Pairing a prognostic target with potential therapeutic strategy for head and neck cancer.

OBJECTIVES: We have previously identified and validated a panel of molecular prognostic markers (ATP13A3, SSR3, and ANO1) for Head and Neck Squamous Cell Carcinoma (HNSCC). The aim of this study was to investigate the consequence of ATP13A3 dysregulation on signaling pathways, to aid in formulating a therapeutic strategy targeting ATP13A3-overexpressing HNSCC. MATERIALS AND METHODS: Gene Set Enrichment Analysis (GSEA) was performed on HNSCC microarray expression data (Internal local dataset [n = 92], TCGA [n = 232], EMBL [n = 81]) to identify pathways associated with high expression of ATP13A3. Validation was performed using immunohistochemistry (IHC) on tissue microarrays (TMAs) of head and neck cancers (n = 333), staining for ATP13A3 and phosphorylated Aurora kinase A (phospho-T288). Short interfering RNA was used to knockdown ATP13A3 expression in patient derived HNSCC cell lines. Protein expression of ATP13A3 and Aurora kinase A was then assessed by immunoblotting. RESULTS: GSEA identified Aurora kinase pathway to be associated with high expression of ATP13A3 (p = 0.026). The Aurora kinase pathway was also associated with a trend towards poor prognosis and tumor aggressiveness (p = 0.086, 0.094, respectively). Furthermore, the immunohistochemical staining results revealed a significant association between Aurora kinase activity and high ATP13A3 expression (p < 0.001). Knockdown of ATP13A3 in human head and neck cell lines showed decrease in Aurora kinase A levels. CONCLUSION: Tumors with high ATP13A3 are associated with high Aurora kinase activity. This suggests a potential therapeutic role of Aurora kinase inhibitors in a subset of poor prognosis HNSCC patients with overexpression of ATP13A3.

Retrospective quality of life study in patients with retroperitoneal sarcoma in an Asian population.

BACKGROUND: Retroperitoneal sarcoma represents 15% of sarcomas. The mainstay of treatment is surgery where a majority of patients require multi-visceral resections that may significantly impact their quality of life (QOL) following surgery. Studies in other cancers have shown that QOL may not be significantly impacted after radical or extensive surgery. However, there are limited studies examining the QOL specifically in patients with retroperitoneal sarcoma. In this pilot study, we retrospectively evaluated the QOL of patients with retroperitoneal sarcoma. METHODS: 32 out of 90 patients who underwent surgical intervention for retroperitoneal sarcoma in National Cancer Centre Singapore from January 1999 to August 2018 who were alive and on follow-up were included in this study. EORTC-QLQ-C30 was administered to the patients. RESULTS: The median age of our patients was 59 years (range, 35-84), and median time from surgery to the implementation of questionnaire was 2.5 years (range, 0.05-9.6). Younger patients had significantly better differences in global health, physical and role functioning scores as compared to older individuals. Female patients reported higher global health, physical, emotional and social functioning scores than males. Patients who were more than 2 years post-surgery exhibited better QOL scores as compared to those who had more recent surgery. Our patients had comparable global health and functioning scores compared to a reference group of outpatient cancer patients at our institution. CONCLUSIONS: Our pilot study investigating the QOL of patients with retroperitoneal sarcoma has shown that patients need to be followed up for at least 2 years following surgery to evaluate their QOL. In general, they achieved better functioning scores when compared with other cancer patients. These findings support the need for larger-scale prospective studies to further evaluate the QOL of these patients.

Adherence of head and neck squamous cell carcinoma patients to tumor board recommendations.

