCC, the most common subsite was tongue in 26 (52%). All patients were treated with primary resection and neck dissection. All but 2 tumors were negative on p16 immunohistochemistry. There were no statistically significant differences between the cases and controls in terms of gender, age, race/ethnicity, alcohol drinking, and cigarette smoking. There was no statistically significant difference between the cancer samples and control samples in the nonhuman DNA reads (medians 4,228,072 vs. 5,719,715, P value = 0.324). HPV was detected in 5 cases (10%) of OC-SCC (genotypes 10, 16, 98) but only 1 tumor sample (genotype 16) yielded a high number of reads to suggest a role in the etiology of OC-SCC. HPV was detected in 4 control patients (genotypes 16, 22, 76, 200) but all had only 1–2 HPV reads per human genome. Genotypes of HPV are rarely found in patients with oral cancer. [ABSTRACT FROM AUTHOR]

Hürthle cell tumors (HCT), including Hürthle cell adenomas (HCA) and Hürthle cell carcinomas (HCCs), arise in the thyroid gland and are defined in part by an accumulation of mitochondria. These neoplasms were long considered a subtype of follicular neoplasm, although HCT is now generally considered a distinct entity. HCTs exhibit overlapping but distinct clinical features compared to follicular tumors, and several studies have demonstrated that HCTs harbor distinct genomic alterations compared to other forms of thyroid cancer. Two studies recently reported the most complete characterization of the HCC genome to date. These studies assessed complementary cohorts of HCC specimens. The study by Ganly et al. consisted of a large panel of primary HCCs, including 32 widely invasive and 24 minimally invasive primary tumors. Exome and RNA sequencing of material isolated from fresh-frozen tumor specimens was performed. The study by Gopal et al. utilized exome and targeted sequencing to characterize the nuclear and mitochondrial genomes of 32 primary tumors and 38 resected regional and distant metastases using DNA isolated from formalin-fixed paraffin-embedded tissues. Here, HCC is briefly reviewed in the context of these studies. [ABSTRACT FROM AUTHOR]

Background: The eighth edition of the American Joint Committee on Cancer (AJCC) staging system has reclassified up to one third of differentiated thyroid cancer patients into one of the younger prognostic stage groups (<55 years of age at diagnosis, stage I or stage II). This reclassification widens the spectrum of disease in these lower stages without significantly impacting overall disease-specific survival (DSS) for the entire stage group. However, the optimistic DSS estimates in the <55-year-old stage groups may not accurately reflect the prognosis of individual patients with American Thyroid Association (ATA) high-risk features. Therefore, the aim of this study was to integrate the ATA risk classification system into the eighth edition AJCC staging system to refine and individualize DSS estimates for differentiated thyroid cancer patients aged <55 years at diagnosis. Methods: Using the Memorial Sloan Kettering Cancer Center tumor registry, 4881 adult DTC patients aged <55 years at diagnosis receiving initial therapy between 1980 and 2016 were retrospectively analyzed. Using Memorial Sloan Kettering Cancer Center registry coded data, all patients were assigned an eighth edition AJCC stage (I or II), ATA risk of recurrence (low, intermediate, or high), and age group at diagnosis (younger patients defined as ≤45 years old, older patients defined as 45–55 years old). The primary outcome was 10-year DSS. Results: A total of 122 (2.5%) disease-related deaths were observed in the cohort of 4881 patients during a median follow-up of 6.6 years. Integration of the AJCC stage, ATA risk, and age groups identified six subgroups with differing outcomes: (i) stage I/ATA low risk, younger and older, 100% DSS; (ii) stage I/ATA intermediate risk, younger and older, 98% DSS; (iii) stage I/ATA high risk, younger, 95% DSS; (iv) stage I/ATA high risk, older, 89% DSS; (v) stage II/ATA high risk, younger, 78% DSS; and (vi) stage II/ATA high risk, older, 61% DSS. Conclusions: Integration of AJCC stage, ATA risk, and age group (i) identifies six subgroups of patients with progressively worse DSS as AJCC stage, ATA risk, and age increases, and (ii) provides a more individualized estimate of DSS, especially in ATA high-risk patients. [ABSTRACT FROM AUTHOR]

Background Due to the rarity of adenoid cystic carcinoma (ACC), information on outcome is based upon small retrospective case series. The aim of our study was to create a large multiinstitutional international dataset of patients with ACC in order to design predictive nomograms for outcome. Methods ACC patients managed at 10 international centers were identified. Patient, tumor, and treatment characteristics were recorded and an international collaborative dataset created. Multivariable competing risk models were then built to predict the 10 year recurrence free probability (RFP), distant recurrence free probability (DRFP), overall survival (OS) and cancer specific mortality (CSM). All predictors of interest were added in the starting full models before selection, including age, gender, tumor site, clinical T stage, perineural invasion, margin status, pathologic N-status, and M-status. Stepdown method was used in model selection to choose predictive variables. An external dataset of 99 patients from 2 other institutions was used to validate the nomograms. Findings Of 438 ACC patients, 27.2% (119/438) died from ACC and 38.8% (170/438) died of other causes. Median follow-up was 56 months (range 1–306). The nomogram for OS had 7 variables (age, gender, clinical T stage, tumor site, margin status, pathologic N-status and M-status) with a concordance index (CI) of 0.71. The nomogram for CSM had the same variables, except margin status, with a concordance index (CI) of 0.70. The nomogram for RFP had 7 variables (age, gender, clinical T stage, tumor site, margin status, pathologic N status and perineural invasion) (CI 0.66). The nomogram for DRFP had 6 variables (gender, clinical T stage, tumor site, pathologic N-status, perineural invasion and margin status) (CI 0.64). Concordance index for the external validation set were 0.76, 0.72, 0.67 and 0.70 respectively. Interpretation Using an international collaborative database we have created the first nomograms which estimate outcome in individual patients with ACC. These predictive nomograms will facilitate patient counseling in terms of prognosis and subsequent clinical follow-up. They will also identify high risk patients who may benefit from clinical trials on new targeted therapies for patients with ACC. Funding None. [ABSTRACT FROM AUTHOR]

Background: In most staging systems, 45 years of age is used to differentiate low risk thyroid cancer from high risk thyroid cancer. However, recent studies have questioned both the precise 45 year age point and the concept of using a binary cut off as accurate predictors of disease specific mortality. Methods: A cohort of 3664 thyroid cancer patients that received surgery and adjuvant treatment at Memorial Sloan Kettering Cancer Center (MSKCC) from the years 1985 to 2010 were analyzed to determine the significance of age at diagnosis as a categorical variable at a variety of age cutoffs (5 year intervals between 30 and 70 years of age). The unadjusted and adjusted hazard ratio for the association between disease-specific survival and age was determined using a Cox proportional hazards model adjusted for other predictive variables sex, histology, and pathological T, N, and M status. Furthermore, predictive nomograms of disease-specific mortality were created and validated on an external dataset of 4551 patients to evaluate the impact of age at diagnosis as both a categorical and continuous variable. Results: In the MSKCC cohort, with a median follow-up time of 54 months (range 1-332), there were 59 deaths from thyroid cancer with a 10 year disease-specific survival of 96%. Adjusted hazard ratios for all age cutoffs from age 30 to age 70 years were significant. There was no specific cutoff age which risk stratifies patients with differentiated thyroid cancer (DTC). Categorizing age into five strata (<40, 40-49, 50-59, 60-69 and >70 years) showed a 37-fold increase in hazard ratio from age <40 years to age >70 years. A predictive nomogram using age as a continuous variable with other predictive variables had a high concordance index of 96%. Validation on the external cohort had a concordance index of 73%. Conclusions: Mortality from DTC increases progressively with advancing age. There is no specific cutoff age which risk stratifies patients with DTC. A predictive nomogram using age as a continuous variable may be a more appropriate tool for stratifying patients with DTC and for predicting outcome. [ABSTRACT FROM AUTHOR]

