N0 neck trial: Does intensification of follow-up (Ultrasound + Physical Examination) influence outcomes in early-stage oral cancer?

AIM OF THE STUDY: We previously reported a survival benefit of elective neck dissection (END) over therapeutic neck dissection (TND) in patients with clinically node-negative early-stage oral cancer. We now report the results of the second question in the same study addressing the impact of adding neck ultrasound to physical examination during follow-up on outcomes. METHODS: Patients with lateralized T1/T2 oral squamous cell carcinoma (SCC) were randomized to END or TND and to follow-up with physical-examination plus neck ultrasound (PE+US) versus physical-examination (PE). The primary endpoint was overall survival (OS). RESULTS: Between January 2004 and June 2014, 596 patients were enrolled. This is an intention to treat analysis of 592 analysable patients, of whom 295 were allocated to PE+US and 297 to PE with a median follow-up of 77.47 months (interquartile range (IQR) 54.51-126.48). There was no significant difference (unadjusted hazard ratio [HR], 0.92, 95% CI, 0.71-1.20, p = 0.54) in 5-year OS between PE+US (70.8%, 95% CI, 65.51-76.09) and PE (67.3%, 95% CI, 61.81-72.79). Among 131 patients with neck node relapse as the first event, the median time to relapse detection was 4.85 (IQR 2.33-9.60) and 7.62 (IQR 3.22-9.86) months in PE+US and PE arms, respectively. The N stage in the PE+US arm was N1 33.8%, N2a 7.4%, N2b/c 44.1% and N3 14.7% while in PE was N1 28.6%, N2a 9.5%, N2b/c 39.7%, N3 20.6% and unknown 1.6%. CONCLUSION: Adding neck ultrasound to physical examination during follow-up detects nodal relapses earlier but does not improve overall survival.

Role of computed tomography in the evaluation of regional metastasis in well-differentiated thyroid cancer.

Background: Accurate neck staging is essential for performing appropriate surgery and avoiding undue morbidity in thyroid cancer. The modality of choice for evaluation is ultrasonography (US), which has limitations, particularly in the central compartment, that can be overcome by adding a computed tomography (CT). Methods: A total of 314 nodal levels were analyzed in 43 patients with CT, and US; evaluations were done between January 2013 and November 2015. The images were reviewed by two radiologists independently who were blinded to histopathological outcomes. The sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), and accuracy of US, CT, and US + CT were calculated using histology as the gold standard. Results: The overall sensitivity, specificity, PPV, and NPV for US, CT, and US + CT were 53.9%, 88.8%, 74.1%, and 76.4%; 81.2%, 68.0%, 60.1%, and 85.9%; and 84.6%, 66.0%, 59.6%, and 87.8%, respectively. The overall accuracy of the US was 75.80%, the CT scan was 72.93%, and the US + CT scan was 72.93%. For the lateral compartment, the sensitivity, specificity, PPV, and NPV for the US, CT, and US + CT were 56.6%, 91.4%, 77.1%, and 80.5%; 80.7%, 70.6%, 58.3%, and 87.8%; and 84.3%, 68.7%, 57.9%, and 89.6%, respectively. The accuracy of the US was 79.67%, the CT scan was 73.98%, and the US + CT scan was 73.98% for the lateral compartment. For the central compartment, the sensitivity, specificity, PPV, and NPV for the US, CT, and US + CT were 47.1%, 76.5%, 66.7%, and 59.1%; 82.4%, 55.9%, 65.1%, and 76.0%; and 85.3%, 52.9%, 64.4%, and 78.3%, respectively. The accuracy of the US was 61.76%, the CT scan was 69.12%, and the US + CT scan was 69.12% for the central compartment. Conclusions: This study demonstrated that CT has higher sensitivity in detecting nodal metastasis; however, its role is complementary to US due to low specificity.

Role of miR-944/MMP10/AXL- axis in lymph node metastasis in tongue cancer.