BACKGROUND: Multidisciplinary team (MDT) meetings or tumor boards (TBs) are fundamental components of cancer treatment. Although their primary function is improved outcomes, this aspect is often underreported. The main objective of this study was to analyze the outcomes of patients with head and neck squamous cell carcinoma (HNSCC) discussed at TBs, and to compare the effect of adherence and nonadherence to recommended treatment plans on outcomes. METHODS: Retrospective data analysis was conducted of HNSCC patients those who were adherent and nonadherent to TB therapy recommendations during 2008-2009 at a comprehensive cancer center. Fisher's exact test and t test were used for group-wise comparison, and Kaplan-Meier and logistic regression models, for survival analysis and determination of the contributing factors to nonadherence. RESULTS: Comprehensive Treatment plans were recommended by TBs in 293 HNSCC patients with curative intent. Seventy-two patients were excluded based on the selection criteria. Among the remaining 221 patients, 172 (77.9%) were adherent to TB recommendations, while 49 (22.1%) failed to comply. Patient (n = 36; 73.5%), clinician (n = 2; 4.1%), and disease-related (n = 11; 22.4%) factors were significant contributors to nonadherence. Mean (±standard deviation (SD)) survival time was 55.6 ± 2.32 and 29.1 ± 4 months in the adherent and nonadherent groups, (P < .0001, respectively). Multivariate analyses showed that gender, ethnicity, higher T-stage, and multimodal treatment were associated with nonadherence. CONCLUSION: Adherence to TB recommendations improved overall survival, reflecting the importance of interdisciplinary expertise in contemporary cancer treatment. Early identification and intervention is crucial in "at risk" patients to prevent subsequent drop-out from optimal cancer care.

Electronic tumor board presentations as the basis for the development of a head and neck cancer database.

BACKGROUND: Multidisciplinary team meetings or tumor boards (TBs) form a pivotal component of oncology practice. The crux of a TB revolves around making treatment decisions based on succinct head and neck cancer (HNC) patient data presentations, which can be challenging and complex. Apart from meticulous TB presentations, discussions and treatment plan documentation is equally important. The aim of this study was to structure an electronic synoptic TB data presentation to address all these areas. The overarching benefits of systematic TB data collection include facilitating audits and research. METHODS: We utilized a secure web-based tool that was used for common scientific research purposes but customized to store HNC patient data. The data points were tabulated across eight TB pages: (a) TB scheduling, (b) patient biodata, (c) diagnosis details, (d) index presentation, (e) images, (f) management and histopathology, (g) TB presentation, and (h) TB discussion and decisions. Each data point leads to additional fields by branching logic to permit further relevant data entry. This was integrated within the patient electronic medical records allowing for a direct internal trajectory to recall TB data. RESULTS: From October 2015 to October 2018, we recorded over 2000 presentations for 1279 individual patients. This is a quality improvement initiative, and hence, the results are more of a broad analysis of our TB presentation process. The most common cancers were squamous cell (523, 41%), thyroid (207, 16%), and nasopharyngeal (139, 11%) carcinomas. Importantly, this system has formed the basis for a number of clinical and translational research projects and audit outcomes. CONCLUSION: Despite TBs being vital to oncologic practice, little attempt has been made to report TB data management. In this study, we present an efficient system that permits the integration of dual functions: TB data presentation and oncologic data collection for research, recall, and audit purposes.

Factors driving frequent attendance at emergency departments for patients with head and neck cancer.

BACKGROUND: Patients with head and neck cancer have a higher risk of emergency department (ED) frequent attender (FA). We hypothesized that FAs present with issues different from non-FAs. METHODS: A retrospective cohort study was conducted on Singapore residents with head and neck cancers using de-identified registry merged with electronic medical record data. A competing risk regression analysis was performed to identify factors associated with FA. Aggregated primary diagnoses were compared for patients with and without FA risk factors. RESULTS: Thirteen percent of patients with head and neck cancer were FAs. FA risk factors were Charlson comorbidity index (3+), and socioeconomic status (SES). FAs had a higher proportion of respiratory infections. The spectrum of diagnosis was similar for patients with low and high SES. Current smokers had a greater proportion of respiratory complaints, relative to never smokers. CONCLUSION: Patients with greater comorbidity scores or higher SES were more likely to be FA. FAs were more likely to present with respiratory complaints, likely related to cancer treatment, or smoking status.

A set of molecular markers predicts chemosensitivity to Mitomycin-C following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastasis.

