Oral Oncology

Oral Oncology

Trimodality therapy for HPV-positive oropharyngeal cancer: A population-based study: Trimodality therapy for HPV+u202fOPC

20-09-2019 – Nina N. Sanford, William L. Hwang, Luke R.G. Pike, Allen C. Lam, Trevor J. Royce, Brandon A. Mahal

Journal Article

Background

Although HPV status is a well-established prognostic factor in oropharyngeal squamous cell carcinoma (OPSCC), approximately 20% of HPV-positive patients die from their disease. We therefore sought to ascertain whether there is a benefit to trimodality therapy with surgery among patients with locally advanced (LA) disease receiving chemoradiation.

Methods

The SEER Head and Neck with HPV Status Database identified adult patients with non-metastatic OPSCC between 2013 and 2014 with known HPV status who received chemoradiation as part of definitive treatment. The primary outcome was cancer-specific mortality (CSM) for locally-advanced (LA) (T3-T4, or N2-N3, per AJCC 7) versus early-stage (ES) (T1-T2 and N0-N1) disease, stratified by HPV status. The secondary outcome was overall survival (OS).

Results

Among 2974 patients who met study criteria, 671 patients (22.6%) received upfront surgery (trimodality therapy). In the LA setting, there was a significant reduction in CSM with trimodality therapy compared to chemoradiation alone in HPV-positive (Adjusted Hazard Ratio AHR 0.19, 95% Confidence Interval CI 0.04–0.80; P = 0.024), but not HPV-negative disease Pinteraction = 0.04. There was no benefit to trimodality therapy for ES disease, regardless of HPV status. There was also an improvement in OS with trimodality therapy for HPV-positive LA patients (AHR = 0.28, p = 0.006, 95% CI = 0.11–0.70). In contrast, trimodality therapy was not associated with improved OS for HPV-negative patients regardless of stage.

Conclusions

HPV status may predict for improved outcomes with surgery/trimodality therapy in LA OPSCC. Our findings support prospective investigations to optimize care for the subset of HPV-positive patients who are at greatest risk of cancer death, where trimodality therapy may be appropriate.

Setting the stage: Contemporary staging of non-melanomatous skin cancer and implementation of the new American Joint Committee on cancer eighth edition staging manual

02-10-2019 – Georgina Casswell, Karda Cavanagh, Aravind S. Ravi Kumar, Charles Giddings, Lachlan McDowell

Journal Article

Non-melanomatous skin cancer (NMSC) generally refers to basal cell and squamous cell carcinoma of the skin. The majority of patients are curatively treated with simple excision. Only few present with locally advanced disease or have evidence of high-risk features, placing them at an elevated risk of relapse. In such cases, further investigations may guide the multidisciplinary management plan. There are no universally agreed on indications for recommending additional staging investigations, due to a lack of prospective data reporting their impact on patient outcomes. Some generally agreed upon indications are discussed in this review article. Most commonly, computed tomography (CT) and magnetic resonance imaging (MR) are used in cases of locally advanced NMSC for staging purposes and surgical planning. While Positron Emission Tomography (PET)/CT and sentinel lymph node biopsy have shown utility, data is lacking to establish their roles in the staging algorithm. An updated NMSC system was included in The American Joint Committee for Cancer eighth edition staging manual (AJCC8). Under AJCC8 the majority of patients with regional disease are upstaged by the presence of extranodal extension, however, this updated system appears to provide limited prognostic discrimination between the nodal categories and the overall TNM stages. This review article will explore the contemporary role of staging investigations, including evolving technologies, and review the changes implemented in AJCC8. It will also discuss the implications of the AJCC8 decision to assign patients with p16-positive cervical nodal SCC with an unknown primary to the oropharyngeal staging system, with particular relevance to clinicians working in areas of high NMSC incidence.

MYB-activated models for testing therapeutic agents in adenoid cystic carcinoma

14-10-2019 – Yue Jiang, Ruli Gao, Chunxia Cao, Lauren Forbes, Jianping Li, Shelby Freeberg, Kristianna M. Fredenburg, Jeb M. Justice, Natalie L. Silver, Lizi Wu, Sushama Varma, Robert West, Jonathan D. Licht, Maria Zajac-Kaye, Alex Kentsis, Frederic J. Kaye

Journal Article

Objective

There are no effective systemic therapies for adenoid cystic cancer (ACC) and lack of tumor lines and mouse models have hindered drug development. We aim to develop MYB-activated models for testing new therapeutic agents.

Materials and methods

We studied new ACC patient-derived xenograft (PDX) models and generated a matched cell line from one patient. In addition, we generated a genetically-engineered MYB-NFIB mouse model (GEMM) that was crossed with Ink4a+//Arf+/ mice to study tumor spectrum and obtain tumor lines. Using human and murine ACC-like tumor lines, we analyzed MYB expression by RNA-Seq and immunoblot and tested efficacy of new MYB inhibitors.

Results

We detected MYB-NFIB transcripts in both UFH1 and UFH2 PDX and observed tumor inhibition by MYB depletion using sh
RNA in vivo. We observed rapid loss of MYB expression when we cultured UFH1 in vitro, but were able to generate a UFH2 tumor cell line that retained MYB expression for 6 months. RNA-Seq expression detected an ACC-like m
RNA signature in PDX samples and we confirmed an identical KMT2A/MLL variant in UFH2 PDX, matched cell line, and primary biopsy. Although the predominant phenotype of the MYB-NFIB GEMM was B-cell leukemia, we also generated a MYB-activated ACC-like mammary tumor cell line. We observed tumor inhibition using a novel MYB peptidomimetic in both human and murine tumor models.

Conclusions

We generated and studied new murine and human MYB-activated tumor samples and detected growth inhibition with MYB peptidomimetics. These data provide tools to define treatment strategies for patients with advanced MYB-activated ACC.

Validation of the 8th edition of AJCC/UICC staging system for nasopharyngeal carcinoma: Results from a non-endemic cohort with 10-year follow-up

07-10-2019 – Li-Rong Wu, Xiu-Ming Zhang, Xiao-Dong Xie, Yue Lu, Jian-Feng Wu, Xia He

Journal Article

Objectives

This study aimed to validate the 8th edition of American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) TNM staging system for nasopharyngeal carcinoma (NPC) in non-endemic region.