Occult lymph-node metastasis is a crucial predictor of tongue cancer mortality, with an unmet need to understand the underlying mechanism. Our immunohistochemical and real-time PCR analysis of 208 tongue tumors show overexpression of Matrix Metalloproteinase, MMP10, in 86% of node-positive tongue tumors (n = 79; p < 0.00001). Additionally, global profiling for non-coding RNAs associated with node-positive tumors reveals that of the 11 significantly de-regulated miRNAs, miR-944 negatively regulates MMP10 by targeting its 3'-UTR. We demonstrate that proliferation, migration, and invasion of tongue cancer cells are suppressed by MMP10 knockdown or miR-944 overexpression. Further, we show that depletion of MMP10 prevents nodal metastases using an orthotopic tongue cancer mice model. In contrast, overexpression of MMP10 leads to opposite effects upregulating epithelial-mesenchymal-transition, mediated by a tyrosine kinase gene, AXL, to promote nodal and distant metastasis in vivo. Strikingly, AXL expression is essential and sufficient to mediate the functional consequence of MMP10 overexpression. Consistent with our findings, TCGA-HNSC data suggests overexpression of MMP10 or AXL positively correlates with poor survival of the patients. In conclusion, our results establish that the miR-944/MMP10/AXL- axis underlies lymph node metastases with potential therapeutic intervention and prediction of nodal metastases in tongue cancer patients.

Sentinel node biopsy in node negative early oral cancers: Solution to the conundrum!

Ideal management of the node-negative neck in early oral cancers is a debated issue. Elective neck dissection (END) is recommended in these patients as it offers a survival benefit. However, about 50-70% of patients who do not harbor occult metastasis are overtreated with this approach. Surgery is associated with morbidity, predominantly shoulder dysfunction. Numerous attempts have been made to identify true node-negative patients through imaging and prediction models but none have high diagnostic accuracy to safely spare the neck dissection. The recent publications of 2 large randomized controlled trials comparing the outcomes of sentinel node biopsy (SNB) and END have spurred interest in SNB. Both the trials reported SNB to be an oncologically safe procedure and spared unnecessary neck dissections. The functional outcomes of the trials showed that SNB limits the morbidity compared to END, which albeit evens out at the end of one-year post-surgery. Despite its benefits, SNB has failed to gain widespread acceptability due to various limitations including the need for infrastructure, equipment costs, staff, and multidisciplinary collaboration of nuclear medicine, surgical, and pathology fraternity. The labor-intensive pathology protocol with serial step sectioning and immunohistochemistry poses a challenge to the feasibility at a high-volume center. This perspective discusses these limitations and propose plausible solutions to the conundrum. To make it widely applicable and feasible across the globe efforts should be directed to understand biology better, find novel solutions, and implement the lessons learned over decades from other sites.

Giant cell tumor of hyoid bone: Diagnostic dilemma with a novel management.

Giant cell tumor of bone (GCTB) is locally aggressive tumor occurring in the epiphysis of long bones. GCTBs are uncommon tumors in the head-and-neck region and rarely involve hyoid bone. We report a case of GCTB of hyoid bone. The patient presented with swelling in left submandibular region. The tumor was surgically excised after initial denosumab therapy. Despite adequate resection and rehabilitation, he was tube dependent. Subsequently it was found that the patient had a coexisting myotonic dystrophy, unknown to exist with GCTB of hyoid. Eventually, the patient succumbed to respiratory failure secondary to myotonic dystrophy. GCTB hyoid is a rare presentation posing a diagnostic dilemma. Ours is the first case to report the use of denosumab for GCT in head-and-neck region. Myotonic dystrophy Type I and GCTB are both known to result from abnormality of closely situated foci on chromosome 19.

STROCSS 2021: Strengthening the reporting of cohort, cross-sectional and case-control studies in surgery.