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is associated with significant perioperative morbidity and mortality. We aim to generate and validate a biomarker set predicting sensitivity to Mitomycin-C to refine selection of patients with colorectal peritoneal metastasis (CPM) for this treatment. A signature predicting Mitomycin-C sensitivity was generated using data from Genomics of Drug Sensitivity in Cancer and The Cancer Genome Atlas. Validation was performed on CPM patients who underwent CRS-HIPEC (n = 62) using immunohistochemistry (IHC). We determined predictive significance of our set using overall survival as a surrogate endpoint via a logistic regression model. Three potential biomarkers were identified and optimized for IHC. Patients exhibiting lower expression of PAXIP1 and SSBP2 had poorer survival than those with higher expression (p = 0.045 and 0.140, respectively). No difference was observed in patients with differing DTYMK expression (p = 0.715). Combining PAXIP1 and SSBP2 in a set, patients with two dysregulated protein markers had significantly poorer survival than one or no dysregulated marker (p = 0.016). This set independently predicted survival in a Cox regression model (HR 5.097; 95% CI 1.731-15.007; p = 0.003). We generated and validated an IHC prognostic set which could potentially identify patients who are likely to benefit from HIPEC using Mitomycin-C.

Elderly Patients with Advanced Head and Neck Carcinoma: Does Aggressive Treatment Result in Better Outcomes?

OBJECTIVE: There are no well-defined treatment recommendations for elderly patients with advanced head and neck squamous cell carcinoma. This study aimed to investigate whether aggressive treatment among the elderly translated into better survival outcomes. STUDY DESIGN: Retrospective cohort study. SETTING: Single tertiary institution. SUBJECTS AND METHODS: Elderly patients (≥60 years) with advanced-stage head and neck squamous cell carcinoma (stage III and IV) treated between January 1991 and May 2014 were reviewed. According to current National Comprehensive Cancer Network guidelines, they were classified to have received standard or substandard treatment. Overall survival (OS), locoregional recurrence-free survival, and distant recurrence-free survival were evaluated. RESULTS: A total of 355 patients were treated curatively: 194 with up-front surgery and 161 with radiotherapy or concurrent chemotherapy and radiotherapy. Median OS was higher among patients who received standard treatment (42.0 vs 16.0 months, P < .001). On multivariate analysis, standard treatment showed superior OS ( P < .001). Use of substandard treatment showed a hazard ratio of 2.09 (95% CI, 1.59-2.74) for poorer OS. CONCLUSION: Aggressive standard treatment protocols should be advocated for elderly patients, where comorbidities permit, as they confer better outcomes.

Are positron emission tomography-computed tomography (PET-CT) scans useful in preoperative assessment of patients with peritoneal disease before cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC)?

INTRODUCTION: CRS and HIPEC confer survival benefit in selected patients with peritoneal metatases (PM). Accurate preoperative assessment of disease burden and exclusion of distant metastases are crucial in selecting the appropriate patient. We evaluate the utility of PET-CT scans in comparison with CT and MRI scans in patients considered for CRS and HIPEC. METHODS: Data were retrospectively collected from patients who had been discussed for CRS and HIPEC between January 2011 and December 2015, at our institutional multidisciplinary tumour board. Patients who underwent PET-CT scan were included. Results of PET-CT were compared against traditional imaging. Patient and tumour factors were analysed to identify those who were most likely to benefit from PET imaging. RESULTS: Four hundred and seven patients were considered for CRS and HIPEC. PET-CT was performed for 128(31.4%) patients: being the only imaging modality in 37 and used as an adjunct in 91. In the latter group, it was not beneficial in 58 patients as it provided no additional information (n = 33) or showed lesions of minimal FDG uptake (n = 25). In 33 patients, PET-CT provided definitive answers for indeterminate lesions seen on CT and MRI, confirmed the diagnosis of peritoneal disease in 10 patients (30.3%), identified extra-peritoneal disease and/or nodal metastases in 15 (45.5%) and excluded peritoneal disease in 8 (24.2%). The usefulness of PET-CT was predicted by tumour histology (p = .009), with non-mucinous tumours benefitting the most. CONCLUSION: Our results suggest that PET-CT can be used as an adjunct to CT and/or MRI scans, when lesions on the CT/MRI scans are indeterminate, and that it is most useful in patients with non-mucinous tumours.