Background: Risk stratification in medullary thyroid cancer (MTC) has traditionally relied on standardized anatomic staging systems that, despite providing valuable prognostic information, do not adequately predict the risk of persistent or recurrent disease. As dynamic risk stratification has been demonstrated to be clinically valuable in nonmedullary thyroid cancer, we adapted our response to therapy definitions in order to apply them to MTC. In this study, we evaluate and compare the clinical utility of our previously proposed MTC response to therapy stratification with a traditional standardized anatomic staging system. Methods: Both the Tumor, Node, Metastasis/American Joint Cancer Committee (TNM/AJCC) staging system and our previously proposed response to initial therapy staging system was evaluated in 287 MTC patients followed for a median of five years. Results: The TNM/AJCC staging system provided adequate risk stratification with regard to disease-specific mortality and the likelihood of having no evidence of disease at final follow-up, but did not adequately stratify patients with regard to the likelihood of having structural persistent disease, biochemical persistent disease, or recurrence. However, the response to initial therapy risk stratification system provided clinically useful risk stratification with regard to disease-specific mortality, the likelihood of having no evidence of disease at final follow-up, the likelihood of having a biochemical persistent disease at final follow-up, and the likelihood of having structural persistent disease at final follow-up. Furthermore, the response to therapy risk stratification system demonstrated a higher proportion of variance explained (54.3%) than the TNM/AJCC system (23.9%). Conclusion: Our data demonstrate that a dynamic risk stratification system that uses response to therapy variables to adjust risk estimates over time provides more useful clinical prognostic information than static initial anatomic staging in MTC thyroid cancer. [ABSTRACT FROM AUTHOR]

Background: The prognostic implications of the diagnosis of a papillary thyroid carcinoma (PTC) with tall-cell features are unknown. Methods: All PTC patients identified between 1985 and 2005 were analyzed histologically. Classical PTC cases were defined as having <30% tall cells, PTC with tall-cell features (PTC TCF) as 30%-49% tall cells, and tall-cell variant of PTC (TCV) as ≥50% tall cells. All classical PTC, PTC TCF, and TCV ≥1 cm in size were included. Results: A total of 453 patients satisfied the inclusion criteria (288 classical PTC, 31 PTC TCF, and 134 TCV). Classical PTC patients were younger than their PTC TCF and TCV counterparts ( p<0.0002). There was an increase in tumor size from classical PTC to PTC TCF and TCV ( p=0.05). Extensive extrathyroid extension and positive margins were more often present in TCV and PTC TCF than in classical PTC ( p=0.0001 and p=0.03 respectively). Overall pathologic tumor (pT) stage was more advanced in TCV and PTC TCF than in classical PTC ( p<0.0001). Total thyroidectomy and radioactive iodine therapy were more often performed and administered in TCV patients than in their PTC TCF and classical PTC counterparts ( p=0.001 and p=0.0001 respectively). Median follow-up was 9.3 years. Ten-year disease-specific survival (DSS) was lower in TCV (96%) and PTC TCF (91%) than in classical PTC (100%; p<0.001). Ten-year distant recurrence-free survival (RFS) was higher in classical PTC (98%) than in PTC TCF (89%) and TCV (96%; p=0.03). In multivariate analysis, the presence of more than five positive nodes and extranodal extension were the only independent prognostic factors of neck and distant RFS respectively. Four (2.4%) of 165 PTC TCF and PTC TCV developed poorly differentiated or anaplastic carcinoma in their recurrence, while none of the 288 classical PTC transformed into higher grades ( p=0.017). Conclusions: PTC TCF and TCV have similar clinicopathologic features that are more aggressive than classical PTC. PTC TCF and TCV have similar DSS and distant RFS but poorer outcomes than classical PTC. PTC TCF are currently being treated like classical PTC, that is, less aggressively than TCV. PTC TCF and TCV TCV have a higher rates of high-grade transformation than classical PTC. Consideration should be given to using a 30% tall-cell threshold to diagnose TCV. [ABSTRACT FROM AUTHOR]

Background: There continues to be controversy regarding which clinicopathological features confer a higher risk of adverse outcome in papillary microcarcinomas (PMC). The aim of this study was to assess the prognostic value of a meticulous histologic examination in PMC. Method: All papillary thyroid carcinoma <1 cm in size without associated larger thyroid carcinomas, identified between 1977 and 2002, were categorized as PMC and subjected to a meticulous histopathologic examination by 2 thyroid pathologists. Results: 148 PMC patients fulfilled the inclusion criteria. Within PMC, young age, male sex, tumor multicentricity, extrathyroidal extension, and infiltrative and larger tumor (≥0.5 cm) correlated with the presence of >1 cm metastatic node (MN) or >3 MN at presentation ( p<0.05). With a median follow-up of 9.9 years, only 1 (0.7%) of 134 PMC patients died of thyroid carcinomas and 3 (2.2%) had recurrences in the neck. The patient who died had harbored a poorly differentiated carcinoma in his MN. The presence of MN and especially a large MN (>1 cm) correlated with worse recurrence-free survival ( p=0.005 and p<0.0001, respectively). Except for one, all individuals with clinically adverse outcomes had >1 cm MN. Patients whose MNs were predominantly composed of poorly differentiated carcinoma or tall cell variant papillary thyroid carcinoma had a significant shorter recurrence-free survival ( p<0.0001). Only 1 of 80 radioactive iodine-naïve PMC patients with absent or small MN (≤1 cm) had recurrence with a median follow-up of 9.2 years. Conclusions: (i) The size and histotype of the MN are predictors of outcome in PMC and should be recorded. (ii) The very rare PMC patients who suffer recurrence or even die of disease have usually aggressive histopathologic features at presentation. (iii) PMC patients with nodal disease that is small or absent at presentation are at a very low risk of recurrence and may be spared radioactive iodine therapy. [ABSTRACT FROM AUTHOR]

Background: The American Thyroid Association guidelines recommend the routine use of radioactive iodine for remnant ablation (RRA) in all T3 or greater primary tumors, and selective use in patients with intrathyroidal disease >1 cm, or evidence of nodal metastases. The guidelines recognize that there is conflicting and inadequate data to make firm recommendations for most patients. The aim of this study was to analyze our institutional experience of the use of RRA in the management of papillary thyroid cancer, with a particular focus on outcomes for those patients selected not to receive RRA. Methods: We retrospectively reviewed 1129 consecutive patients who underwent total thyroidectomy at the Memorial Sloan-Kettering Cancer Center between 1986 and 2005. Of these, 490 were pT1-2 N0, 193 pT1-2 N1, and 444 pT3-4. Details on recurrence and disease-specific survival were recorded by the Kaplan-Meier method and compared using the log-rank test. Results: The five-year disease-specific survival and recurrence-free survival in the pT1/T2 N0, pT1-2 N1, and pT3-4 were 100% and 92%, 100% and 92%, and 98% and 87% respectively. Low-risk patients who were managed without RRA (who tended to have limited primary disease, pT1-2, and low-volume metastatic disease in the neck, pT1-2 N1-fewer than five nodes, all <1 cm greatest dimension) had five-year recurrence-free survival of >97%. In the group with advanced local tumors (pT3-4), those patients who did not receive RRA (who tended to have pT3 N0 disease) had five-year recurrence-free survival of >90%. Conclusion: Following appropriate surgical management, the majority of patients with low-risk local disease and even some patients with more advanced-stage (pT3) tumors or regional metastases have low rates of recurrence and high rates of survival when managed without RRA. [ABSTRACT FROM AUTHOR]