INTRODUCTION: Strengthening The Reporting Of Cohort Studies in Surgery (STROCSS) guidelines were developed in 2017 in order to improve the reporting quality of observational studies in surgery and updated in 2019. In order to maintain relevance and continue upholding good reporting quality among observational studies in surgery, we aimed to update STROCSS 2019 guidelines. METHODS: A STROCSS 2021 steering group was formed to come up with proposals to update STROCSS 2019 guidelines. An expert panel of researchers assessed these proposals and judged whether they should become part of STROCSS 2021 guidelines or not, through a Delphi consensus exercise. RESULTS: 42 people (89%) completed the DELPHI survey and hence participated in the development of STROCSS 2021 guidelines. All items received a score between 7 and 9 by greater than 70% of the participants, indicating a high level of agreement among the DELPHI group members with the proposed changes to all the items. CONCLUSION: We present updated STROCSS 2021 guidelines to ensure ongoing good reporting quality among observational studies in surgery.

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 hidden curve behind COVID-19 outbreak: the impact of delay in treatment initiation in cancer patients and how to mitigate the additional risk of dying-the head and neck cancer model.

PURPOSE: The rapid spread of the SARS-CoV-2 pandemic around the world caused most healthcare services to turn substantial attention to treatment of these patients and also to alter the structure of healthcare systems to address an infectious disease. As a result, many cancer patients had their treatment deferred during the pandemic, increasing the time-to-treatment initiation, the number of untreated patients (which will alter the dynamics of healthcare delivery in the post-pandemic era) and increasing their risk of death. Hence, we analyzed the impact on global cancer mortality considering the decline in oncology care during the COVID-19 outbreak using head and neck cancer, a known time-dependent disease, as a model. METHODS: An online practical tool capable of predicting the risk of cancer patients dying due to the COVID-19 outbreak and also useful for mitigation strategies after the peak of the pandemic has been developed, based on a mathematical model. The scenarios were estimated by information of 15 oncological services worldwide, given a perspective from the five continents and also some simulations were conducted at world demographic data. RESULTS: The model demonstrates that the more that cancer care was maintained during the outbreak and also the more it is increased during the mitigation period, the shorter will be the recovery, lessening the additional risk of dying due to time-to-treatment initiation. CONCLUSIONS: This impact of COVID-19 pandemic on cancer patients is inevitable, but it is possible to minimize it with an effort measured by the proposed model.

Masseter Flap for Reconstruction of Defects After Excision of Buccal Mucosa Cancers with Intact Mandible.

Among the reconstructive options available for buccal mucosa defects with an intact mandible, free flap with microvascular anastomosis is the best option. However, in the developing world, with poor resources, limited in- frastructure, and high patient load, this cannot be offered to all patients. We report on the success of the masseter flap for reconstruction of such defects in carefully selected patients. Despite some known limitations, this flap is easy to learn and carries acceptable complications. The results of this flap may not be comparable to those of microvas- cular reconstructions, but they are better than those from other options such as skin graft, nasolabial flap, submental flap, etc. in terms of surgical time required, no donor site morbidity, and minimal aesthetic deformity.

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.

Nimotuzumab-cisplatin-radiation versus cisplatin-radiation in HPV negative oropharyngeal cancer.