Materials and methods

We recruited 607 patients with histology-proven, previously untreated, non-metastatic NPC treated by intensity-modulated radiotherapy (IMRT) at our center. Harrell’s concordance index (c-index) and Akaike information criterion (AIC) were applied to compare the prognostic discrimination between the 7th and 8th edition staging system.

Results

For T category, the local recurrence-free survival (LRFS) Kaplan-Meier curves of T1, T2 and T3 were well separated in the 8th edition; however, LRFS did not significantly differ between T3 and T4 (P = 0.166). Moreover, the 7th edition achieved higher c-index (0.702 95% CI, 0.618–0.787 vs. 0.685 95% CI, 0.604–0.767) and lower AIC (766.1 vs. 770.8) than 8th edition for LRFS. With regard to N category, the 8th edition achieved higher c-index (0.796 95% CI, 0.749–0.843 vs. 0.751 95% CI, 0.696–0.805) and lower AIC (1439.4 vs. 1471.9) for distant metastasis-free survival. In terms of overall stage, the 8th edition also had higher c-index (0.798 95% CI, 0.753–0.844 vs. 0.721 95% CI, 0.672–0.770) and lower AIC (1963.9 vs. 2007.2) compared with the 7th edition for overall survival. Furthermore, interval validation by bootstrapping the sample randomly for ~100–1000 times also validated above findings.

Conclusion

The 8th edition of AJCC/UICC TNM staging system achieved significantly better prognostic discrimination than the 7th edition with regard to N category and overall stage but not T category.

Clinical outcome and toxicity after simultaneous integrated boost IMRT in head and neck squamous cell cancer patients

07-10-2019 – Tatiana Dragan, Sylvie Beauvois, Michel Moreau, Marianne Paesmans, Christophe Vandekerkhove, Lionel Cordier, Dirk Van Gestel

Journal Article

Introduction

A simultaneous integrated boost (SIB) intensity modulated radiotherapy (IMRT) in patients with head and neck squamous cell carcinoma (HNSCC) allows to irradiate different target volumes to different dose levels within a single treatment session without increasing the toxicity.

Aim

To analyze the outcome and toxicity of patients treated by definitive or postoperative SIB IMRT for HNSCC.

Material and methods

106 patients with HNSCC of the oral cavity (OC), oropharynx (OP), larynx (L) and hypopharynx (HP), consecutively treated at our cancer center between 3/2012 and 3/2014 were retrospectively analyzed. The prescribed SIB IMRT doses were in the postoperative setting (group A) 60–66 Gy and 53 Gy in 30–33 fractions for PTV high risk and PTV elective, respectively; and 70 Gy and 56 Gy in 35 fractions for PTV high risk and PTV elective, respectively when given as primary treatment (group B). Toxicity was consistently graded according to RTOG/EORTC scale.

Results

Median follow-up duration was 31 months. Thirty (28%) patients were postoperatively irradiated (group A) and 76 (72%) patients received definitive IMRT (group B).

At 3 years, loco-regional control, distant control and overall survival were 78%, 78%, 57% and 64%, 76%, 52% in the postoperative (group A) and the definitive SIB IMRT group (group B), respectively. The observed acute grade 3 toxicities were dysphagia (44%), oral and/or oropharyngeal mucositis (40%) and dermatitis (21%). Late toxicity was predominantly clinically significant xerostomia (42%), dysgeusia (23%) and dysphagia (8%).

Conclusion

SIB IMRT is feasible, safe and effective in the treatment of HNSCC patients.

Lymph node yield, depth of invasion, and survival in node-negative oral cavity cancer

07-10-2019 – Joseph Zenga, Vasu Divi, Michael Stadler, Becky Massey, Bruce Campbell, Monica Shukla, Musaddiq Awan, Christopher J. Schultz, Aditya Shreenivas, Stuart Wong, Ryan S. Jackson, Patrick Pipkorn

Journal Article

Objective

To determine the effects of nodal yield on survival in early stage oral cavity squamous cell carcinoma (OCSCC) in the context of primary tumor depth of invasion (DOI).

Materials and methods

Patients with early-stage clinically node-negative OCSCC who underwent upfront surgery at the primary site were identified using the National Cancer Database between 2004 and 2015.

Results

There were 3384 patients with <4 mm DOI and 1387 patients with ≥4 mm DOI identified. Management of the neck included observation (40%), END with <18 nodes harvested ± postoperative radiation (ND < 18, 16%), and END with ≥18 nodes harvest ± postoperative radiation (ND ≥ 18, 44%). When adjusted for relevant covariates, ND ≥ 18 demonstrated statistically significant improvements in overall survival for both DOI < 4 mm and ≥4 mm (DOI < 4 mm: HR 0.67, 95%CI 0.54–0.85; DOI ≥ 4 mm: HR 0.47, 95%CI 0.34–0.64). However, ND < 18 showed no significant difference from observation of the neck regardless of DOI (DOI < 4 mm: HR 0.82, 95%CI 0.63–1.07; DOI ≥ 4 mm: HR 0.72, 95%CI 0.51–1.03). Of patients undergoing END, the most significant factors associated with obtaining a nodal yield of 18 or more were age less than 40 years (HR 2.58, 95%CI 1.84–3.63) and treatment at an academic facility (HR 2.47, 95%CI 2.06–2.96).

Conclusions

END with 18 or more nodes is associated with improved survival outcomes in patients with early stage OCSCC regardless of DOI. END with less than 18 nodes, however, does not appear significantly different than observation of the neck alone. Achieving a lymph node yield of 18 or more is multifactorial and includes both patient and provider factors.

Leading edge or tumor core: Intratumor cancer stem cell niches in oral cavity squamous cell carcinoma and their association with stem cell function

07-10-2019 – Farshad N. Chowdhury, Julie Reisinger, Karina E. Gomez, Tugs-Saikhan Chimed, Carissa M. Thomas, Phuong N. Le, Bettina Miller, John J. Morton, Cera M. Nieto, Hilary L. Somerset, Xiao-Jing Wang, Stephen B. Keysar, Antonio Jimeno

Journal Article

Objectives

To describe differences in cancer stem cell (CSC) presence and behavior associated with their intratumor compartment of origin using a patient-derived xenograft (PDX) model of oral cavity squamous cell carcinoma (OCSCC).

