Implications of cancer stem cells in developing therapeutic resistance in oral cancer

Publication date: November 2016
Source:Oral Oncology, Volume 62
Author(s): Prajna Paramita Naik, Durgesh Nandini Das, Prashanta Kumar Panda, Subhadip Mukhopadhyay, Niharika Sinha, Prakash Priyadarshi Praharaj, Rajesh Agarwal, Sujit Kumar Bhutia
Conventional therapeutics are often frequented with recurrences, refraction and regimen resistance in oral cavity cancers which are predominantly manifested by cancer stem cells (CSCs). During oncoevolution, cancer cells may undergo structural and functional reprogramming wherein they evolve as highly tolerant CSC phenotypes with greater survival advantages. The CSCs possess inherent and exclusive properties including self-renewal, hierarchical differentiation, and tumorigenicity that serve as the basis of chemo-radio-resistance in oral cancer. However, the key mechanisms underlying the CSC-mediated therapy resistance need to be further elucidated. A spectrum of dysfunctional cellular pathways including the developmental signaling, apoptosis, autophagy, cell cycle regulation, DNA damage responses and epigenetic regulations protect the CSCs from conventional therapies. Moreover, tumor niche shelters CSCs and creates an immunosuppressive environment favoring the survival of CSCs. Maintenance of lower redox status, epithelial-to-mesenchymal transition (EMT), metabolic reprogramming and altered drug responses are the accessory features that aid in the process of chemo-radio-resistance in oral CSCs. This review deals with the functional and molecular basis of cancer cell pluripotency-associated resistance highlighting the abrupt fundamental cellular processes; targeting these events may hold a great promise in the successful treatment of oral cancer.



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Clinical implications of the extent of BRAFV600E alleles in patients with papillary thyroid carcinoma

Publication date: November 2016
Source:Oral Oncology, Volume 62
Author(s): Lihua Liu, Jae Won Chang, Seung-Nam Jung, Hee Sung Park, Taejeong Oh, Young Chang Lim, Bon Seok Koo
ObjectiveThere are many conflicting reports about the clinical implications of BRAF^V600E in papillary thyroid cancer (PTC). We investigated the associations between the extent of BRAF^V600E alleles and both clinico-pathological features and recurrence of PTC.Materials and methodsCarcinoma tissues from 60 patients with PTC were genotyped for BRAF^V600E using pyrosequencing, and the clinico-pathological factors and disease outcomes of the patients were examined. The associations between the extent of mutant BRAF alleles and both clinico-pathological parameters and recurrence-free survival (RFS) were analyzed.ResultsThe BRAF^V600E mutation was detected in 66.7% (40/60) of our PTC patients. When we defined four groups on the basis of the extent of BRAF^V600E alleles by pyrosequencing—negative (less than 5%), low (5 – less than 15%), intermediate (15 – less than 25%), and high (25% or greater)— the four groups showed statistically significant differences regarding lymph node (LN) metastasis and recurrence (P<0.05). However, age, gender, tumor size, multicentricity, capsular invasion, and lymphovascular invasion were not significantly different among the groups. The 10-year RFS rates in PTC patients with greater than 25% and less than 25% mutated BRAF alleles were 74% and 100%, respectively. This difference was significant (P=0.043).ConclusionsA high extent more than 25% of BRAF^V600E alleles may be associated with disease outcome in PTC patients. We need more data to verify a hypothesis that the extent of BRAF mutations may be clinically informative in the management of PTC, such as by tailoring proper surgical and radioactive iodine treatments and determining appropriate management during follow-up.



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Optimize the cycle of neoadjuvant chemotherapy for locoregionally advanced nasopharyngeal carcinoma treated with intensity-modulated radiotherapy: A propensity score matching analysis