BACKGROUND: Addition of nimotuzumab to weekly cisplatin and radiation improves outcomes in head and neck cancer. HPV negative oropharyngeal cancer has unsatisfactory treatment outcomes and is a candidate for escalation of treatment. We wanted to determine whether the addition of nimotuzumab to cisplatin-radiation could improve outcomes in these poor-risk tumors. METHODS: This was a subgroup analysis of a phase 3 randomized study. In this study, locally advanced head and neck cancer patients undergoing definitive chemoradiation were randomly allocated to weekly cisplatin (30 mg/m2 IV)- radiation (66-70 Gy) {CRT arm} or nimotuzumab (200 mg weekly) -weekly cisplatin (30 mg/m2)-radiation (66-70 Gy) {NCRT arm}. The data of HPV negative oropharyngeal cancer was extracted from the database of this study for the analysis. HPV testing was done with p16 immunohistochemistry (IHC) staining and reported according to the CAP criteria. The outcomes assessed were progression-free survival (PFS), disease-free survival (DFS), locoregional control, and overall survival (OS). Interaction test was performed between the study arms and HPV status prior to doing any HPV specific analysis for each of the studied outcomes. Kaplan Meier estimates for 2 year OS with 95%CI was calculated. The hazard ratio was obtained using COX regression analysis. RESULTS: We had 187 HPV negative oropharyngeal cancers, 91 in the CRT arm and 96 in NCRT arm. The interaction test was significant for PFS (p = 0.000), locoregional control (p = 0.007) and overall survival (p = 0.002) but not for DFS (p = 0.072). The 2- year PFS was 31.5% (95%CI 21.5-42) in CRT arm versus 57.2% (95%CI 45.8-67.1) in NCRT arm (HR -0.54; 95%CI 0.36-0.79, p = 0.002). The 2-year LRC was 41.4% (95%CI 29.8-52.6) in the CRT arm versus in 60.4% (95%CI 48.7-70.2) in the NCRT arm (HR -0.61; 95%CI 0.4-0.94, p = 0.024). The addition of nimotuzumab also lead to an improvement in 2-year OS from 39.0% (95%CI 28.4-49.6) to 57.6% (95%CI 46.3-67.4) (HR-0.63, 95%CI 0.43-0.92, p = 0.018). CONCLUSIONS: The addition of nimotuzumab to weekly cisplatin-radiation improves outcomes inclusive of OS in HPV negative oropharyngeal cancers.

Salvage surgery in head and neck cancer: Does it improve outcomes?

BACKGROUND: Studies reporting outcomes of salvage surgery in locally advanced head and neck squamous cell carcinoma (LAHNSCC) have inherent biases like biological and temporal selection. Our study considered all patients deemed fit for salvage surgery and compared to those who underwent surgery versus those who refused it thus throwing light on the real world benefit of salvage surgery. METHODS: This was a post hoc analysis of a phase 3 randomized trial conducted between 2012 and 2018. Out of 536 LAHNSCC patients randomised in the study, 113 patients had residual disease or recurrent disease and were planned for salvage surgery in a multidisciplinary clinic. Patients were divided into 2 cohorts for comparison, willing for salvage surgery (n = 91) and unwilling for salvage surgery(n = 22). The primary endpoint was overall survival. RESULTS: The median follow up was 28.7 months (95%CI 23.9-33.5 months). Out of the 91 patients who were willing for salvage surgery, 78 underwent same. The median survival in cohort of patients willing for salvage surgery was 22.0 months (95%CI 10.1-33.9) while it was 9.7 months (95%CI 6.6-12.8) in patients who were unwilling for salvage surgery (HR = 0.262 95%CI HR 0.147-0.469, p = 0.000). CONCLUSION: Salvage surgery leads to a substantial improvement in outcomes in head and neck cancers and should be the de facto standard of care in patients who are eligible for the same.

Myeloid-derived suppressor cells impede T cell functionality and promote Th17 differentiation in oral squamous cell carcinoma.