Exploring the trend in referrals for consideration of CRS and HIPEC to understand the attitudes of clinicians in the development of a national cancer centre programme in peritoneal disease.

INTRODUCTION: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) improve survival in selected patients with peritoneal metastases. However, only some patients who are potentially eligible for the procedure are considered and referred to the appropriate surgical department. By studying the trends of patients being considered for CRS and HIPEC in our centre, we hope to better understand the demographics of our patient cohort and the attitudes of physicians involved towards CRS and HIPEC. METHODS: Patients who were presented and discussed at our institution's multidisciplinary tumour board (MDTB) for consideration of CRS and HIPEC, between 5 January 2011 and 16 December 2015, were identified from the institutional database and included in the study. Patient demographics and clinico-pathological data were retrospectively collected from electronic records and clinical charts. RESULTS: A total of 407 patients were presented at the MDTB for consideration of CRS and HIPEC. Referrals were most commonly from oncology-related departments (65.8%, n = 268). This was followed by referrals from other hospitals (15.0%, n = 61), overseas self-referrals (12.0%, n = 49) and non-oncologic departments within the same institution (7.1%, n = 29). Referrals made by oncology-related departments and overseas self-referrals showed an increasing trend over the years. Of the patients discussed, 197 patients (48.4%) were recommended for CRS and HIPEC, and 134 (68.0%) successfully underwent the procedure. CONCLUSIONS: There is growing acceptance of CRS and HIPEC in patients and oncologic-related departments. However, consideration of this procedure as a treatment option remains low in non-oncologic departments. Dissemination of information and well-defined clinical recommendations may help physicians identify and select potentially eligible patients for consideration of CRS and HIPEC.

GNA13 expression promotes drug resistance and tumor-initiating phenotypes in squamous cell cancers.

Treatment failure in solid tumors occurs due to the survival of specific subpopulations of cells that possess tumor-initiating (TIC) phenotypes. Studies have implicated G protein-coupled-receptors (GPCRs) in cancer progression and the acquisition of TIC phenotypes. Many of the implicated GPCRs signal through the G protein GNA13. In this study, we demonstrate that GNA13 is upregulated in many solid tumors and impacts survival and metastases in patients. GNA13 levels modulate drug resistance and TIC-like phenotypes in patient-derived head and neck squamous cell carcinoma (HNSCC) cells in vitro and in vivo. Blockade of GNA13 expression, or of select downstream pathways, using small-molecule inhibitors abrogates GNA13-induced TIC phenotypes, rendering cells vulnerable to standard-of-care cytotoxic therapies. Taken together, these data indicate that GNA13 expression is a potential prognostic biomarker for tumor progression, and that interfering with GNA13-induced signaling provides a novel strategy to block TICs and drug resistance in HNSCCs.

A three gene immunohistochemical panel serves as an adjunct to clinical staging of patients with head and neck cancer.

BACKGROUND: Current management of head and neck squamous cell carcinoma (HNSCC) depends on tumor staging. Despite refinements in clinical staging algorithms, outcomes remain unchanged for the last two decades. In this study, we set out to identify a small, clinically applicable molecular panel to aid prognostication of patients with HNSCC. MATERIALS AND METHODS: Data from The Cancer Genome Atlas (TCGA) was used to derive copy number aberrations and expression changes to identify putative prognostic genes. To account for cross entity relevance of the biomarkers, HNSCC (n = 276), breast (n = 808) and lung cancer (n = 282) datasets were used to identify robust and reproducible markers with prognostic potential. Validation was performed using immunohistochemistry (IHC) on tissue microarrays of an independent cohort of HNSCC (n = 333). FINDINGS: Using GISTIC algorithm together with gene expression analysis, we identified six putative prognostic genes in at least two out of three cancers analyzed, of which four were successfully optimized for automated IHC. Of these, three were successfully validated; each molecular target being significantly prognostic on univariate analysis. Patients were differentially segregated into four prognostic groups based on the number of genes dysregulated (p < 0.001). The IHC panel remained an independent predictor of survival after adjusting for known survival covariates including clinical staging criteria in a multivariate Cox regression model (p < 0.001). . INTERPRETATION: We have identified and validated a clinically applicable IHC biomarker panel that is independently associated with overall survival. This panel is readily applicable, serving as a useful adjunct to current staging systems and provides novel targets for future therapeutic strategies.