Materials and methods

Four HPV-negative OCSCC PDX cases were selected (CUHN004, CUHN013, CUHN096, CUHN111) and the percentage of CSCs (ALDH+CD44high) was measured in the tumor Leading Edge (LE) and Core compartments of each PDX tumor case via fluorescence activated cell sorting (FACS). The fraction of cells in the proliferative phase was measured by Ki-67 labelling index of paraffin embedded tissue. The proliferation and invasion of LE versus Core CSCs were compared using sphere and Matrigel invasion assays, respectively.

Results

Both CUHN111 and CUHN004 demonstrate CSC enrichment in their LE compartments while CUHN013 and CUHN096 show no intratumor difference. Cases with LE CSC enrichment demonstrate greater Ki-67 labelling at the LE. CSC proliferative potential, assessed by sphere formation, reveals greater sphere formation in CUHN111 LE CSCs, but no difference between CUHN013 LE and Core CSCs. CUHN111 CSCs do not demonstrate an intratumor difference in invasiveness while CUHN013 LE CSCs are more invasive than Core CSCs.

Conclusion

A discrete intratumor CSC niche is present in a subset of OCSCC PDX tumors. The CSC functional phenotype with regard to proliferation and invasion is associated with the intratumor compartment of origin of the CSC: LE or Core. These individual functional characteristics appear to be modulated independently of one another and independently of the presence of an intratumor CSC niche.

A multidimensional nomogram combining overall stage, dose volume histogram parameters and radiomics to predict progression-free survival in patients with locoregionally advanced nasopharyngeal carcinoma

01-10-2019 – Kaixuan Yang, Jiangfang Tian, Bin Zhang, Mei Li, Wenji Xie, Yating Zou, Qiaoyue Tan, Lihui Liu, Jinbing Zhu, Arthur Shou, Guangjun Li

Journal Article

Objectives

To develop a multidimensional nomogram for predicting the progression-free survival (PFS) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) (stage III-IVa).

Materials and methods

A total of 224 patients with locoregionally advanced NPC (training cohort, n = 149; validation cohort, n = 75) were retrospectively included. We extracted 260 radiomic features from the primary tumor and lymph nodes on the axial contrast-enhanced T1 weighted and T2 weighted MRI. Radiomic signatures of the gross tumor volume (RSnx) and lymph node (RSnd), Dose Volume Histogram (DVH) signature reflecting planning score (PS), and clinical characteristics were included as potential predictors of PFS. The least absolute shrinkage and selection operator (LASSO) regression were applied for feature selection and data dimension reduction. A nomogram was developed by incorporating the selected predictors. The C-index and calibration curve were used to assess discrimination and calibration power of the nomogram, respectively.

Results

RSnd, PS, and tumor-node-metastasis (TNM) stage were the independent predictors for PFS (all p < 0.05). The nomogram integrating the three factors achieved a C-index of 0.811 (95% CI: 0.74–0.882) in the validation cohort for predicting PFS, which outperformed than that of the TNM stage alone (C-index, 0.613, 95% CI: 0.532–0.694). Subgroup analysis showed Epstein–Barr virus (EBV) DNA status improved the predictive accuracy of the nomogram (C-index, 0.86, 95% CI: 0.787–0.933).

Conclusions

The multidimensional nomogram incorporating RSnd, PS, and TNM stage showed high performance for predicting PFS in patients with locoregionally advanced NPC.

Orbital outcomes after orbit-sparing surgery and free flap reconstruction

29-09-2019 – Ramez Philips, Michael C. Topf, Alexander Graf, Howard Krein, Ryan Heffelfinger, Adam Luginbuhl, Joseph Curry

Journal Article

Objective

To identify functional outcome and orbital complication rate of the preserved orbit and to identify predictors of orbital impairment in periorbital free flap reconstruction.

Materials and methods

A retrospective review was conducted on patients undergoing orbit-sparing surgery with periorbital free flap reconstruction at a tertiary institution from 2006 to 2017. Orbital complication rate and orbital functional outcomes were analyzed. A univariable and multivariable logistic regression analysis was used to assess predictors of functional outcome.

Results

Forty-nine patients met inclusion criteria. Ninety-eight percent of patients maintained a functional eye post-operatively. Most periorbital free flaps, 37 (75.5%), were performed following oncologic resection. Overall orbital function was graded as functional without impairment in 29 (59.2%) patients, functional with impairment in 19 (38.8%) patients, and nonfunctional in 1 (2.0%) patient. Postoperative orbital sequelae occurred in 32 (65.3%) patients. Twenty-one (42.9%) patients underwent 35 revision operations for late orbital sequelae. Extent of resection (OR, 5.93; CI 95%, 1.05–33.4; p = 0.044) and adjuvant RT (OR, 4.69; CI 95% 1.18–18.6; p = 0.028) significantly correlated with impairment in a functional orbit on multivariable analysis.

Conclusion

Orbit-sparing surgery with periorbital free flap reconstruction carries a significant risk of a variety of orbital sequelae, most commonly ectropion, requiring surgical intervention. However, most patients maintain a functional eye. The need for delayed exenteration/enucleation is low and is primarily limited to cancer recurrence. Significant predictors of complications include extent of resection and adjuvant radiation therapy.

Construction of a comprehensive nutritional index and its correlation with quality of life and survival in patients with nasopharyngeal carcinoma undergoing IMRT: A prospective study

22-09-2019 – Jun Deng, Yan He, Xue-Song Sun, Jian-Mei Li, Ming-Zhu Xin, Wen-Qiong Li, Zhen-Xiu Li, Shan Nie, Cong Wang, Yan-Zhu Li, Li-Ping Chen, Lin-Min Chen, Shi-Heng Zhu, Jia-Wen Li, Wen Hu, Yu-Ying Fan, Shan-Shan Guo, Hai-Qiang Mai

Journal Article

Objectives

The aim of this study was to investigate the relationship between a comprehensive nutritional index (CNI) and QoL in patients with NPC who undergo IMRT and to explore the relationship between CNI and survival.

Methods

359 patients with newly diagnosed NPC were enrolled. QoL was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 and Quality of Life Questionnaire Head and Neck Cancer Module at three time points: before, immediately after, and 3 months after IMRT. The CNI comprised five values including body mass index, usual body weight percentage, hemoglobin, albumin, and total lymphocyte count, and was evaluated before and immediately after IMRT. The correlation between the CNI and QoL and the effect of CNI on prognosis were analysed.