Oral tumor microenvironment is characterized by chronic inflammation signified with infiltrating leukocytes and soluble mediators which cause immune suppression. However, how immunosuppressive cells like myeloid-derived suppressor cells (MDSCs) maintain the immunosuppressive tumor microenvironment and influence T cell function in oral squamous cell carcinoma (OSCC) patients remains poorly understood. In the present study, we found that percentages of MDSCs were higher in oral cancer patients compared to healthy individuals and correlated with cancer stage. Monocytic MDSCs (M-MDSCs) were prevalent in the periphery, while granulocytic/polymorphonuclear subset dominated the tumor compartment. M-MDSCs suppressed the lymphocyte proliferation and decreased the CD3-ζ (zeta) chain expression and interferon gamma production. The percentage of M-MDSCs in peripheral blood correlated inversely with CD3-ζ chain expression in T cells of these patients. Interleukin 6 (IL-6)-induced phosphorylated STAT3-regulated programmed cell death ligand 1, CCAAT/enhancer-binding proteins alpha and beta and Interleukin 10 expression in MDSCs. MDSCs inhibited TGF-ß-driven generation of induced regulatory T cells in vitro. M-MDSCs secreted interleukins IL-6, IL-1ß, IL-23 and PGE2 and facilitated T-helper 17 (Th17) cell differentiation which utilizes nitric oxide synthase and cyclooxygenase 2 enzyme activity. Interestingly, OSCC patients showed increased levels of Th17 cells in peripheral blood and tumor tissue. Thus, increased frequency of MDSCs, Th17 cells and decreased expression of CD3-ζ chain portray T cell tolerance and chronic inflammatory state facilitating tumor growth.

A randomized phase 3 trial comparing nimotuzumab plus cisplatin chemoradiotherapy versus cisplatin chemoradiotherapy alone in locally advanced head and neck cancer.

BACKGROUND: Because the addition of nimotuzumab to chemoradiation in patients with locally advanced head and neck cancer improved outcomes in a phase 2 study, the authors conducted a phase 3 study to confirm these findings. METHODS: This open-label, investigator-initiated, phase 3, randomized trial was conducted from 2012 to 2018. Adult patients with locally advanced head and neck cancer who were fit for radical chemoradiation were randomized 1:1 to receive either radical radiotherapy (66-70 grays) with concurrent weekly cisplatin (30 mg/m2 ) (CRT) or the same schedule of CRT with weekly nimotuzumab (200 mg) (NCRT).The primary endpoint was progression-free survival (PFS); key secondary endpoints were disease-free survival (DFS), duration of locoregional control (LRC), and overall survival (OS). An intent-to-treat analysis also was performed. RESULTS: In total, 536 patients were allocated equally to both treatment arms. The median follow-up was 39.13 months. The addition of nimotuzumab improved PFS (hazard ratio [HR], 0.69; 95% CI, 0.53-0.89; P = .004), LRC (HR, 0.67; 95% CI, 0.50-0.89; P = .006), and DFS (HR, 0.71; 95% CI, 0.55-0.92; P = .008) and had a trend toward improved OS (HR, 0.84; 95% CI, 0.65-1.08; P = .163). Grade 3 through 5 adverse events were similar between the 2 arms, except for a higher incidence of mucositis in the NCRT arm (66.7% vs 55.8%; P = .01). CONCLUSIONS: The addition of nimotuzumab to concurrent weekly CRT improves PFS, LRC, and DFS. This combination provides a novel alternative therapeutic option to a 3-weekly schedule of 100 mg/m2 cisplatin in patients with locally advanced head and neck cancer who are treated with radical-intent CRT.

Lymph node metastasis in oral cancer is strongly associated with chromosomal instability and DNA repair defects.

Oral squamous cell carcinoma (OSCC) is highly prevalent in south and southeast Asia. Many (30-50%) OSCC patients develop lymph node metastasis (LNM), which is the most important prognostic factor in OSCC. To identify genomic correlates of LNM, we compared exome sequences and copy number variation data of blood and tumor DNA from highly contrasting subgroups of patients to reduce false inferences-(i) patients with LNM and (ii) patients with late stage disease but without LNM. We found that LNM is associated with (i) specific hotspot somatic mutations in TP53 and CASP8; (ii) rare nonsilent germline mutations in BRCA2 and FAT1; (iii) mutations in mito-G2/M and nonhomologous end joining (NHEJ) pathways; (iv) recurrent deletion of genes for DNA repair by homologous recombination; and (v) chromosomal instability. LN+ patients with NHEJ pathway mutations have longer disease-free survival. Five genomic features have a high predictive value of LNM.