BACKGROUND: The objectives of this study were to determine the incidence of locoregional failure in patients with low-risk, early stage oral tongue squamous cell cancer (OTSCC) who undergo partial glossectomy and ipsilateral elective neck dissection without receiving postoperative radiation. METHODS: A combined database of patients with OTSCC who received treatment at Memorial Sloan-Kettering Cancer Center and Princess Margaret Cancer Center from 1985 to 2005 was established. In total, 164 patients with pathologic T1-T2N0 OTSCC who underwent partial glossectomy and ipsilateral elective neck dissection without postoperative radiation were identified. Patient-related, tumor-related, and treatment-related characteristics were recorded. Local recurrence-free survival, regional recurrence-free survival, and disease-specific survival were calculated by the Kaplan-Meier method. Predictors of outcome were analyzed by univariate and multivariate analysis. RESULTS: At a median follow-up of 66 months (range 1-171 months), the 5-year rates of local recurrence-free survival, regional recurrence-free survival, and disease-specific survival were 89%, 79.9%, and 85.6%, respectively. Regional recurrence was ipsilateral in 61% of patients and contralateral in 39% of patients. The regional recurrence rate was 5.7% for tumors <4 mm and 24% for tumors ≥4 mm. Multivariate analysis indicated that tumor thickness was the only independent predictor of neck failure (regional recurrence-free survival, 94% vs 72% [ P = .02] for tumors <4 mm vs ≥4 mm, respectively). Patients who developed recurrence in the neck had a significantly poorer disease-specific survival compared with those who did not (33% vs 97%; P < .0001). CONCLUSIONS: Patients with low-risk, pathologic T1-T2N0 OTSCC had a greater than expected rate of neck failure, with contralateral recurrence accounting for close to 40% of recurrences. Failure occurred predominantly in patients who had primary tumors that were ≥4 mm thick. Cancer 2013. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Papillary thyroid carcinoma (PTC) patients presenting with cervical lymph nodes (LN) metastases (M) have a variable outcome. The objective of this study is to assess the value of meticulous histopathologic examination and genotyping in stratifying these patients into clinically relevant prognostic subgroups. Methods: This was a retrospective clinical and histopathological review of PTC patients with lymph node metastases at presentation identified between 1980 and 2002 in a single institution. Primary tumors from patients who later recurred were matched to a group of patients who did not recur and subjected to mass spectrometry genotyping encompassing the most significant oncogenes in thyroid carcinomas. Results: There were 246 patients who satisfied the inclusion criteria. The median follow-up was 10.8 years. The presence of >3 metastatic nodes was an independent predictor of decreased recurrence free survival ( p=0.03). In patients <45 years, none of 45 with 1-2 metastatic LN recurred, including 26 patients followed for a median of 13 years without radioactive iodine (RAI) therapy. BRAF mutations were found in 28 (78%) of 36 genotyped tumors. Combined positivity for BRAF and extra-nodal extension was much stronger in predicting disease specific survival (DSS) ( p=0.004) than the single analysis of BRAF ( p=0.12) or extra-nodal extension ( p=0.02). Conclusions: (i) The number of metastatic LN is an independent predictor of recurrence in all age groups and identifies a subset of young patients with excellent prognosis who may not benefit from RAI therapy. (ii) Combined positivity for BRAF and extra-nodal extension has additive prognostic value in predicting DSS. (iii) Classification systems that assign the same magnitude of risk for recurrence or death to all patients with N1 disease should be revisited. [ABSTRACT FROM AUTHOR]

BACKGROUND: The objective of this study was to report the authors' experience in the management of patients with early stage squamous cell cancer (SCC) of the oral tongue and determine clinicopathologic factors predictive of outcome. METHODS: Two hundred sixteen patients with early stage (cT1T2N0) SCC of the oral tongue were identified from a pre-existing database of patients with oral cancer who were treated at Memorial Sloan-Kettering Cancer Center from 1985 to 2005. Patient, tumor, and treatment characteristics were recorded. Overall survival (OS), disease-specific survival (DSS), and recurrence free survival (RFS) were calculated using the Kaplan-Meier method. Predictors of outcome were identified using multivariate analysis. RESULTS: With a median follow-up of 80 months (range, 1-186 months), the 5-year DSS, OS, and RFS rates were 86%, 79%,and 70%, respectively. Local, neck, and distant recurrences occurred in 24 patients (11%), 40 patients (18%), and 5 patients (2%), respectively. Multivariate analysis identified occult neck metastases as the main independent predictor of OS, DSS, and RFS; patients who had occult metastases had a 5-fold increased risk of dying of disease compared with patients who did not have occult metastases (5-year DSS, 85.5% vs 48.5%; P = .001). A positive surgical margin was the main independent predictor for local RFS (91% vs 66% for a negative surgical margin; P = .0004), and depth of invasion was the main predictor for neck RFS (91% vs 73% for depth of invasion <2 mm and >2 mm, respectively; P = .02). CONCLUSIONS: In the authors' experience, patients with early stage oral tongue cancer have excellent outcomes. In the current study, the presence of occult metastases was the main predictor of survival outcome. Cancer 2012;. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Death from well-differentiated thyroid cancer (WDTC) is rare, and over the past century there has been a trend away from local recurrence as the primary cause of death. The objective of our study was to report the cause of death from thyroid cancer in patients with WDTC treated with curative intent with surgery ± adjuvant radioactive iodine. Methods: An institutional database of 1811 patients with WDTC treated surgically for WDTC between 1986 and 2005 was analyzed and identified 165 (9.4%) who had died. Case records were studied to determine the cause of death in each patient. Results: Of the 165 deaths, 17 (10%) patients were confirmed to have died of thyroid cancer and 6 (4%) died of an unknown cause but had thyroid cancer present at the time of last follow-up. The remaining 142 (86%) died from other causes and were considered free of thyroid cancer at their last follow-up. We therefore identified only 23 cause-specific deaths from the entire cohort (1.3%). Of the 17 patients known to have died of thyroid cancer, all had distant recurrence. Ninety-four percent had pulmonary metastases. Of these, 47% also had bony metastasis at the time of death. Two patients had recurrent disease in the neck at the time of death, but both also had distant disease. Of the six patients (4%) who died of unknown causes but had thyroid cancer at last follow-up, four (67%) had distant disease alone, one (17%) had local and regional recurrence, and one had local and distant recurrence at last follow-up. Conclusion: After successful resection of WDTC, we report a low disease-specific death rate (1.3%). In contrast to earlier reports, death caused by central compartment disease in this recent series is very rare, with metastatic disease accounting for almost all fatalities. [ABSTRACT FROM AUTHOR]

BACKGROUND: In this study by the International Collaborative Group, the authors examined a large cohort of patients accumulated from multiple institutions that had experience in craniofacial surgery with the objective of reporting outcomes and complications for craniofacial resection (CFR) in the elderly. METHODS: One hundred seventy patients aged ≥70 years were included in the study. The median age was 75 years (range, 70-98 years). One hundred four patients (61%) had received previous single-modality or combined treatment, which included surgery in 79 patients (46%), radiation in 47 patients (28%), and chemotherapy in 13 patients (8%). The most common histology was squamous cell carcinoma (67 patients; 39%). The margins of resection were close or microscopically positive in 56 patients (33%). Sixty-eight patients received adjuvant radiotherapy (40%), and 3 patients received chemotherapy (2%). Complications were classified into overall, local, central nervous system (CNS), systemic, and orbital. Overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) were determined by using the Kaplan-Meier method. Outcomes were compared with patients aged <70 years. Statistical analyses for outcomes were performed in relation to patient characteristics, tumor characteristics (including histology and extent of disease), surgical resection margins, previous radiation, and previous chemotherapy to determine predictive factors. RESULTS: Postoperative mortality occurred in 16 patients (9%), and postoperative complications occurred in 72 patients (42%). Local wound complications occurred in 40 patients (24%), CNS complications occurred in 24 patients (14%), systemic complications occurred in 19 patients (11%), and orbital complications occurred in 4 patients (2%). Postoperative mortality and complications were significantly more frequent in elderly patients compared with patients aged <70 years (postoperative mortality: 9% vs 3%; P=.04; complications: 42% vs 32%; P=.0009). The 5- year OS, DSS, and RFS rates were significantly poorer than those for patients aged <70 years (OS: 42% vs 56%; P < .0001; DSS: 53% vs 61%; P=.04; RFS: 46% vs 54%; P=.03). Surgical margin status and primary tumor histology were independent predictors of OS, DSS, and RFS in multivariate analysis. CONCLUSIONS: CFR for malignant skull base tumors in elderly patients (aged ≥70 years) was associated with increased mortality, complications, and poorer outcomes compared with patients aged <70 years. [ABSTRACT FROM AUTHOR]

Summary: Oral cavity squamous cell carcinoma (OCSCC) is uncommon in young patients and rare in the pediatric population. OCSCC is believed to behave aggressively in this age group, but the existing literature is limited to case reports. The objective of this study was to compare survival outcomes in pediatric and adult patients with oral cavity squamous cell carcinoma. We performed a population-based study of 54 pediatric (age⩽20) and 22,162 adult cases of OCSCC, recorded in the SEER cancer registry. Overall survival (OS) and disease-specific survival (DSS) were analyzed using the Kaplan–Meier method. Cox multivariable regression was used to control for covariates including gender, stage, histologic grade and treatment modality. Pediatric patients with OCSCC experienced significantly better 5year DSS than adult patients (75.3% vs. 63.5%, p =0.02). Pediatric patients were also more likely to be female (37.0% vs. 31.7%, p =0.04) and to receive surgery (87.0% vs. 68.6%, p <0.001). When these factors, as well as non-significant differences in rates of metastases and histologic grade were controlled for on multivariable analysis, the pediatric and adult groups experienced equivalent DSS (p =0.64). Pediatric patients with OCSCC experience better survival than adult patients. When differences in patient, tumor and treatment-related characteristics are adjusted for, the two groups experience equivalent survival. [Copyright &y& Elsevier]