Publication date: November 2016
Source:Oral Oncology, Volume 62
Author(s): Hao Peng, Lei Chen, Wen-Fei Li, Yuan Zhang, Li-Zhi Liu, Li Tian, Ai-Hua Lin, Ying Sun, Jun Ma
ObjectivesThe aim of this study is to optimize the cycle for patients with locoregionally advanced nasopharyngeal carcinoma (NPC) receiving neoadjuvant chemotherapy (NCT) in the era of intensity-modulated radiotherapy (IMRT).Materials and methodsData on 569 locoregionally advanced NPC patients treated with IMRT were retrospectively reviewed. Propensity score matching (PSM) method was adopted to balance prognostic factors and match patients. Survival outcomes of matched patients between different NCT cycle groups were compared.ResultsThe median cycle of NCT was 2 (range, 2–4 cycles) for the whole cohort, and patients were therefore stratified as low cycle (=2) and high cycle (>2) groups. In total, 247 pairs of NPC patients were selected by PSM. Univariate analysis found no significantly prognostic difference between the low cycle and high cycle groups, and multivariate analysis did not establish NCT cycle as an independent factor. However, stratified analysis revealed patients in the low cycle group had better OS than those of patients in the high cycle group (92.4% vs. 80.8%, P=0.029), and NCT was identified as an independent prognostic factor for OS in patients with N2-3 category (HR, 2.252; 95% CI, 1.024–4.953; P=0.043).ConclusionTwo cycles of NCT may be enough and additional more cycles are not associated with improved survival outcomes for patients with locoregionally advanced NPC in the era of IMRT.



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Free flap outcome of salvage surgery compared to primary surgery for head and neck defects: A propensity score analysis

Publication date: November 2016
Source:Oral Oncology, Volume 62
Author(s): Chung-Hwan Baek, Woori Park, Nayeon Choi, Seonhye Gu, Insuk Sohn, Man Ki Chung
ObjectivesTo compare free flap outcomes for head and neck defects between primary surgery and salvage surgery and identify factors affecting the outcomes in the two settings.MethodsA total of 225 patients (primary group, n=56; salvage group, n=169) were retrospectively identified. The salvage group was previously treated with radiotherapy, chemoradiation, surgery, or any combination of these treatments. Clinical data were retrieved and analyzed between the two groups to compare the incidence and contributing factors of flap-related complications and flap failure. A propensity score analysis with matching T stage, defect, and flap types was also performed for unbiased comparisons.ResultsFlap-related complication rate was 22.2% in all patients. The salvage group showed higher rates of wound dehiscence than the primary group (3.6% in primary vs. 13.0% in salvage; p=0.04). Flap failures occurred in 10 patients (4.4%), including 3 (5.4%) in the primary group and 7 (4.1%) in the salvage group (p=0.71). Multivariate analysis showed no critical factor that influenced the occurrence of flap-related complications or flap failure, including surgery type (primary or salvage). In propensity score analysis, incidences and types of flap-related complications and flap failure were not statistically different between the two groups (primary and salvage).ConclusionsFree flap reconstruction is a safe and reliable method to restore the ablative defects in previously irradiated or operated head and neck defects.



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Risk factors for radiation failure in early-stage glottic carcinoma: A systematic review and meta-analysis

Publication date: November 2016
Source:Oral Oncology, Volume 62
Author(s): Görkem Eskiizmir, Yasemin Baskın, Femin Yalçın, Hülya Ellidokuz, Robert L. Ferris
BackgroundRadiotherapy is one of the main treatment modalities for early-stage glottic carcinoma. Unfortunately, local failure may occur in a group of cases with T1-T2 glottic carcinoma. This meta-analysis sought to determine risk factors for radiation failure in patients with early-stage glottic carcinoma.MethodsA systematic and comprehensive search was performed for related studies published between 1995 and 2014. The primary end-point was 5-year local control. Data extraction and analysis were performed using the software STATA/SE 13.1 for Windows.ResultsTwenty-seven studies were eligible. A higher risk of radiation failure was demonstrated in male patients [relative risk (RR): 0.927, p<0.001] and those with low hemoglobin level (RR: 0.891, p<0.001) with a high agreement between studies (I-squared=0.0%). Moreover, T2 tumors (RR: 0.795, p<0.001), tumors with anterior commissure involvement (RR: 0.904, p<0.001), tobacco use during/after therapy (RR: 0.824, p<0.001), and "bulky" tumors (RR: 1.270, p<0.001] or tumors bigger in size (RR: 1.332, p<0.001]. Poorly differentiated tumors had a questionable risk of local failure, although a moderate to high interstudy heterogeneity was determined. A statistically significant contribution was not detected for age, presence of comorbidity, alcohol use or subglottic extension.ConclusionThis is the first meta-analysis which assessed the potential risk factors for radiation failure in patients with early-stage glottic carcinoma. Gender and pretreatment hemoglobin level are major influential factors associated with radiation failure in patients with early-stage glottic carcinoma. However, prospective, randomized clinical trials may permit better stratification of their relative contributions, and those who may benefit more from upfront surgery.



