Uracil as a biomarker for spatial pyrimidine metabolism in the development of gingivobuccal oral squamous cell carcinoma.

No biomarker has yet been identified that allows accurate diagnosis and prognosis of oral cancers. In this study, we investigated the presence of key metabolites in oral cancer using proton nuclear magnetic resonance (NMR) spectroscopy to identify metabolic biomarkers of gingivobuccal oral squamous cell carcinoma (GB-OSCC). NMR spectroscopy revealed that uracil was expressed in 83.09% of tumor tissues and pyrimidine metabolism was active in GB-OSCC; these results correlated well with immunohistochemistry (IHC) and RNA sequencing data. Based on further gene and protein analyses, we proposed a pathway for the production of uracil in GB-OSCC tissues. Uridinetriphosphate (UTP) is hydrolyzed to uridine diphosphate (UDP) by CD39 in the tumor microenvironment (TME). We hypothesized that UDP enters the cell with the help of the UDP-specific P2Y6 receptor for further processing by ENTPD4/5 to produce uracil. As the ATP reserves diminish, the weakened immune cells in the TME utilize pyrimidine metabolism as fuel for antitumor activity, and the same mechanism is hijacked by the tumor cells to promote their survival. Correspondingly, the differential expression of ENTPD4 and ENTPD5 in immune and tumor cells, respectively, indicatedtheir involvement in disease progression. Furthermore, higher uracil levels were detected in patients with lymph node metastasis, indicating that metastatic potential is increased in the presence of uracil. The presence of uracil and/or expression patterns of intermediate molecules in purine and pyrimidine pathways, such asCD39, CD73, and P2Y6 receptors together with ENTPD4 and ENTPD5, hold promise as biomarker(s) for oral cancer diagnosis and prognosis.

A Nationwide Survey to Assess the Practices and Patterns of Use of Intraoperative Nerve Monitoring During Thyroid Surgery Among Surgeons in India.

There is still equipoise for the routine use of intraoperative nerve monitoring (IONM) for thyroid surgeries; however, some surgeons tend to use it for various reasons. In our study, we did a national survey to assess the patterns and practice of the use of IONM among surgeons during thyroid surgery in India. A questionnaire survey was sent to surgeons (head and neck surgical oncologists, general surgical oncologists, endocrine surgeons and otolaryngologists) in different zones in India via email, and their responses were analysed. One hundred and one responses were received. The majority of the respondents were head and neck surgical oncologists (n = 56, 55.4%). Forty-three (42.6%) respondents used IONM during thyroid surgeries in this survey. Surgeons with ≤ 15 years of experience performing thyroid surgeries (p = 0.02) and surgeons performing > 50 thyroid surgeries also tended to use IONM. Mostly IONM was used for surgeries on thyroid malignancies (p = 0.016). The respondents used IONM for more than one reason such as medicolegal purposes and surgeon comfort among others. IONM was most often used during redo surgeries (n = 46, 45.5%) and in patients with already one fixed cord (n = 39, 38.6%). The majority felt IONM was not cost-effective (n = 53, 52.5%). The use of IONM during thyroid surgery in our survey was nearly 43%. It was used mostly for surgery for thyroid malignancies, and it was found to be used for more than one reason and indications such as redo surgeries (most commonly). Supplementary Information: The online version contains supplementary material available at 10.1007/s13193-023-01818-5.

Sentinel lymph node biopsy in early oral cancers: are we ready for it yet? Results from a survey among Indian surgeons treating oral cancers.

OBJECTIVE: Emerging evidence has shown that sentinel node biopsy (SNB) is an oncologically safe option in patients with early oral cancer compared with elective neck dissection (END). However, its use on a routine basis could be associated with many challenges. STUDY DESIGN: This online survey was conducted among the Indian surgeons treating patients with oral cancer to understand and comprehend the incidence and patterns of usage of SNB in their practice, their approach toward the use of SNB, and the possible challenges they face or perceive in its routine use in patients with early oral cancer. RESULTS: We received 352 responses with a response rate of 47.63%. Most of the respondents (82.6%) were managing N-zero necks with END, only 15.1% (n = 53) respondents practiced SNB currently. Most respondents believed that SNB offered the advantage of better shoulder function compared with END (76.4% [n = 269]). The deterrents considered for routine use of SNB in early oral cancer were additional costs (71.9% [n = 253]), the unavailability of necessary expertise and infrastructure (87.2% [n = 307]), SLNB being a more time-consuming treatment (58.8% [n = 207]), a higher false negative rate (74.1% [n = 261]), and the possible need of a second surgery (82.4% [n = 290]). CONCLUSIONS: Though SNB presently could be considered as an alternative treatment option, there seem to be various issues that need to be addressed before it can be adopted as a standard of care across centers.