Aims: Papillary thyroid carcinoma, tall cell subtype (PTC‐TC) is a potentially aggressive histotype. The latest World Health Organisation (WHO) classification introduced a novel class of tumours; namely, high‐grade differentiated thyroid carcinoma (HGDTC), characterised by elevated mitotic count and/or necrosis, which can exhibit a tall cell phenotype (HGDTC‐TC). Methods and results: We analysed the clinical outcomes in a large retrospective cohort of 1456 consecutive thyroid carcinomas with a tall cell phenotype, including PTC‐TC and HGDTC‐TC. HGDTC‐TC is uncommon, accounting for 5.3% (77 of 1379) of carcinomas with tall cell morphology. HGDTC‐TC was associated with significantly older age, larger tumour size, angioinvasion, gross extrathyroidal extension, higher AJCC pT stage, positive resection margin and nodal metastasis (P < 0.05). Compared with PTC‐TC, HGDTC was associated with a significantly decreased DSS, LRDFS and distant metastasis‐free survival (DMFS; P < 0.001). The 10‐year DSS was 72 and 99%, the 10‐year LRDFS was 61 and 92% and the 10‐year DMFS was 53 and 97%, respectively, for HGDTC‐TC and PTC‐TC. On multivariate analysis, the classification (HGDTC‐TC versus PTC‐TC) was an independent adverse prognostic factor for DSS, LRDF, and DMFS when adjusted for sex, age, angioinvasion, margin status, AJCC pT and pN stage. Conclusions: Compared with PTC‐TC, HGDTC‐TC is associated with adverse clinicopathological features, a higher frequency of TERT promoter mutations (59% in HGDTC‐TC versus 34% in PTC‐TC) and incurs a significantly worse prognosis. HGDTC‐TC is an independent prognostic factor for carcinoma with tall cell morphology. This validates the concept of HGDTC and the importance of tumour necrosis and high mitotic count for accurate diagnosis and prognosis of differentiated thyroid carcinomas. [ABSTRACT FROM AUTHOR]

Aims: Recently, there have been attempts to improve prognostication and therefore better guide treatment for patients with medullary thyroid carcinoma (MTC). In 2022, the International MTC Grading System (IMTCGS) was developed and validated using a multi‐institutional cohort of 327 patients. The aim of the current study was to build upon the findings of the IMTCGS to develop and validate a prognostic nomogram to predict recurrence‐free survival (RFS) in MTC. Methods and Results: Data from 300 patients with MTC from five centres across the USA, Europe, and Australia were used to develop a prognostic nomogram that included the following variables: age, sex, AJCC stage, tumour size, mitotic count, necrosis, Ki67 index, lymphovascular invasion, microscopic extrathyroidal extension, and margin status. A process of 10‐fold cross‐validation was used to optimize the model's performance. To assess discrimination and calibration, the area‐under‐the‐curve (AUC) of a receiver operating characteristic (ROC) curve, concordance‐index (C‐index), and dissimilarity index (D‐index) were calculated. Finally, the model was externally validated using a separate cohort of 87 MTC patients. The model demonstrated very strong performance, with an AUC of 0.94, a C‐index of 0.876, and a D‐index of 19.06. When applied to the external validation cohort, the model had an AUC of 0.9. Conclusions: Using well‐established clinicopathological prognostic variables, we developed and externally validated a robust multivariate prediction model for RFS in patients with resected MTC. The model demonstrates excellent predictive capability and may help guide decisions on patient management. The nomogram is freely available online at https://nomograms.shinyapps.io/MTC_ML_DFS/. [ABSTRACT FROM AUTHOR]

This article explores the growth rate and safety of observing pleomorphic adenomas (PAs) in pregnant patients. The study reveals that PAs in the parotid gland grow at a median rate of 4.6 mm/year, with potential acceleration during pregnancy and the post-partum period. All patients in the study chose to delay surgery until after pregnancy, and there were no significant complications to the mother or fetus. The study also found no evidence of malignant transformation in any of the cases. The authors conclude that pregnant patients with PAs can be safely monitored until surgery is necessary. The article emphasizes the challenges and considerations in managing benign parotid tumors in pregnant patients, highlighting the importance of comprehensive evaluation, quality imaging, and a reassuring cytologic report in determining the need for surgery. [Extracted from the article]

Simple Summary: Sinonasal and skull base malignancies are rare tumors which present adjacent to numerous critical anatomical structures. Despite the increased use of endoscopic techniques, many patients still require open surgery. Treatment with surgery requires careful pre-operative planning. Virtual surgical planning and three-dimensional, patient-specific models offer a range of benefits to clinicians in terms of planning tumor resection and reconstruction. In additional, these technologies improve communication with patients, trainee doctors and other colleagues. In this article, we explore the applications of virtual surgical planning in sinonasal and skull base surgery. Sinonasal and skull base malignancies represent a rare, heterogenous group of pathologies with an incidence of 0.556 per 100,000 persons in the population. Given the numerous critical anatomic structures located adjacent to the sinonasal cavity and skull base, surgery for tumors in this region requires careful pre-operative planning with the assistance of radiological imaging and intraoperative image guidance technologies to reduce the risk of complications. Virtual surgical planning (VSP) and three-dimensional models (3DMs) are adjunctive technologies which assist clinicians to better visualize patient anatomy using enhanced digital radiological images and physical stereolithographic models based on patients' personal imaging. This review summarizes our institutional experience with VSP and 3DMs in sinonasal and skull base surgical oncology. A clinical case series is used to thematically illustrate the application of VSP and 3DMs in surgical ablation, reconstruction, patient communication, medical education, and interdisciplinary teamwork in sinonasal and skull base surgery. [ABSTRACT FROM AUTHOR]

Reports on a potential limitation of oncolytic adenoviruses, the development of acquired cellular resistance to cytolysis of the E1B-attenuated adenovirus, dl1520, in ovarian tumor cell lines. Ability of resistant cells to maintain 60 PFU/cell of virus and still replicate normally with an unchanged doubling time compared to the parental cell.

Ameloblastoma is a histologically benign but locally aggressive tumor of the jaws. We conducted a retrospective cohort study to review the clinical, radiologic, and pathologic features of patients with ameloblastoma of the mandible and maxilla and to report the outcomes of treatment. Our study population was made up of a series of 30 consecutively presenting patients—15 men and 15 women, aged 19 to 81 years (median: 61.5)— who had undergone their primary treatment of ameloblastoma of the mandible or maxilla at Memorial Sloan Kettering Cancer Center from January 1987 through December 2012. In addition to demographic data, we compiled information on clinical characteristics, imaging findings, the type of surgery, surgical margins, adjuvant treatments, histologic patterns, length of follow-up, time to recurrence, treatment of recurrence, and factors that had an influence on recurrence. All but 2 patients with negative margins were cured. Favorable outcomes were associated with the administration of adjuvant postoperative radiotherapy for patients with positive margins and a repeat resection for patients with recurrences. Complete excision with negative margins, however, remains the gold standard for curative treatment. [ABSTRACT FROM AUTHOR]

PARPi-FL is a molecularly specific fluorescent agent that targets poly ADP-ribose polymerase 1, a DNA repair enzyme overexpressed in the nuclei of tumor cells. This imaging agent is being investigated in a clinical trial (NCT03085147) for the detection of oral cancer. The PARPi-FL mouthwash formulation currently being used in the phase I/II clinical trial comprises 1,000 nM of PARPi-FL dissolved first in 4.5 ml of polyethylene glycol (PEG) 300 and then in 9.5 ml of water. This formulation requires a 2-step process that can be cumbersome for routine clinical use. To minimize errors and simplify the formulation process, we have developed a new one-step formulation, which requires only the direct addition of water into a vial containing a mixture of the PARPi-FL and PEG 3350, which is also a powder. In a series of analytical and preclinical studies, we demonstrate that the new formulation of PARPi-FL is stable over 365 days, sustains its characteristics, and performs similar to the previous formulation. Moving forward, the new formulation of the PARPi-FL will be used for patients accrued in the phase II clinical trial. [ABSTRACT FROM AUTHOR]