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Diagnosis of HPV driven oropharyngeal cancers: Comparing p16 based algorithms with the RNAscope HPV-test

Publication date: November 2016
Source:Oral Oncology, Volume 62
Author(s): Haïtham Mirghani, Odile Casiraghi, Joanne Guerlain, Furrat Amen, Ming-Xiao He, Xiao-Jun Ma, Yuling Luo, Céline Mourareau, Françoise Drusch, Aïcha Ben Lakdhar, Antoine Melkane, Lacau St Guily, Cécile Badoual, Jean Yves Scoazec, Isabelle Borget, Anne Aupérin, Veronique Dalstein, Philippe Vielh
BackgroundAccurate identification of HPV-driven oropharyngeal cancer (OPC) is a major issue and none of the current diagnostic approaches is ideal. An in situ hybridization (ISH) assay that detects high-risk HPV E6/E7 mRNA, called the RNAscope HPV-test, has been recently developed. Studies have suggested that this assay may become a standard to define HPV-status.MethodsTo further assess this test, we compared its performance against the strategies that are used in routine clinical practice: p16 immunohistochemistry (IHC) as a single test and algorithms combining p16-IHC with HPV-DNA identification by PCR (algorithm-1) or ISH (algorithm-2).Results105 OPC specimens were analyzed. The prevalence of HPV-positive samples varied considerably: 67% for p16-IHC, 54% for algorithm-1, 61% for algorithm-2 and 59% for the RNAscope HPV-test. Discrepancies between the RNAscope HPV-test and p16-IHC, algorithm-1 and 2 were noted in respectively 13.3%, 13.1%, and 8.6%.The 4 diagnostic strategies were able to identify 2 groups with different prognosis according to HPV-status, as expected. However, the greater survival differential was observed with the RNAscope HPV-test [HR: 0.19, 95% confidence interval (CI), 0.07–0.51, p=0.001] closely followed by algorithm-1 (HR: 0.23, 95% CI, 0.08–0.66, p=0.006) and algorithm-2 (HR: 0.26, 95% CI, 0.1–0.65, p=0.004). In contrast, a weaker association was found when p16-IHC was used as a single test (HR: 0.33, 95% CI, 0.13–0.81, p=0.02).ConclusionsOur findings suggest that the RNAscope HPV-test and p16-based algorithms perform better that p16 alone to identify OPC that are truly driven by HPV-infection. The RNAscope HPV-test has the advantage of being a single test.



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Lateral lymph node recurrence after total thyroidectomy and central neck dissection in patients with papillary thyroid cancer without clinical evidence of lateral neck metastasis

Publication date: November 2016
Source:Oral Oncology, Volume 62
Author(s): Young Chang Lim, Lihua Liu, Jae Won Chang, Bon Seok Koo
BackgroundThis study analyzed the incidence, pattern, and predictive factors for lateral lymph node (LN) recurrence in patients with papillary thyroid cancer (PTC) without clinical evidence of lateral LN metastasis.MethodsA retrospective analysis was performed on 246 patients with PTC who underwent total thyroidectomy and central neck dissection from 2004 to 2010. None of the patients had clinical evidence of lateral LN metastasis at the time of diagnosis. Predictive factors for lateral LN recurrence were evaluated using the chi-square test. Binary logistic regression was used for the multivariate analysis. Recurrence-free survival rates were estimated by the Kaplan–Meier and Cox regression methods.ResultsOf the 246 patients, 11 (4.5%) developed lateral LN recurrence with a median follow-up of 49months. In the multivariate analysis, tumor size >1cm (odds ratio [OR], 8.14; 95% confidence interval [CI], 1.01–65.68; p=0.049) and central LN metastasis (OR, 10.59; 95% CI, 1.32–85.17; p=0.026) were independent predictive factors of lateral LN recurrence. Especially, extranodal extension of a metastatic central LN (OR, 38.82; 95% CI, 5.71–264.10; p<0.001) was an independent predictor of lateral LN recurrence.ConclusionsTumor size and central LN metastasis were independent predictors of lateral LN recurrence in patients with PTC without initial clinical lateral neck metastasis who underwent total thyroidectomy and central neck dissection. Close surveillance may be necessary for early detection of lateral LN recurrence in PTC patients with tumor size ⩾1cm, and central LN metastasis with extranodal extension.



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