Seeing Is Not Believing: Intraoperative Nerve Monitoring (IONM) in the Thyroid Surgery.

Ensuring the integrity of the recurrent laryngeal nerve (RLN), the external branch of superior laryngeal nerve (EBSLN) and preservation of normal voice are the prime 'functional' goals of thyroid surgery. More in-depth knowledge of neuronal mechanisms has revealed that anatomical integrity does not always translate into functional integrity. Despite meticulous dissection, neural injuries are not always predictable or visually evident. Intraoperative nerve monitoring (IONM) is designed to aid in nerve identification and early detection of functional impairment. With the evolution of technique, intermittent monitoring has given way to continuous-IONM. Over the years, IONM gathered both support and flak. Despite numerous randomised studies, systematic reviews, and meta-analyses, there still prevails a state of clinical equipoise concerning the utility of IONM and its cost-effectiveness. This article inspects the true usefulness of IONM, elaborates on the optimal way to practice it, and presents a critical literature review.

The evolving role of molecular pathology in the diagnosis of salivary gland tumours with potential pitfalls.

Salivary gland tumors are diagnostically challenging owing to the morphological diversity within any tumor type and overlapping histomorphology and immunohistochemistry amongst different tumours. In past two decades, rapid progress has been made in the field of understanding the pathogenesis of these tumours with the discovery of many tumour specific translocations and rearrangements. This includes CRTC1-MAML2 and CRTC-MAML2 in mucoepidermoid carcinoma, MYBNFIB and MYBL1-NFIB fusions in adenoid cystic carcinoma, PLAG1 and HMGA2 in pleomorphic adenoma, ETV6-NTRK3 in secretory carcinoma, NR4A3 rearrangements in acinic cell carcinoma, PRKD1 mutations in polymorphous adenocarcinoma and EWSR1-ATF1 in clear cell carcinoma. This review is a lens for progress made till date in the molecular pathology of salivary gland tumours with a special focus on their role as diagnostic tools and implications on clinical management of the patient as prognostic and predictive markers.

Identification of patients for a delayed extubation strategy versus elective tracheostomy for postoperative airway management in major oral cancer surgery: A prospective observational study in seven hundred and twenty patients.

OBJECTIVES: Tracheostomy (TT) and delayed extubation (DE) are two approaches to postoperative airway management in patients after major oral cancer surgery. We planned a study to determine the safety of overnight intubation followed by extubation the next morning (DE) compared to elective TT and to identify factors that were associated with a safe DE (maintenance of a patent airway). MATERIAL AND METHODS: We conducted a prospective observational study in a tertiary referral cancer care center. We included adult patients undergoing elective major oral cancer surgery under general anesthesia with tracheal intubation. The decision regarding postoperative airway management using either TT or DE was made according to the usual practice at our center. RESULTS: We screened a total of 4477 patients, 720 patients were included. DE was performed in 417 patients (58.4%) and TT in 303 patients (42.4%). On multivariable analysis, T1-T2 tumor stage, absence of extensive resection, primary closure or reconstruction using fasciocutaneous flap, absence of preoperative radiation, no neck dissection or unilateral neck dissection and shorter duration of anesthesia were independent predictors for a safe DE. Overall complications (4.3% versus 22.5%, p = 0.00) and airway complications (1.7% versus 8.7%, p = 0.00) were lower in the DE compared to the TT group respectively. DE was associated with a shorter hospital stay (7.2 ± 3.7 versus 11.5 ± 7.2 days, p = 0.00), time to oral intake and speech compared to TT. CONCLUSIONS: A DE strategy after major oral cancer surgery is a safe alternative to TT in a select group of patients.

Depth of invasion in early oral cancers- is it an independent prognostic factor?

INTRODUCTION: Depth of invasion (DOI) has been incorporated into oral cancer staging. Increasing DOI is known to be associated with an increased propensity to neck metastasis and adverse tumor factors and hence may not be an independent prognosticator but a surrogate for a biologically aggressive tumor. METHODS: 570 patients, median follow up 79.01 months from a previously reported randomized trial (NCT00193765) designed to establish appropriate neck treatment [elective neck dissection (END) vs therapeutic neck dissection (TND)] in clinically node-negative early oral cancers were restaged (nT) according to AJCC TNM 8th edition. Overall survival (OS) was estimated for the entire cohort, END, and TND arms. Multivariate analysis performed for stratification and prognostic factors, and interaction term between revised T-stage and neck treatment, for tumours with DOI≤10mm. Presence of adverse factors was compared between nT3 (DOI>10 mm) and those with DOI≤10 mm. RESULTS: Stage migration occurred in 44.38% of patients. 5-Year OS was nT1-79%, nT2-69.4% and nT3-53.8%, (p < 0.001). In TND arm 5-year OS was nT1-81.1% versus nT2-65%,p = 0.004, while that in END arm was nT1 -76.9% versus nT2 -73.7%,p = 0.73. There was a significant interaction between T stage and neck treatment (p = 0.03). T3 tumors (>10 mm) were associated with a higher proportion of adverse factors (occult nodal metastasis, p = 0.035; LVE/PNI, p = 0.001). CONCLUSION: Elective neck treatment negates the prognostic impact of DOI for early oral cancers (T1/T2 DOI≤10 mm). T3 tumors with DOI>10 mm have a higher association with other adverse risk factors resulting in poorer outcomes in spite of elective neck dissection.