Background: The change in size of the papillary thyroid cancer (PTC) nodule during active surveillance has traditionally been characterized as either stable, increasing, or decreasing based on changes in maximal tumor diameter or tumor volume. More recently, it has been observed that the changes in tumor size observed during observation are more complex with tumor volume kinetic patterns that can be characterized either as stable (Pattern I), early increase in volume (Pattern II), later increase in volume (Pattern III), early increase in volume followed by stability (Pattern IV), stability followed by an increase in volume (Pattern V), or a decrease in tumor volume (Pattern VI). Methods: The frequency, time course, and clinical correlates of these six tumor volume kinetic patterns were analyzed in a cohort of 483 patients with low-risk PTC up to 1.5 cm in maximal diameter followed with active surveillance at our center for a median of 3.7 years. Results: The cumulative incidence of an increase in tumor volume for the entire cohort was 15.9% [confidence interval (CI) 11.8–20.0] at 5 years. At 5 years, most tumors demonstrated stability (78.8%, Pattern I) with 10.0% showing early growth (Pattern II), 4.1% late growth (Pattern III), 1.9% growth then stability (Pattern IV), 0.6% stability then growth (Pattern V), and 5.6% with a decrease in tumor volume (Pattern VI). Tumor volume doubling time during exponential growth significantly differed across the kinetic patterns, with median values of 2.4, 7.1, and 3.3 years for Patterns II, III, and IV, respectively (p < 0.01). Similarly, the time to a change in tumor volume was significantly different across the kinetic patterns, with median values of 1.5, 3, 1.6, 4.7, and 4.1 years for Patterns II, III, IV, V, and VI, respectively (analysis of variance, p < 0.01). Clinical correlates at baseline were not associated with tumor volume kinetic pattern. Conclusions: These six kinetic tumor volume patterns provide a comprehensive description of the changes in PTC tumor volume observed during the first 5 years of active surveillance. [ABSTRACT FROM AUTHOR]

Background: Tumor grade is a new validated prognostic factor for medullary thyroid cancer (MTC). Calcitonin doubling time can predict MTC recurrence. We aimed to describe the association of tumor grade with calcitonin doubling and its effect on disease-specific outcomes times after resection. Methods: A retrospective analysis of MTC patients who underwent resection at a single tertiary-care cancer center between 1986 and 2017 were evaluated. Tumors were designated as high-grade MTC if two head and neck pathologists identified mitotic index ≥5 per 2 mm2, tumor necrosis, or a Ki67 proliferative index ≥5% within the tumor. Calcitonin doubling time was calculated using a validated calculator with at least three consecutive levels. Using Cox proportional hazards models, outcomes evaluated included locoregional relapse-free survival (LRFS), distant metastasis-free survival (DMFS), and overall survival (OS). Results: Among 117 patients, 95 were low grade and 22 high grade. Median follow-up was 70.2 months. High-grade patients demonstrated significantly faster calcitonin doubling times when compared with low-grade patients (8.51 ± 3.22 months vs. 38.42 ± 11.19 months; p < 0.001). In addition, most high-grade patients (66.7%) had calcitonin doubling times less than 1 year compared with fewer low-grade patients (1.0%; p < 0.001). High- and low-grade patients were further stratified by those who had calcitonin doubling times less than or greater than 2 years—a previously validated prognostic cutoff point. For patients with calcitonin doubling times less than 2 years, 70% were high grade, while 30% were low grade (p < 0.001). On multivariate analysis comparing grade and calcitonin doubling times, high-grade patients had significantly worse LRFS (hazards ratio [HR] 4.77 [confidence interval; CI 1.19–8.81]), DMFS (HR 7.25 [CI 2.36–22.28]), and OS (HR 6.04 [CI 1.85–19.72]; p < 0.05 for all), while calcitonin doubling times less than 2 years had worse DMFS (HR 7.22 [CI 1.05–49.75]). High-grade patients with calcitonin doubling times less than 2 years had associated worse LRFS and OS (both p < 0.05) compared with low-grade patients. Conclusions: The majority of high-grade MTC patients have calcitonin doubling times less than 2years. Close monitoring should be advocated for patients assessed to have high-grade tumors as they are at risk for poor disease-specific outcomes and structural recurrence. [ABSTRACT FROM AUTHOR]

Objective  This study was aimed to describe our institutional experience on characteristics and treatment outcomes of sinonasal sarcomas invading the anterior skull base. Design  Present study is a retrospective review. Setting  The study was conducted at an academic cancer care center. Participants  Thirty-one patients with skull base sarcomas treated with primary surgery from 1979 to 2015 were identified for this study from a preexisting database. Main Outcome Measures  Survival and recurrence outcomes using the Kaplan–Meier method were the focus areas of the study. Results  The median age was 44 years (range: 13–69 years). Twenty patients were male (64.5%). Twenty-nine patients underwent open craniofacial resection (93.5%) and two patients underwent endoscopic resection (6.5%). The majority of tumors were staged pT4 (77.4%). The most common pathologies were leiomyosarcoma (19.4%), osteosarcoma (16.1%), and chondrosarcoma (12.9%). Of those with known margin status, 10 patients had positive/close margins (32.2%) and 16 patients had negative margins (51.6%). Most tumors were high grade (74.2%). Twenty-three patients (74.2%) received adjuvant radiation and four patients (12.9%) received adjuvant chemotherapy. There were nine postoperative complications (29%) including one mortality and three cerebrospinal fluid leaks. There were 10 local, 2 regional, and 5 distant recurrences over a median follow-up of 74 months (range: 1–300 months). The 5-year disease-specific survival (DSS) was 69.8%. The 5-year locoregional recurrence-free probability (RFP) was 63.2% and the 10-year distant RFP was 71.7%. The 5-year DSS for high grade tumors was 64.2 and 85.7% for low grade tumors (p  = 0.117). Conclusion  This study contributes an updated analysis of anterior skull base sarcomas. Five-year DSS is approximately 70%. Analysis of survival outcomes based on grade, tumor size, and other factors is limited by small sample size and the rarity of these tumors. [ABSTRACT FROM AUTHOR]

Background: Follicular thyroid carcinoma (FTC) and Hurthle cell carcinoma (HCC) are rare and aggressive thyroid cancers with limited published data comparing their outcomes or regarding their subtypes. The aim of this study was to describe clinicopathological features and compare clinical outcomes of patients with FTC and HCC based on the 2017 World Health Organization definition and extent of vascular invasion (VI). Methods: We retrospectively studied 190 patients with HCC and FTC primarily treated with surgery at Memorial Sloan Kettering Cancer Center between 1986 and 2015. Patients were classified as minimally invasive (MI), encapsulated angioinvasive with focal VI (EA-FVI), encapsulated angioinvasive with extensive VI (EA-EVI), and as widely invasive (WI). To compare clinical outcomes, patients were grouped as follows: group 1 = FTC-MI and FTC EA-FVI, group 2 = FTC EA-EVI and FTC-WI, group 3 = HCC-MI and HCC EA-FVI, group 4 = HCC EA-EVI and HCC-WI. Outcomes of interest were overall survival (OS), disease-specific survival (DSS), recurrence-free survival (RFS), locoregional recurrence-free survival (LRRFS), and distant recurrence-free survival (DRFS). Outcomes were determined using the Kaplan–Meier method and compared with log-rank test. Results: Patients with HCC (n = 111) were more likely to be older than 55 years old (59% vs. 27%, p < 0.001) with a tendency to present with more extensive VI (33% vs. 19%, p = 0.07) compared with FTC (n = 79). Comparing groups 1, 2, 3, and 4, group 4 patients were more likely to recur (DFS 98%, 93%, 98% vs. 73%, respectively, p = 0.0069). There was no statistically significant difference in OS, DSS LRRFS, or DRFS. Stratified by extent of VI (no, focal, and extensive VI), patients with extensive VI were more likely to recur (RFS 100%, 95%, 77%, p = 0.0025) and had poorer distant control (DRFS: 100%, 95%, 80%, p = 0.022), compared with patients absent or focal VI. Conclusions: Accurate assessment of the extent of VI and tumor phenotype (follicular vs. Hurthle) are essential in identifying patients at higher risk of recurrence. [ABSTRACT FROM AUTHOR]