Results

QoL and CNI scores decreased remarkably after IMRT (P < 0.05). The CNI was quite low in patients with III–IV clinical tumor stage and those undergoing induction chemotherapy plus concurrent chemotherapy. After IMRT, lower CNI score correlated worse QoL (P < 0.05). The Kaplan-Meier curve indicated that patients with lower CNI had significantly poorer survival outcomes (P = 0.02). In multivariate analysis, CNI remained an independent prognostic factor of overall survival (P = 0.046).

Conclusions

CNI can be recommended as an appropriate indicator reflecting the integrated nutrition status of NPC patients. Low CNI was associated with poor QoL and predicted a poor survival outcome. More interventions should be taken to improve the nutrition status of NPC patients to improve QoL and enhance survival outcomes.

Characterization of a head and neck cancer-derived cell line panel confirms the distinct TP53-proficient copy number-silent subclass

22-09-2019 – Anne M. van Harten, Jos B. Poell, Marijke Buijze, Arjen Brink, Susanne I. Wells, C. René Leemans, Rob M.F. Wolthuis, Ruud H. Brakenhoff

Journal Article

Introduction

Head and neck squamous cell carcinomas (HNSCC) arise in the mucosal lining of the upper aerodigestive tract. Risk factors are exogenous carcinogen exposure, human papillomavirus (HPV) infection, and genetic predisposition such as Fanconi anemia (FA). Clinically, tumors are stratified based on stage, site and HPV-status. The majority of HPV-positive and -negative HNSCC is characterized by frequent copy number (CN) changes and an abrogated p53-pathway. A third genetically-defined HPV-negative subclass of HNSCC is emerging: tumors that lack gross chromosomal changes (CN-silent), are mostly TP53-proficient, and have a relatively favorable prognosis.

Methods

A representative panel of HPV-positive, HPV-negative and FA-HNSCC-derived cell lines was genetically characterized.

Results

Despite apparent differences in etiology, FA-HNSCC cell lines show comparable genetic alterations as sporadic non-FA-HNSCC-derived cell lines.

Furthermore, we identified a near diploid CN-silent HPV-negative HNSCC line: VU-SCC-040. Molecular characterization uncovers the absence of TP53 mutations, a functional p53-pathway and a CASP8 mutation. TP53 gene knockout using CRISPR-Cas9 resulted in resistance to MDM2 inhibition. Whereas p53-status is often proposed as a predictive biomarker for treatment response, TP53-knockout did not change sensitivity to cisplatin, Chk1 and Wee1 inhibition. Additionally, 84 CN-silent tumors were identified in the HNSCC Pan
Cancer cohort and shown to be enriched for female gender, HRAS and CASP8 mutations.

Conclusion

FA-derived HNSCC cell lines share comparable CN-profiles and mutation patterns as sporadic HPV-negative HNSCC. In contrast, a subclass of CN-silent, HPV-negative and TP53 wild-type HNSCC separates from the majority of HNSCC tumors. We show that VU-SCC-040 is a HNSCC cell model representative of this subclass.

Cutaneous keratinocyte cancers of the head and neck: Epidemiology, risk factors and clinical, dermoscopic and reflectance confocal microscopic features

05-10-2019 – Katie J. Lee, H. Peter Soyer

Journal Article

Keratinocyte cancers are the most common malignancy among people with European ancestry, and are very common on sun-exposed areas of the head and neck. Incidence is directly correlated with latitude and annual ultraviolet radiation incidence, although there are a number of other environmental, occupational and genetic risk factors, and keratinocyte cancers become more common at middle age. Basal cell carcinomas (BCC) are the most common, comprising 80% of keratinocyte cancers, but have a very low rate of metastases and low mortality. Squamous cell carcinomas (SCC) make up 20% of keratinocyte cancers, and have relatively infrequent metastases, at 5–16%. While there are no precursor lesions for BCC, SCC represents the final stage in a spectrum of cellular atypia and dysplasia, from actinic keratoses to in situ SCC to invasive SCC. Dermoscopy is a well-established diagnostic tool for keratinocyte cancers, and reflectance confocal microscopy is emerging as another useful diagnostic tool, particularly on functionally and cosmetically sensitive sites like the face.

Radiotherapy for early non-melanoma skin cancer

02-10-2019 – Benjamin Chua, James E. Jackson, Charles Lin, Michael J. Veness

Journal Article

This article reviews the important role of radiotherapy in the management of early non-melanoma skin cancer, in the definitive and adjuvant settings. Therapeutic considerations and appropriate patient selection will be discussed, as well as evidence for efficacy and potential side-effects. Additionally, we present some recent advances which may improve accessibility and quality of radiotherapy, such as more convenient dose-fractionation, wide-field treatments, electronic brachytherapy and 3D printed bolus.

Human papillomavirus-associated squamous cell carcinoma of the larynx or hypopharynx: Clinical outcomes and implications for laryngeal preservation

20-09-2019 – Ryan T. Hughes, William J. Beuerlein, Stacey S. ONeill, Mercedes Porosnicu, Thomas W. Lycan, Joshua D. Waltonen, Bart A. Frizzell, Kathryn M. Greven

Journal Article

Objectives

Human papillomavirus (HPV) can be detected in approximately 25% of squamous cell carcinomas (SCC) of the larynx and hypopharynx. Though HPV is associated with improved survival and disease control in patients with oropharyngeal SCC, the role of HPV as a marker of favorable treatment outcomes in laryngeal and hypopharyngeal cancer is unclear.

Materials and Methods

Patients treated for laryngeal or hypopharyngeal SCC were reviewed. HPV status detected by p16 and/or HPV DNA PCR were abstracted from the medical record. A subset of samples (stage III-IV treated with primary radiotherapy) was retrospectively tested for p16 and HPV DNA. Overall survival (OS), disease-free survival (DFS), and locoregional control (LRC) were determined and compared between HPV-positive (p16+, PCR+ or both) and HPV-negative (p16- or PCR-) patients.

Results

In total, 279 patients were identified, 94 of which were tested for HPV. Eighty-two (87%) were negative and 12 (13%) were positive for HPV. At 3 years, there were no significant differences in OS (72% v. 83%), DFS (60% v. 71%) and LRC (80% v. 89%). Performance status, smoking history and stage predicted for OS, while performance status and stage predicted for DFS. Analysis of patients treated with primary radiotherapy revealed non-significantly higher rates of laryngeal preservation at 3 years (75% v. 100%).