The results of sequential swallowing assessments after total laryngectomy for laryngeal and hypopharyngeal malignancies.

BACKGROUND: Swallowing after total laryngectomy (TL) is altered and the swallowing related issues are largely underreported. It is important to identify factors that may negatively influence swallowing after TL in order to rehabilitate these patients appropriately. METHODS: The study included patients who underwent TL from June 2015 to November 2017 for laryngeal and hypopharyngeal malignancy. Sequential swallowing assessment was done in these patients over time. The assessments were done using the FOIS scale and the PSS-HN normalcy of diet scores and analysed to assess the presence of swallowing related issues, factors influencing swallowing and its recovery over time. RESULTS: Sixty-seven who underwent total laryngectomy (TL) were included in the study. Swallowing assessments were done once in 3 months. Overall there was an improvement in swallowing over time. Both the FOIS (Median score of 3.82 in first to 5.77 in the fifth visit) and the PSS-HN scores (median score of 33.63 at first visit to 63.66 at fifth visit) improved over time. Patients undergoing TL after treatment failure with chemoradiotherapy (p value < 0.001) and those with advanced stage disease (p-value < 0.001) did poorly in terms of swallowing. At the last follow up only 8 patients were dependent on feeding tube; the rest of the patients were able to take food orally. CONCLUSION: Following total laryngectomy swallowing gradually improves in the first 18 months after surgery. It is essential to identify factors influencing swallowing negatively so that these patients can get appropriate attention to improve swallowing.

Management of locally advanced oral cancers.

Despite easy access to clinical examination majority of oral cancer patients ironically present with locally advanced disease, which is a heterogeneous group that includes all stage III/IV tumours in absence of distant metastasis. The AJCC TNM classification has included all tumours with depth of invasion >1 cm into locally advanced group irrespective of their surface dimensions. Surgery followed by adjuvant therapy provides best results and should be offered to all patients when operable. There have been a slew of recent publications popularising the concept of compartmental excision in variance to traditional resection with adequate margins. The role of chemotherapy has been explored in this group of patients for both organ preservation as well as to aid bioselection of suitable patients with borderline operable tumours for surgery.

Referral Practice for Radioactive Iodine Ablation (RAI) after ATA guidelines 2015: results from a Tertiary Cancer Care Centre.

INTRODUCTION: The ATA guidelines for differentiated thyroid cancer (DTC) are one of the most widely referred to. Their 2015 edition proposed a new risk stratification system and modified the indications for radioactive iodine (RAI) ablation especially for the low risk category. We attempted to analyze whether the new guidelines altered referral practices for RAI ablation at our institute. METHODOLOGY: Patients who underwent total or completion thyroidectomy for DTC during 2016-2017 were included. Relevant demographical and pathological data was tabulated. Patients were classified as per the new stratification system and referral practice for RAI ablation documented. RESULTS: 238 patients were included. Of these 20.6% were low risk, 44.1% were intermediate and 35.3% were high risk as per modified guidelines. All patients within the intermediate and high-risk group and 77.8% of the low risk group were referred for RAI ablation. Analysis of risk factors revealed that within the low risk group there were three patients with < 5 metastatic nodes, all within 3 cm in size-a category that the ATA failed to stratify appropriately. Among those labeled as Intermediate risk due to microscopic extra thyroidal extension (ETE), 85% had no other risk factors and were upstaged solely due to microscopic ETE, which is interestingly no longer included in the TNM staging. CONCLUSION: Majority of low risk patients continue to receive RAI ablation due to persistent belief emanating from literature that remnant ablation improves outcomes and aids in follow up. The issue of RAI ablation for low risk group and prognostic implications of microscopic ETE and limited nodal disease need to be revisited.

Poorly differentiated thyroid carcinoma (PDTC) characteristics and the efficacy of radioactive iodine (RAI) therapy as an adjuvant treatment in a tertiary cancer care center.