Aims: We aimed to study the clinicopathological and molecular features of high-grade non-anaplastic thyroid carcinomas (HGTCs), a carcinoma with a prognosis intermediate between those of well-differentiated carcinoma and anaplastic carcinoma. Methods and results: This study included 364 HGTC patients: 200 patients (54.9%) were diagnosed with poorly differentiated thyroid carcinoma (PDTC), based on the Turin consensus (HGTC-PDTC), and 164 were diagnosed with high-grade features that did not meet the Turin criteria (HGTC-nonPDTC). HGTCs are aggressive: the 3-year, 5-year, 10-year and 20-year diseasespecific survival (DSS) rates were 89%, 76%, 60%, and 35%, respectively. Although DSS was similar between HGTC-PDTC and HGTC-nonPDTC patients, HGTC-PDTC was associated with higher rate of radioactive iodine avidity, a higher frequency of RAS mutations, a lower frequency of BRAF V600E mutations and a higher propensity for distant metastasis (DM) than HGTCnonPDTC. Independent clinicopathological markers of worse outcome were: older age, male sex, extensive necrosis and lack of encapsulation for DSS; older age, male sex and vascular invasion for DM-free survival; and older age, necrosis, positive margins and lymph node metastasis for locoregional recurrence-free survival. The frequencies of BRAF, RAS, TERT, TP53 and PTEN alterations were 28%, 40%, 55%, 11%, and 10%, respectively. TP53, PTEN and TERT were independent molecular markers associated with an unfavourable outcome, independently of clinicopathological parameters. The coexistence of BRAF V600E and TERT promoter mutation increased the risk of DM. Conclusions: The above data support the classification of HGTC as a single group with two distinct subtypes based on tumour differentiation: HGTC-PDTC and HGTC-nonPDTC. [ABSTRACT FROM AUTHOR]

Background: The success of an active surveillance management approach to low-risk papillary thyroid cancer (PTC) is heavily dependent on proper patient selection. For example, primary tumors located in a subcapsular position immediately adjacent to the trachea or a recurrent laryngeal nerve (RLN) are considered to be inappropriate for active surveillance. Since preoperative imaging cannot reliably rule out extrathyroidal extension or reveal the full course of the RLN relative to the thyroid gland, it is important for clinicians to understand subcapsular tumor locations and minimum tumor sizes that are most likely to be associated with gross invasion of the RLNs. Methods: We assessed the medical records of 123 patients treated at Memorial Sloan Kettering Cancer Center (MSK) between 1986 and 2015 who had a primary PTC tumor demonstrating gross extrathyroidal extension to either the right or left RLN. Thirty patients with a primary tumor ≤2 cm in diameter demonstrating extrathyroidal extension into an RLN were included in the analysis. Results: Gross invasion of an RLN by tumors ≤2 cm is a rare event that was seen in only 0.8% (35/4334) of patients with PTC who underwent initial thyroid surgery at MSK between 1986 and 2015. Gross RLN invasion was associated with subcapsular PTC tumors located in either the right paratracheal area (60%), left paratracheal area (36.7%), or right lateral posterior lobe area not adjacent to the trachea (3.3%). Only a quarter of the patients had imaging findings suggestive of extrathyroidal extension and only 30% had clinically apparent vocal paresis/paralysis on preoperative examination. Invasion of the RLN was not observed for primary tumors <0.9 cm in diameter, regardless of tumor location. Conclusions: Well-differentiated PTC tumors ≥0.9 cm in maximal diameter that are located in the right paratracheal, left paratracheal, and right lateral posterior lobe subcapsular positions are usually not appropriate for active surveillance even in the absence of definitive evidence for nerve invasion on preoperative imaging or vocal cord examination. Patient selection for active surveillance management should take into account not only the size and growth rate of a tumor but also its location in relation to the expected course of RLNs. [ABSTRACT FROM AUTHOR]

Aims: We aimed to study the clinicopathological and molecular features of high‐grade non‐anaplastic thyroid carcinomas (HGTCs), a carcinoma with a prognosis intermediate between those of well‐differentiated carcinoma and anaplastic carcinoma. Methods and results: This study included 364 HGTC patients: 200 patients (54.9%) were diagnosed with poorly differentiated thyroid carcinoma (PDTC), based on the Turin consensus (HGTC‐PDTC), and 164 were diagnosed with high‐grade features that did not meet the Turin criteria (HGTC‐nonPDTC). HGTCs are aggressive: the 3‐year, 5‐year, 10‐year and 20‐year disease‐specific survival (DSS) rates were 89%, 76%, 60%, and 35%, respectively. Although DSS was similar between HGTC‐PDTC and HGTC‐nonPDTC patients, HGTC‐PDTC was associated with higher rate of radioactive iodine avidity, a higher frequency of RAS mutations, a lower frequency of BRAF V600E mutations and a higher propensity for distant metastasis (DM) than HGTC‐nonPDTC. Independent clinicopathological markers of worse outcome were: older age, male sex, extensive necrosis and lack of encapsulation for DSS; older age, male sex and vascular invasion for DM‐free survival; and older age, necrosis, positive margins and lymph node metastasis for locoregional recurrence‐free survival. The frequencies of BRAF, RAS, TERT, TP53 and PTEN alterations were 28%, 40%, 55%, 11%, and 10%, respectively. TP53, PTEN and TERT were independent molecular markers associated with an unfavourable outcome, independently of clinicopathological parameters. The coexistence of BRAF V600E and TERT promoter mutation increased the risk of DM. Conclusions: The above data support the classification of HGTC as a single group with two distinct subtypes based on tumour differentiation: HGTC‐PDTC and HGTC‐nonPDTC. [ABSTRACT FROM AUTHOR]

Background: The approach for surgical treatment of patients with low-/intermediate-risk T1T2N0/Nx well-differentiated thyroid cancer (WDTC)—total thyroidectomy (TT) versus thyroid lobectomy (TL)—remains a controversial topic. Conducting a randomized controlled trial (RCT) would be the gold standard to address this issue. However, this is challenging due to excellent survival outcomes, and therefore, high number of patients and long-term follow-up would be required. As an alternative to RCT, we have used propensity score (PS) matching to determine if T1T2N0/Nx patients selected to have TL had equivalent outcomes to a similar group treated with TT. Methods: After institutional review board approval, a database of 6259 patients with WDTC treated with primary surgery at our institution between 1985 and 2016 was analyzed to identify patients with T1T2N0/Nx cancers. Of 3756 patients identified, 943 were managed by TL and 2813 by TT. To control for possible confounders and reduce potential bias, we selected age, sex, histology, 131I therapy, American Thyroid Association risk, and American Joint Committee Cancer stage as our PS matching criteria. Subsequently, 918 TL patients were successfully matched with 918 TT patients. The Pearson χ2 test or Fisher's exact test was used to compare categorical covariates, and Student's t-test was used for comparison of continuous variables between the two groups. Disease-specific survival (DSS), overall survival (OS), and recurrence-free survival (RFS) were calculated using the Kaplan–Meier method and compared using the log-rank test. Results: After PS matching, there were no significant differences between TL and TT patients for OS (10-year OS: 92.2% vs. 91.3%, p = 0.9668), DSS (10-year DSS: 100% vs. 99.1%, p = 0.1967), or RFS (10-year RFS: 99.5% vs. 98.3%, p = 0.079). Conclusions: For low-/intermediate-risk patients with intrathyroidal thyroid cancer <4 cm, patients selected for TL have similar survival outcomes to a comparable group treated by TT. [ABSTRACT FROM AUTHOR]

Background: The use of external-beam radiotherapy for locally advanced nonanaplastic thyroid cancer remains controversial. This prospective study evaluated the efficacy and tolerability of intensity-modulated radiation therapy (IMRT) with or without concurrent chemotherapy in patients with locally advanced thyroid cancer.Methods: The authors conducted a nonrandomized phase 2 trial of IMRT with or without concurrent doxorubicin in patients with gross residual or unresectable nonanaplastic thyroid carcinoma (ClinicalTrials.gov identifier NCT01882816). The primary end point was 2-year locoregional progression-free survival (PFS). Secondary end points included overall survival (OS), safety, patient-reported outcomes, and functional outcomes.Results: Twenty-seven patients were enrolled: 12 (44.4%) with unresectable disease and 15 (55.6%) with gross residual disease. The median follow-up was 45.6 months (interquartile range, 42.0-51.6 months); the 2-year cumulative incidences of locoregional PFS and OS were 79.7% and 77.3%, respectively. The rate of grade 3 or higher acute and late toxicities was 33.4%. There were no significant functional differences 12 months after treatment (assessed objectively by the modified barium swallow study). Patient-reported quality of life in the experimental group was initially lower but returned to the baseline after 6 months and improved thereafter. In a post hoc analysis, concurrent chemotherapy with intensity-modulated radiation therapy (CC-IMRT) resulted in significantly less locoregional failure at 2 years (no failure vs 50%; P = .001), with higher rates of grade 2 or higher acute dermatitis, mucositis, and dysphagia but no difference in long-term toxicity, functionality, or patient-reported quality of life.Conclusions: In light of the excellent locoregional control rates achieved with CC-IMRT and its acceptable toxicity profile as confirmed by functional assessments and patient-reported outcomes, CC-IMRT may be preferred over IMRT alone. [ABSTRACT FROM AUTHOR]