Conclusion

HPV was detected in 13% of tested laryngeal/hypopharyngeal cancers. HPV does not appear to significantly impact survival or disease control in patients with SCC of the larynx or hypopharynx. Non-significant improvements in laryngeal preservation were observed in HPV-positive patients.

Malignant peripheral nerve sheath tumors: Analysis of the national cancer database

17-09-2019 – Alia Mowery, Daniel Clayburgh

Journal Article

Objectives

Malignant peripheral nerve sheath tumor (MPNST) is a rare type of soft tissue sarcoma (STS) that carries significant mortality. Given the rarity of MPNST, current knowledge on the disease is limited. We aim to characterize patient, tumor, and treatment factors, and determine variables associated with 5-year overall survival (OS) in individuals with MPNST.

Materials and Methods

We utilized the National Cancer Database (NCDB) to identify adult patients diagnosed with MPNST from 2004 to 2015, and analyze patient, tumor, treatment, and survival data. American Joint Committee on Cancer (AJCC 8) staging criteria for STS was utilized.

Results

In our cohort of 2,858 patients with MPNST, median age at diagnosis was 47. The 5-year OS rate was 52%. Age, race, tumor size, and treatment regimen significantly predicted 5-year OS on univariate analysis. AJCC 8 stage appeared to predict 5-year OS in head and neck tumors (though not significantly), but not trunk and extremity tumors.

Conclusion

While our cohort of patients with MPNST are typically relatively young and healthy, 5-year OS is only 52%. Notably, age extremes, large tumor size, and certain treatment regimens are associated with worse outcomes. While AJCC 8 staging guidelines may have some value in predicting OS in head and neck tumors, they do not reliably risk stratify patients with trunk and extremity MPNST. Ultimately, MPNST is associated with high mortality with few modifiable risk factors, and survival may not be adequately predicted by current staging systems.

Prognostic factors associated with achieving total oral diet following osteocutaneous microvascular free tissue transfer reconstruction of the oral cavity

16-09-2019 – Sagar Kansara, Tao Wang, Sina Koochakzadeh, Nelson E. Liou, Evan M. Graboyes, Judith M. Skoner, Joshua D. Hornig, Vlad C. Sandulache, Terry A. Day, Andrew T. Huang

Journal Article

Introduction

Osteocutaneous microvascular free tissue transfer (OMFTT) is the current standard in reconstruction of large bony defects of the oral cavity. Although being able to swallow ranks as a top priority for patients undergoing OMFTT, factors associated with achieving an oral diet following surgery remain unclear. We sought to describe the rate of total oral diet achievement, and to identify possible pre-, intra-, and post-operative factors associated with achievement in patients undergoing OMFTT.

Methods

Retrospective review between January 1, 2010 and March 31, 2018 at two tertiary academic centers.

Results

249 patients (67% male, mean age 58 years) met inclusion criteria, with a median follow up of 15 months. Overall, 142 (57%) of patients achieved a total PO diet post-operatively, with median time to achievement of 3.2 months. Multivariate analysis identified that lack of concurrent glossectomy (SHR 1.72 1.09–2.70, p = 0.02), N0/1 disease (SHR 1.92 1.16–3.13, p = 0.011), avoidance of post-operative fistula formation (SHR 1.96 1.22–3.23, p = 0.005), pre-operative G-tube independence (SHR 3.33 1.69–6.25, p < 0.001), and successful dental rehabilitation (SHR 2.08 1.43–3.03, p < 0.001) are independently associated with total oral diet achievement.

Conclusions

Bony resections not requiring glossectomy, limited nodal disease burden, pre-operative gastrostomy-independence, avoidance of post-operative fistula, and dental rehabilitation are independently associated with achievement of total oral diet following OMFTT reconstruction of the oral cavity. Counseling patients on associated risk factors is important in guiding post-treatment expectations. Minimization of post-operative fistula, and maximization of dental rehabilitation may significantly improve total oral diet achievement in this patient population.

LIN28: A cancer stem cell promoter for immunotherapy in head and neck squamous cell carcinoma

02-10-2019 – Mengxue Li, Heng Chen, Tianfu Wu

Journal Article, Review

Lin28, a highly conserved RNA-binding protein, plays an important role in differentiation, metabolism, proliferation, pluripotency, and tumourigenicity. Lin28 overexpression promotes tumour-cell proliferation and metastasis in various human cancers, including head and neck cancer. Multiple studies demonstrate that Lin28 critically contributes to anti-tumour immunity and production of cancer stem cells in head and neck squamous cell carcinoma (HNSCC). Thus, Lin28 has potential application in HNSCC treatment.

A systematic review and meta-analysis of margins in transoral surgery for oropharyngeal carcinoma

24-09-2019 – Philippe Gorphe, Christian Simon

Journal Article, Review

Background

The objective of this study was to conduct a systematic review and meta-analysis of the incidence of positive surgical margins after transoral surgery for oropharyngeal carcinoma, as well as the factors associated with positive margins and their impact on local tumor control.

Method

An electronic search of English-language literature databases was conducted, and a systematic review was performed in accordance with the PRISMA guidelines.

Results

A total of 42 articles were included in the analysis. The overall rate of positive margins using transoral conventional surgery (CTS), transoral laser microsurgery (TLM), or transoral robotic surgery (TORS) was 7.8% in a cumulative total of 3619 patients. A positive margin status was associated with a reduction in local control. Assessment of intraoperative frozen sections was associated with a reduced risk of definitive positive margins, whereas a T4 classification was associated with an increased risk of definitive positive margins. Neither the primary site (the tonsillar fossa versus the base of the tongue), nor the HPV status, were associated with the margin status. The level of heterogeneity between the various studies was very high.

Conclusion

The currently used transoral procedures are safe in regard to proper tumor resection and they should continue to be part of the armamentarium of surgical techniques used in head and neck surgery. The very high level of heterogeneity between studies calls for a definition consensus for margin status assessments in transoral surgery.