BACKGROUND: Poorly differentiated thyroid cancer (PDTC) is biologically more aggressive. Surgery remains the mainstay of treatment. The utility of radioactive iodine (RAI) after surgery is unclear. METHODS: In this retrospective study, patients treated between Jan 2012 and Dec 2017 were included. The demographic, clinical and treatment-related details, including RAI ablation, were recorded and their survival analyzed. RESULTS: Thirty-five patients fulfilled the eligibility criteria. Majority was treatment naïve at presentation. All patients underwent surgery followed by RAI ablation, with a cumulative median dose of 220 mCi (range 40-1140). Sixteen patients received more than one radioiodine treatment for distant metastases. Incomplete resection, age > 45 years and the presence of distant metastasis influenced survival the most. The 3-year PFS of patients with PDTC was 69%. CONCLUSION: All patients in our series showed uptake and responded to treatment. Further use of molecular markers and functional molecular imaging would better our understanding of this entity.

Utility of response assessment PET-CT to predict residual disease in neck nodes: A comparison with the Histopathology.

OBJECTIVE: To assess the ability of Positron Emission Tomography-Computed Tomography (PET-CT) scans to detect residual disease in neck nodes with the Histopathology (HPR) as the gold standard. To obtain a Standardized Uptake Value max cutoff in these patients to predict residual disease in neck. METHODS: Head and neck squamous cell carcinoma patients who underwent Salvage neck dissection with or without primary site surgery post Concurrent Chemo-Radiotherapy (CCRT) during the period January 2008-December 2017 were included. All patients had response assessment PET-CT scan at 10-14 weeks. Agreement analysis was performed between PET-CT and HPR, fine needle aspiration cytology and HPR. Positive predictive value, Negative predictive value of PET-CT to detect residual neck nodal disease in comparison to HPR was analyzed. A Receiver Operating Characteristic (ROC) curve was plotted between the SUV max values and the HPR. A SUV max cutoff value was obtained from the ROC curve. RESULTS: A total of 75 patients were included. Thirty-one underwent salvage neck dissection along with surgery for primary disease and 45 underwent salvage neck dissection alone. PET-CT showed good agreement with the HPR to detect residual disease in neck nodes (Kappa=0.604). PET-CT had a PPV and NPV of 87.5% and 79.15% respectively as compared against the HPR. A SUV max cutoff of 4.62 had a specificity of 92.3% and sensitivity of 73.5% to detect residual disease in neck nodes on the HPR. CONCLUSION: PET-CT surveillance is an accepted treatment strategy. A neck node with SUV max of 4.62 and above is most likely to harbor residual nodal disease. LEVEL OF EVIDENCE: Level 2b.

Oral cancers: Current status.

Oral cancer is a global disease. Despite a well elucidated tumour progression model, these cancers present late. Attempts at early detection by way of adjunctive diagnostic technologies and screening have not lived up to expectations in spite initial promise. Surgery is the mainstay of treatment. Treatment intensification by way of adjuvant radiation/chemo radiation is warranted for those with high risk features. Recent studies have explored intensification in those with intermediate risk factors in an attempt to improve outcomes. There has been generation of recent robust evidence that has influenced the need and extent of neck dissection. Neoadjuvant chemotherapy (NACT) may have a potential role in organ preservation and borderline resectable oral cancers. Recurrent tumours should be offered surgery whenever feasible while the addition of biological agents to chemotherapy gives best results in the palliative settings.

Head and neck cancers in India.

Head and neck cancers constitute a third of the cancer burden in India. These cancers have unique patient characteristics, presentation, and etiological differences from those in the West. Socioeconomic constraints, large patient population, scarcity of trained health workers, and inadequate infrastructure are major challenges faced in the management of these cancers. Despite these constraints, patients are treated with evidence based guidelines that are tailored to the local scenario.

The Indian scenario of head and neck oncology - Challenging the dogmas.

Head and neck cancers (HNCs) are the most common malignancies worldwide. Asian populations bear major burden of this disease, with certain unique characteristics. Although significant research in HNCs is ongoing globally, many clinical issues still remain unanswered. We performed a literature search to find noteworthy Indian studies that changed practice of HNC as well as to look for areas for further research in this field. Many randomized controlled trials as well as large patient series are reported in the field of radiotherapy, chemotherapy, and surgical management of HNC. Still, many areas such as palliative therapy, targeted agents, and newer chemotherapeutic agents remain unexplored. Planned collaborative research is need of the hour to provide more evidenced based.

Primary thyroid schwannoma masquerading as a thyroid nodule.

The thyroid gland is a very rare site for head and neck schwannomas. Till date there have been only 19 reported cases in English literature. Only 25% of schwannomas occur in the head and neck region, most of them arising in relation to the peripheral nerves and cervical sympathetic chain. We report a similar case, with clinical and sonological features of a benign thyroid nodule. The diagnosis of schwannoma was established on the final histopathology report and a review of the slides and the imaging was done to confirm the site of origin. A thorough review of earlier reported cases was done. We summarize the existing knowledge on this entity, emphasizing the challenge of diagnosing it pre-operatively.