Background: Visual inspection and biopsy is the current standard of care for oral cancer diagnosis, but is subject to misinterpretation and consequently to misdiagnosis. Topically applied PARPi-FL is a molecularly specific, fluorescent contrast-based approach that may fulfill the unmet need for a simple, in vivo, non-invasive, cost-effective, point-of-care method for the early diagnosis of oral cancer. Here, we present results from a phase I safety and feasibility study on fluorescent, topically applied PARPi-FL. Twelve patients with a histologically proven oral squamous cell carcinoma (OSCC) gargled a PARPi-FL solution for 60 s (15 mL, 100 nM, 250 nM, 500 nM, or 1000 nM), followed by gargling a clearing solution for 60 s. Fluorescence measurements of the lesion and surrounding oral mucosa were taken before PARPi-FL application, after PARPi-FL application, and after clearing. Blood pressure, oxygen levels, clinical chemistry, and CBC were obtained before and after tracer administration. Results: PARPi-FL was well-tolerated by all patients without any safety concerns. When analyzing the fluorescence signal, all malignant lesions showed a significant differential in contrast after administration of PARPi-FL, with the highest increase occurring at the highest dose level (1000 nM), where all patients had a tumor-to-margin fluorescence signal ratio of >3. A clearing step was essential to increase signal specificity, as it clears unbound PARPi-FL trapped in normal anatomical structures. PARPi-FL tumor cell specificity was confirmed by ex vivo tabletop confocal microscopy. We have demonstrated that the fluorescence signal arose from the nuclei of tumor cells, endorsing our macroscopic findings. Conclusions: A PARPi-FL swish & spit solution is a rapid and non-invasive diagnostic tool that preferentially localizes fluorescent contrast to OSCC. This technique holds promise for the early detection of OSCC based on in vivo optical evaluation and targeted biopsy of suspicious lesions in the oral cavity. Trial registration: Clinicaltrials.gov—NCT03085147, registered on March 21st, 2017. [ABSTRACT FROM AUTHOR]

Background: Oral cancer is typically related to environmental carcinogen exposure including tobacco and alcohol. Other less investigated risk factors may be related to a suppressed or dysregulated immune state, and in oral cancer, various levels of immune dysregulation have been found to affect survival and recurrence rates. The rationale for this systematic review was to investigate the possible role that a growing chronic host condition like an autoimmune disease may play in this disease. Methods: A systematic search of the literature was carried out using four electronic databases in order to identify original research of any analytic study design type that investigated the relationship between autoimmune disease and oral cancer. Out of 1,947 identified records, 24 observational studies were included for qualitative synthesis. Results: The studies varied in end points ranging from overall survival (OS), standardized incidence ratio (SIR), and hazard ratio (HR). Due to the heterogenous sampling of studies even within the same study design group, a meta‐analysis was not employed. The current state of the literature is varied and heterogenous in both study design and endpoints. Conclusion: Major limitations existed introducing significant bias especially in determining cancer risk such as lack of information surrounding known etiologic risk factors such as alcohol and tobacco consumption. Despite these limitations, a signal was seen between autoimmune disease and oral cancer outcomes and risk. Future studies investigating the relationship between autoimmune disease and oral cancer in a more focused and quantitative manner are therefore needed. [ABSTRACT FROM AUTHOR]

Aims: The 8th edition of the American Joint Committee on Cancer (AJCC) Staging introduced depth of invasion (DOI) into the pT category of oral cavity squamous cell carcinoma. However, we noted multiple practical obstacles in accurately measuring DOI histologically in our daily practice. Methods and results: To compare the prognostic effects of DOI and tumour thickness (TT), a meticulous pathology review was conducted in a retrospective cohort of 293 patients with AJCC 7th edition pT1/T2 oral tongue squamous cell carcinoma. Overall survival (OS) and nodal metastasis rate at initial resection were the primary and secondary outcomes, respectively. We found that TT and DOI were highly correlated with a correlation coefficient of 0.984. The upstage rate was only 6% (18 of 293 patients) when using TT in the pT stage compared with using DOI. More importantly, DOI and TT, as well as pT stage using DOI and pT stage using TT, performed identically in predicting risk of nodal metastasis and OS. Conclusions: We therefore propose to replace DOI, a complicated measurement with many challenges, with TT in the pT staging system. [ABSTRACT FROM AUTHOR]

Importance This study reports the impact of laser surgery on quality of life in patients with oral cavity lesions. Objective: To compare postoperative pain and quality of life in patients treated with flexible fiberoptic CO2 laser vs electrocautery in patients with oral cavity precancerous lesions and early stage cancers. Design Randomized controlled trial. Setting: Single center. Participants: Patients with premalignant oral cavity lesions and early stage oral cancer. Intervention: Patients were randomized to have surgical resection using either flexible fiber carbon dioxide laser (Laser) or electrocautery (EC). The patients were then followed over a period of 28 days to assess for outcomes including pain, quality of life, performance status, return to work, and return to diet. Quality of life was measured by the University of Washington Quality of Life (UWQOL) questionnaire and the performance status score (PSS). Main outcome measure: The primary endpoint for this study was the numerical pain rating on postoperative day (POD) 7. Results: Sixty‐two patients were randomized (32 laser and 30 electrocautery). Lesions excised were carcinoma in 30(48%), dysplasia in 31(50%) and benign in 1(2%). There was no difference in the location of lesion, size of lesion, defect size, type of closure, resection time, and blood loss between Laser and EC arms. Patients who had Laser had less pain compared to EC (mean pain score on POD 7 L = 2.84 vs EC = 3.83, P = 0.11). better UW QOL scores and PSS scores, quicker return to normal diet (median days L = 26.0 vs EC = 28.5, P = 0.17) and faster return to work (median days L = 13.0 vs EC = 16.5, P = 0.14). However, these results were not statistically significant. Conclusion: There was a trend for patients treated with laser to have less pain and better quality of life scores but these result were not statistically significant. Based on the actual observed difference, a large multicenter RCT with 90 patients in each arm is required to determine the clinical relevance of our results. [ABSTRACT FROM AUTHOR]

ONYX-015 is an adenovirus with the E1B 55-kDa gene deleted, engineered to selectively replicate in and lyse p53-deficient cancer cells while sparing normal cells. Although ONYX-015 and chemotherapy have demonstrated anti-tumoral activity in patients with recurrent head and neck cancer, disease recurs rapidly with either therapy alone. We undertook a phase II trial of a combination of intratumoral ONYX-015 injection with cisplatin and 5-fluorouracil in patients with recurrent squamous cell cancer of the head and neck. There were substantial objective responses, including a high proportion of complete responses. By 6 months, none of the responding tumors had progressed, whereas all non-injected tumors treated with chemotherapy alone had progressed. The toxic effects that occurred were acceptable. Tumor biopsies obtained after treatment showed tumor-selective viral replication and necrosis induction. [ABSTRACT FROM AUTHOR]