“Organs at risks tolerance and dose limits for head and neck cancer re-irradiation: A literature review”

20-09-2019 – F. Dionisi, F. Fiorica, E. DAngelo, M. Maddalo, I. Giacomelli, E. Tornari, A. Rosca, F. Vigo, D. Romanello, M. Cianchetti, F. Tommasino, M. Massaccesi, E. Orlandi

Journal Article, Review

Re-irradiation is becoming an established treatment option for recurrent or second primary head and neck cancer(HNC). However, acute and long-term RT-related toxicities could dramatically impact patients quality of life. Due to the sparse literature regarding HNC re-irradiation, data on tolerance doses for various organs at risk (OARs) are scarce. Our aim was to systematically review the clinical literature regarding HNC re-irradiation, focusing on treatment toxicity, OARs tolerance, and dose limit recommendations. Thirty-nine studies (three randomized, five prospective, 31 retrospective) including 3766 patients were selected. The median interval time between the first course and re-irradiation was 28  months (range, 6–90). In 1043 (27.6%) patients, postoperative re-irradiation was performed. Re-irradiation doses ranged from 30 Gy in 3 fractions using stereotactic technique to 72 Gy in conventional fractionation using intensity-modulated radiotherapy. Pooled acute and late toxicityrates ≥G3 were 32% and 29.3%, respectively. The most common grade 3–4 toxic effects were radionecrosis, dysphagia requiring feeding tube placement and trismus. In 156 (4.1%) patients, carotid blowout was reported. Recommendations for limiting toxicity included the time interval between radiation treatments, the fractionation schedules, and the re-irradiation treatment volumes. Cumulative dose limit suggestions were found and discussed for the carotid arteries, temporal lobes, and mandible.

The potential use of big data in oncology

16-09-2019 – Stefan M. Willems, Sanne Abeln, K. Anton Feenstra, Remco de Bree, Egge F. van der Poel, Robert J. Baatenburg de Jong, Jaap Heringa, Michiel W.M. van den Brekel

Journal Article, Review

In this era of information technology, big data analysis is entering biomedical sciences. But what is big data, where do they come from and what can we do with it? In this commentary, the main sources of big data are explained, especially in (head and neck) oncology. It also touches upon the need to integrate various sources of clinical, pathological and quality-of-life data. It discusses some initiatives in linking of such datasets on a nation-wide scale in the Netherlands. Finally, it touches upon important issues regarding governance, FAIRness of data and the need to bring into place the necessary infrastructures needed to fully exploit the full potential of big data sets in head and neck cancer.

The role of single-nucleotide polymorphism (SNPs) in toxicity of induction chemotherapy based on cisplatin and paclitaxel in patients with advanced head and neck cancer

21-09-2019 – Pedro De Marchi, Matias E. Melendez, Ana C. Laus, Pamela A. Kuhlmann, Ana Carolina de Carvalho, Lidia Maria R.B. Arantes, Adriane F. Evangelista, Edilene S. Andrade, Gilberto de Castro, Rui M. Reis, André Lopes Carvalho, Luciano de Souza Viana

Journal Article

Background

Induction chemotherapy in locally-advanced head and neck squamous cell carcinoma (LAHNSCC) patients is potentially associated to serious adverse events. Biomarkers associated with toxicity could tailor its indication. This study evaluated the association between single-nucleotide polymorphisms (SNPs) in metabolic genes and toxicity to induction chemotherapy.

Methods

59 LAHNSCC phase II clinical trial patients (NCT00959387) were assessed regarding 47 metabolic genes (366 SNPs). Toxicities were graded (CTCAE 3.0) and statistical analysis was performed.

Results

The SNPs rs8187710 (ABCC2) and rs1801131 (MTHFR) were associated to increased risk of gastrointestinal toxicity, whereas the SNPs rs3788007 (ABCG1) and rs4148943 (CHST3) were associated to decreased risk. Two other SNPs, rs2301159 (SLC10A2) and rs2470890 (CYP1A2), were associated with increased risk of hematological toxicity. Nevertheless, these SNPs did not remain significant after adjusting for multiple comparisons.

Conclusions

This study could not demonstrate relationship between SNPs and toxicity to induction chemotherapy in LAHNSCC patients. The small number of patients may have affected the results.

Mucinous cystadenoma of oral minor salivary glands: Precursor of mucocele?

05-10-2019 – Adriana Handra-Luca

Letter

A preliminary Bayesian network model to identify factors associated with treatment outcome in T2 and T3 laryngeal carcinoma

29-09-2019 – Aaro Haapaniemi, Antti Mäkitie, Pekka Kekolahti, Olli-Pekka Ryynänen

Letter

Prognostic determinants of locally advanced buccal mucosa cancer: Do we need to relook the current staging criteria? – Needs to be interpreted carefully

29-09-2019 – Shivakumar Thiagarajan, Sudhir V. Nair

Letter

Function restoration after laryngectomy – Present and future

25-09-2019 – Bipin T. Varghese

Letter

18FPARPi-PET in locally advanced oral cavity carcinoma

25-09-2019 – Francesca De Felice, Vincenzo Tombolini

Letter

A unique case of mandibular metastasis from primary lung mucoepidermoid carcinoma

16-09-2019 – Chrissa Sioka, Georgia Karpathiou, Alexandra Papoudou-Bai, Anastasia Zikou, Elpida Tsina, Vanesa Bellou, Vasilios Ragos, Maria I. Argyropoulou, Andreas Fotopoulos, Athanasios Konstantinidis

Letter

Bilateral infrahyoid muscle, myofascial and myoperichondrial flaps in laryngectomy

16-09-2019 – Bipin Thomas Varghese

Letter

Background

Protection of suture line of neopharynx after a laryngectomy or near total laryngectomy with vascularized tissues is of utmost importance in preventing a wound related complication.

Method

A simple technique of harvesting bilateral pedicled infrahyoid muscle myofascial or myoperichondrial flap to protect the fashioned neopharynx in a Total or Near Total laryngectomy is described.

Conclusion

Pedicled infrahyoid muscle, myofascial or myoperichondrial flap is a simple quick and reliable option to protect the fashioned neopharynx in a Total or Near Total laryngectomy against major wound complications like pharyngocutaneous leaks and fistula formation.

Mandible Ewing Sarcoma in a child: Clinical, radiographic and diagnosis considerations

10-09-2019 – S.V. Oliveira, L.G. Fernandes, L.A.V. Soares, M.F. Moraes, M.T.A. Almeida, D.S. Pinto, F.A. Alves

Letter

Key approaches to interpret the findings of a meta-analysis on role of chemotherapy in 5000 patients with head and neck cancer treated by curative surgery

04-09-2019 – Rama Jayaraj, Madurantakam Royam Madhav, Shanthi Sabarimurugan, Chellan Kumarasamy, Sameep S. Shetty, Ajay Gupta, Siddhartha Baxi

Letter

Potential role of autofluorescence imaging in determining biopsy of oral potentially malignant disorders: A large prospective diagnostic study

17-08-2019 – Linjun Shi, Chenxi Li, Xuemin Shen, Zengtong Zhou, Wei Liu, Guoyao Tang

Journal Article

Autofluorescence examination of oral tissues using the VELscope has been suggested as an adjunctive tool for cancer detection and diagnosis. This study aimed to determine the diagnostic value of VELscope in a large prospective study of 517 patients with oral potentially malignant disorders (OPMD). For the outcome assessments of discrimination of carcinoma form general OPMD and distinguishing high-risk lesions (moderate/severe dysplasia and carcinoma) from low-risk lesions (no/mild dysplasia), high sensitivity (100% and 95.9% respectively) and negative predictive value (100% and 98.2% respectively) were observed. All the carcinoma and showed loss of autofluorescence (LAF) and only 3 (0.6%) moderate/severe dysplasia were observed without LAF.

These data indicate that the cases without LAF using VELscope substantially rule out the presence of high-risk lesions including cancer. This may prove to be useful specially to alleviate patient anxiety regarding a clinically suspicious oral lesion without the LAF, and to avoid a unnecessary biopsy for these cases. Collectively, a perspective to highlight was that a no biopsy strategy may be appropriate for OPMD without LAF using VELscope after conventional oral examination.

Oral melanomas in HIV-positive patients: Report of two cases and review of the literature

03-08-2019 – Thayná Melo de Lima Morais, Ciro Dantas Soares, Arthur Eric Costa Wanderley, Catarina Rodrigues Rosa de Oliveira, Camila Maria Beder Ribeiro, Oslei Paes de Almeida, Maria Goretti Freire de Carvalho, Sonia Maria Soares Ferreira

Letter

Oral melanoma in HIV-positive patients is exceedingly rare, with only two cases reported in the literature published in English. Herein, we report two additional cases of oral melanomas which occurred as oral masses in the upper gingiva and hard palate in 35- and 27-year-old HIV-positive women. Significant thrombocytopenia, anemia, reduced CD4 cells, and high HIV load occurred in both patients. Microscopically, the lesions showed a variable proliferation of fusiform and epithelioid-pigmented cells, with cellular pleomorphism and high mitotic index. The diagnosis of melanoma was supported by positive immunoreactivity for S-100, Melan
A, and HMB-45. Both cases had an unfavorable outcome, and the patients died a few months after the initial diagnosis. Because of its rarity, oral melanoma occurring in HIV-positive patients can pose problems in diagnosis and should be clinically distinguished from Kaposi’s sarcoma, which is more common in the context of the immunodeficiency syndrome.

Incidental finding of tongue cancer in a PET scan: A fusion of anatomic and metabolic imaging

29-07-2019 – Sameep S. Shetty, Akshay Kudpaje, Vishal Rao

Letter

Podoplanin and ABCG2 expression in oral erythroplakia revisited: Potential evidence for cancer stem cells driving the process of field cancerization

14-07-2019 – Xi Yang, Linjun Shi, Zengtong Zhou, Wei Liu

Letter

A model of field cancerization orchestrated by the cancer stem cells (CSC) was proposed. Podoplanin and ABCG2 are promising marker of CSCs for head and neck cancer. We revisited the correlation of the two markers with the follow-up data of the patients with oral erythroplakia (OE). Strikingly, we observed that the expression of podoplanin and ABCG2 within a single pre-neoplastic OE lesion significantly correlate with subsequently developing multiple and multifocal carcinomas, thus to some extent demonstrating the concept of field cancerization. Collectively, a point to highlight was that a preliminary evidence that provided by this revisited study supported the perspective on cancer stem cells driving the process of field cancerization.

Current evidence on DNA aneuploidy cytology in noninvasive detection of oral cancer

14-07-2019 – Linjun Shi, Yufeng Wang, Chenxi Li, Wei Liu

Letter

DNA-aneuploidy cytology as a promising noninvasive tool in diagnosing oral precancer and cancer has been proposed in 2015. In this letter, we identified 9 studies on DNA aneuploidy cytology with special emphasis on using fresh tissue sample in detection of oral precancer and cancer. Evidence was updated as follows, for detection of OSCC in general oral lesions, the pooled sensitivity and specificity was 84.8 and 99.0 respectively; for discrimination of dysplasia and OSCC form oral lesions, the sensitivity and specificity was 75.7 and 76.8 respectively. On the whole, current evidence on the theme is not robust, and multicenter prospective studies are needed to consolidate the evidence.

Nivolumab in patients with rare head and neck carcinomas: A single center’s experience

14-07-2019 – Stefania Kokkali, Anna Ntokou, Maria Drizou, Konstantina Perdikari, Panagiotis Makaronis, Elena Katsarou, Nektarios Koufopoulos, Alexandros Tzovaras, Alexandros Ardavanis

Letter

Immunotherapy (IO) with anti-PD1 inhibitors is available for the treatment of recurrent/metastatic squamous cell carcinomas of the head and neck (SCCHD) since 2016. Both nivolumab and pembrolizumab were tested in phase 3 randomized trials in adults progressing on or after platinum-based therapy and were found to confer an overall survival benefit compared to investigator’s choice. However, very limited data exist concerning IO use in rare subtypes of head and neck carcinoma, like salivary gland carcinoma.

We retrospectively collected clinical data of all patients diagnosed with rare subtypes of head and neck carcinoma, who were treated with immune checkpoint inhibitors in our department during the last 5 years. We analyzed safety and efficacy of these therapies.

We identified six patients who received nivolumab for recurrent or metastatic head and neck carcinomas, between 31 and 57 years old. All patients had received at least one line of platinum-chemotherapy, as well as radiation therapy. Treatment was administered every 2 weeks, at a dose of 3 mg per kilogram of body weight. Number of nivolumab cycles varied between 2 and 18. Progression-free survival varied from 1 to 12 months and overall survival from 4 to 24 months. Tolerance was very good, except for one case of diabetes and hypothyroidism requiring medication.