Background: The aims of this study were to provide data on the safety of head and neck cancer surgery currently being undertaken during the coronavirus disease 2019 (COVID‐19) pandemic. Methods: This international, observational cohort study comprised 1137 consecutive patients with head and neck cancer undergoing primary surgery with curative intent in 26 countries. Factors associated with severe pulmonary complications in COVID‐19–positive patients and infections in the surgical team were determined by univariate analysis. Results: Among the 1137 patients, the commonest sites were the oral cavity (38%) and the thyroid (21%). For oropharynx and larynx tumors, nonsurgical therapy was favored in most cases. There was evidence of surgical de‐escalation of neck management and reconstruction. Overall 30‐day mortality was 1.2%. Twenty‐nine patients (3%) tested positive for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) within 30 days of surgery; 13 of these patients (44.8%) developed severe respiratory complications, and 3.51 (10.3%) died. There were significant correlations with an advanced tumor stage and admission to critical care. Members of the surgical team tested positive within 30 days of surgery in 40 cases (3%). There were significant associations with operations in which the patients also tested positive for SARS‐CoV‐2 within 30 days, with a high community incidence of SARS‐CoV‐2, with screened patients, with oral tumor sites, and with tracheostomy. Conclusions: Head and neck cancer surgery in the COVID‐19 era appears safe even when surgery is prolonged and complex. The overlap in COVID‐19 between patients and members of the surgical team raises the suspicion of failures in cross‐infection measures or the use of personal protective equipment. Lay Summary: Head and neck surgery is safe for patients during the coronavirus disease 2019 pandemic even when it is lengthy and complex.This is significant because concerns over patient safety raised in many guidelines appear not to be reflected by outcomes, even for those who have other serious illnesses or require complex reconstructions.Patients subjected to suboptimal or nonstandard treatments should be carefully followed up to optimize their cancer outcomes.The overlap between patients and surgeons testing positive for severe acute respiratory syndrome coronavirus 2 is notable and emphasizes the need for fastidious cross‐infection controls and effective personal protective equipment. Among 1137 patients who underwent head and neck cancer surgery during the first peak of the coronavirus disease 2019 (COVID‐19) pandemic, the overall 30‐day mortality rate was 1.2%, and severe pulmonary complications of COVID‐19 were seen in 1.2%. There is evidence of therapeutic migration away from surgery to a radiotherapy‐based primary modality and of de‐escalation in those undergoing surgery, which may not be justified in view of this reassuring patient safety profile. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to evaluate the differences in surgical capacity for head and neck cancer in the UK between the first wave (March‐June 2020) and the current wave (Jan‐Feb 2021) of the COVID‐19 pandemic. Design: REDcap online‐based survey of hospital capacity. Setting: UK secondary and tertiary hospitals providing head and neck cancer surgery. Participants: One representative per hospital was asked to report the capacity for head and neck cancer surgery in that institution. Main outcome measures: The principal measures of interests were new patient referrals, capacity in outpatients, theatres and critical care; therapeutic compromises constituting delay to surgery, de‐escalated surgery and therapeutic migration to non‐surgical primary modality. Results: Data were returned from approximately 95% of UK hospitals with a head and neck cancer surgery specialist service. 50% of UK head and neck cancer patients requiring surgery have significantly compromised treatments during the second wave: 28% delayed, 10% have received radiotherapy‐based treatment instead of surgery, and 12% have received de‐escalated surgery. Surgical capacity has been more severely constrained in the second wave (58% of pre‐pandemic level) compared with the first wave (62%) despite the time to prepare. Conclusions: Some hospitals are overwhelmed by COVID‐19 and unable to offer essential cancer surgery, but all have neighbouring hospitals in their region retaining good (or even normal) capacity. It is noteworthy that very few patients have been appropriately redirected away from the hospitals most constrained by their burden of COVID‐19. The paucity of an effective central or regional strategic response to this evident mismatch between demand and surgical capacity is to the detriment of our head and neck cancer patients. [ABSTRACT FROM AUTHOR]

Dear Editor, Merkel cell carcinoma is a rare aggressive primary neoplasm of neuroendocrine origin, typically presenting as dermal tumour; uncommonly, it can present as a neoplasm limited to the epidermis (intraepidermal Merkel cell carcinoma).1 Most intraepidermal Merkel cell carcinomas arise in association with other tumours (i.e. collision tumours).1,2 Reported cases in the literature mainly described dermatopathologic features and lacked detailed clinical and reflectance confocal microscopy (RCM) description. Recent data suggest that they might have a different cell origin: Merkel cell polyomavirus-negative Merkel cell carcinoma emerges from epidermal keratinocytes and Merkel cell polyomavirus-positive Merkel cell carcinoma from dermal fibroblast (classic Merkel cell carcinoma). The RCM appearance seen in this case, however, differs from what has been described in classic Merkel cell carcinoma.5,6 The presence of aggregates of small cells surrounded by fibrotic septae has been described.5 We hypothesise that intraepidermal Merkel cell carcinoma and Merkel cell carcinoma have a different RCM appearance given the different skin compartment from which they arise (i.e. epidermis in intraepidermal Merkel cell carcinoma and dermis in classic Merkel cell carcinoma). [Extracted from the article]

Objectives: Determine whether the insertion site of the recurrent laryngeal nerve (RLN) occurs at a predictable distance from the midline trachea, to help guide safe dissection during thyroid surgery. Design: Prospective clinical trial. At the inferior edge of the cricoid cartilage, we measured the distance from mildline trachea to the RLN insertion site. Setting: Single institution. Participants: 50 consecutive patients undergoing thyroid surgery. Main outcome measures: Distance from midline trachea to laryngeal insertion of RLN. Results: The study population included 36 women and 14 men, with 72 total nerves measured. The average distance‐to‐midline + standard deviation (range) of the RLN was 20.7 + 2.3 (17‐26) mm in women compared to 26.3 + 2.1 (22‐32) mm in men. Conclusion: The insertion point of the RLN into the larynx at the level of inferior border of the cricoid cartilage can be reliably predicted, to facilitate early identification of the RLN during thyroid surgery. [ABSTRACT FROM AUTHOR]

Because of the national emergency triggered by the coronavirus disease 2019 (COVID-19) pandemic, government-mandated public health directives have drastically changed not only social norms but also the practice of oncologic medicine. Timely head and neck cancer (HNC) treatment must be prioritized, even during emergencies. Because severe acute respiratory syndrome coronavirus 2 predominantly resides in the sinonasal/oral/oropharyngeal tracts, nonessential mucosal procedures are restricted, and HNCs are being triaged toward nonsurgical treatments when cures are comparable. Consequently, radiation utilization will likely increase during this pandemic. Even in radiation oncology, standard in-person and endoscopic evaluations are being restrained to limit exposure risks and preserve personal protective equipment for other frontline workers. The authors have implemented telemedicine and multidisciplinary conferences to continue to offer standard-of-care HNC treatments during this uniquely challenging time. Because of the lack of feasibility data on telemedicine for HNC, they report their early experience at a high-volume cancer center at the domestic epicenter of the COVID-19 crisis. [ABSTRACT FROM AUTHOR]

Background: Distant metastases (DMs) are the primary cause of treatment failure in patients with salivary gland carcinoma. There is no consensus on the standard treatment.Methods: Patients with DMs were identified from an institutional database of 884 patients with salivary gland cancer who underwent resection of the primary tumor between 1985 and 2015. Survival outcomes for patients with DMs were determined with the Kaplan-Meier method. Univariate and multivariate analyses were performed to identify factors associated with DM.Results: Of the 884 patients identified, 137 (15%) developed DMs during follow-up. Most of the primary tumors (n = 77 [56%]) were located in a major salivary gland. At clinical presentation, 53% of the tumors were classified as T3 or T4, and 32% had clinical node metastases. The median time to DM was 20.3 months. The factors associated with shorter distant recurrence-free survival were male sex, high-risk tumor histology, and advanced pathological T and N classifications. Patients with bone metastases had a lower survival rate than patients with lung metastases. The total number of DMs in a patient was inversely associated with survival. Patients who underwent surgical resection of DMs had a significantly higher 5-year rate of metastatic disease-specific survival than patients who underwent observation or nonsurgical treatment (44%, 29%, and 19%, respectively; P = .003).Conclusions: In patients with DMs of salivary gland carcinoma, survival is negatively associated with high-grade histology, bone DMs, and the total number of DMs. Metastasectomy can help to lengthen disease-free survival. [ABSTRACT FROM AUTHOR]

The evaluation of disease extent and post-therapy surveillance of head and neck cancer using 2-deoxy-2-18F]fluoro- d -glucose (18F]FDG) PET is often complicated by physiological uptake in normal tissues of the head and neck region, especially after surgery or radiotherapy. However, irrespective of low positive predictive values, 18F]FDG PET remains the standard of care to stage the disease and monitor recurrences. Here, we report the preclinical use of a targeted poly (ADP-ribose) polymerase1 (PARP1) binding PET tracer, fluorine-18 labeled poly (ADP-ribose) polymerase1 inhibitor (18F]PARPi), as a potential alternative with greater specificity. Using an orthotopic xenograft mouse model injected with either FaDu or Cal 27 (human squamous cell carcinoma cell lines) we performed PET/CT scans with the 2 tracers and compared the results. Gamma counts and autoradiography were also assessed and correlated with histology. The average retained activity of 18F]PARPi across cell lines in tumor-bearing tongues was 0.9 ± 0.3%ID/g, 4.1 times higher than in control (0.2 ± 0.04%ID/g). Autoradiography and histology confirmed that the activity arose almost exclusively from the tumor areas, with a signal/normal tissue around a ratio of 42.9 ± 21.4. In vivo , 18F]PARPi-PET allowed delineation of tumor from healthy tissue (p <.005), whereas 18F]FDG failed to do so (p =.209). We demonstrate that 18F]PARPi is more specific to tongue tumor tissue than 18F]FDG. 18F]PARPi PET allows for the straightforward delineation of oral cancer in mouse models, suggesting that clinical translation could result in improved imaging of head and neck cancer when compared to 18F]FDG. [ABSTRACT FROM AUTHOR]