There is currently insufficient evidence regarding the optimal treatment of the rare non-squamous cell carcinoma of the head and neck. Our case series supports a role for immunotherapy in these patients. However, larger collaborative studies are needed to evaluate this treatment.

Different responses to nivolumab therapy between primary and metastatic tumors in a patient with recurrent hypopharyngeal squamous cell carcinoma

14-07-2019 – Kiminobu Sato, Takeharu Ono, Fumihiko Sato, Akihiko Kawahara, Koichi Azuma, Toshihiko Kawaguchi, Jun Akiba, Hirohito Umeno

Letter

We report the case of a 70-year-old man with primary and metastatic tumors, showing clinically progressive disease and complete response to nivolumab therapy, respectively. He underwent total pharyngo-laryngectomy, bilateral neck dissection, and reconstruction with free-jejunum after nivolumab therapy failure, and had no recurrent or newly arising lesions 8 months after the surgery. Immunohistochemistry analysis revealed that metastatic neck tumor with the clinical complete response to nivolumab showed higher PD-L1 expression with higher CD8+ TIL density, while primary lesion with progressive disease showed lower PD-L1 expression with lower CD8+ TIL density. This represents the first case reported on head and neck squamous cell carcinoma treated with salvage surgery after nivolumab therapy failure.

Comment on “Resolution without surgery of an advanced stage of medication-related osteonecrosis of the jaw (MRONJ) in a patient who could not suspend her treatment for osteoporosis”, by Sarmiento (2019)

07-07-2019 – Patrícia Carlos Caldeira

Letter

Combined parameter SUVmax/ADCmean predicts microvessel density in head and neck squamous cell carcinoma. Preliminary results

08-07-2019 – Alexey Surov, Hans Jonas Meyer, Anne-Kathrin Höhn, Andreas Wienke, Osama Sabri, Sandra Purz

Letter

Complete response with neoadjuvant avelumab in Merkel cell carcinoma – A case report

07-07-2019 – Nadine Abdallah, Misako Nagasaka, Tahmida Chowdhury, Kunil Raval, Jeffrey Hotaling, Ammar Sukari

Letter

Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine skin malignancy. We report here a case of localized MCC achieving pathologic complete response upon treatment with avelumab in the neoadjuvant setting. Preclinical and clinical studies have revealed a close relationship between MCC and the immune system, thus supporting a role for PD-1/PD-L1 inhibitors in MCC. This neoadjuvant use of PD-1/PD-L1 inhibitors can avoid potentially disfiguring surgery in MCC. As the incidence of MCC is rising, clinical trials are needed to evaluate the efficacy and safety of immunotherapy in resectable disease.

Tongue cancer: A discrete oral cavity subsite

06-07-2019 – Sameep S. Shetty, Akshay Kudpaje, Rama Jayaraj, Vishal Rao, Prit Kiran Shah

Letter

Intraoperative flow cytometry for head and neck lesions. Assessment of malignancy and tumour-free resection margins

06-07-2019 – George Vartholomatos, Lentiona Basiari, George Exarchakos, Ioannis Kastanioudakis, Ioannis Komnos, Maria Michali, Georgios S. Markopoulos, Anna Batistatou, Alexandra Papoudou-Bai, George A. Alexiou

Letter

Head and neck cancer poses a significant health problem worldwide. We set out to investigate the value of rapid intraoperative cell cycle analysis by flow cytometry for the intraoperative characterization of head and neck lesions and surgical margins. Seventy patients with head and neck lesions suspicious of malignancy were included in the study. There were 31 neoplastic and 39 benign lesions. Flow cytometry permitted the intraoperative detection of neoplastic lesions within 6 min with high sensitivity and specificity based on cell cycle fractions. In the cases in which surgical margins were assessed, intraoperative flow cytometry had complete concordance with pathology. Intreoperative flow cytometry is a novel promising technique for rapid intraoperative characterization of malignancy and tumour free resection margins in head and neck lesions.

“Cowdens syndrome: A case report”

03-07-2019 – Zhongfeng Liu, Qi Wang, Jun Li

Letter

Agreement between skeletal muscle mass measurements using computed tomography imaging and magnetic resonance imaging in head and neck cancer patients

30-06-2019 – N. Chargi, E. Ansari, L.F.J. Huiskamp, G. Bol, R. de Bree

Letter

Medication related osteonecrosis of jaw in a leukemia patient undergoing systemic arsenic trioxide therapy: A rare case report

01-07-2019 – Mathangi Kumar, Ravindranath Vineetha, Adarsh Kudva

Letter

Osteonecrosis of the jaw is a potential side effect of certain pharmaceutical agents used in the field of medicine. Early diagnosis and effective management of this condition can be challenging to the clinicians. Bisphosphonates and other anti-angiogenic agents are the most common drugs that are attributed to cause medication-related osteonecrosis of the jaw. In the past, arsenic-based compounds were commonly used local agents for pulp devitalization therapy. Arsenic is also one of the components of the chemotherapeutic regimen in the management of refractory leukemia. Although local diffusion of the arsenic compounds is known to cause osteonecrosis, there are no reports of the same caused by its systemic administration. Here, we present the first ever case of mandibular bone necrosis in a patient with acute promyelocytic leukemia who underwent systemic arsenic trioxide therapy.

Limiting radiotherapy field to ipsilateral side only in unresected lateralised HPV positive N2b squamous cell carcinoma of the tonsil

17-06-2019 – Muhammad Shahid Iqbal, Josef Kovarik, Charles Kelly

Letter

Conceptual interpretation of findings on systematic review and meta-analysis of altered-fractionation radiotherapy improves local control in the early-stage glottic carcinoma

12-06-2019 – Rama Jayaraj, Chellan Kumarasamy, Shanthi Sabarimurugan, Madurantakam Royam Madhav, Sameep S. Shetty, Siddhartha Baxi

Letter

Together consideration of microenvironment and tumor cells: Analysis of papers published in Oral Oncology

11-06-2019 – Gargi S. Sarode, Sachin C. Sarode, Nilookumari Choudhary, Nilesh Kumar Sharma, Gopalakrishnan Dharmarajan, Shankargouda Patil

Letter