Phenotype-driven precision oncology as a guide for clinical decisions one patient at a time.

Genomics-driven cancer therapeutics has gained prominence in personalized cancer treatment. However, its utility in indications lacking biomarker-driven treatment strategies remains limited. Here we present a "phenotype-driven precision-oncology" approach, based on the notion that biological response to perturbations, chemical or genetic, in ex vivo patient-individualized models can serve as predictive biomarkers for therapeutic response in the clinic. We generated a library of "screenable" patient-derived primary cultures (PDCs) for head and neck squamous cell carcinomas that reproducibly predicted treatment response in matched patient-derived-xenograft models. Importantly, PDCs could guide clinical practice and predict tumour progression in two n = 1 co-clinical trials. Comprehensive "-omics" interrogation of PDCs derived from one of these models revealed YAP1 as a putative biomarker for treatment response and survival in ~24% of oral squamous cell carcinoma. We envision that scaling of the proposed PDC approach could uncover biomarkers for therapeutic stratification and guide real-time therapeutic decisions in the future.Treatment response in patient-derived models may serve as a biomarker for response in the clinic. Here, the authors use paired patient-derived mouse xenografts and patient-derived primary culture models from head and neck squamous cell carcinomas, including metastasis, as models for high-throughput screening of anti-cancer drugs.

Survival of patients with head and neck squamous cell carcinoma by housing subsidy in a tiered public housing system.

BACKGROUND: Socioeconomic status affects survival in patients diagnosed with head and neck squamous cell carcinoma (HNSCC), even in health systems with universal health care. Singapore has a tiered subsidized housing system, in which income determines eligibility for subsidies by size of apartment. The objective of this study was to assess whether a patient's residential type (small/heavily subsidized, medium/moderate subsidy, large/minimal or no subsidy) influenced mortality. A secondary analysis examined whether patients in smaller subsidized apartments were more likely to present with advanced disease. METHODS: An historical cohort study of patients in a tertiary referral center with HNSCC was identified in the multidisciplinary cancer database from 1992 to 2014. Clinicopathologic data were extracted for analysis. Patient residential postal codes were matched to type of housing. Logistic regression was performed to evaluate the relationship between all-cause mortality and the predictors of interest as well as the association between housing type and disease stage at presentation. RESULTS: Of the 758 patients identified, most were men (73.4%), the median age was 64 years, 30.5% and 15.2% were smokers and former smokers, respectively. Over one-half (56.8%) of patients presented with advanced disease. Male gender, age, stage at presentation, survival time from diagnosis, and smoker status were significant predictors of mortality. Patients living in the smaller, higher subsidy apartments had poorer survival, although they were not more likely to present with advanced disease, suggesting that the survival difference was not because of delayed presentation. CONCLUSIONS: Patients with HNSCC living in smaller, higher-subsidy apartments have poorer survival despite no apparent delays in presentation. Cancer 2017;123:1998-2005. © 2017 American Cancer Society.

Salivary fistula: Blue dye testing as part of an algorithm for early diagnosis.

Objective: Orocutaneous and pharyngocutaneous fistula (OPCF) is a debilitating complication of head and neck surgery for squamous cell carcinoma (SCC), resulting in delayed adjuvant treatment and prolonged hospitalization. As yet, there is no established test that can help in prompt and accurate diagnosis of OPCF. This study aims to determine the accuracy of bedside blue dye testing and its role as part of an algorithm for early diagnosis. We also analyze the risk factors predisposing to OPCF. Study Design: Retrospective cohort study from 2012 to 2014. Methods: Patients with head and neck SCC who underwent major resection and reconstruction, at risk of OPCF, were included. Results of blue-dye and video-fluoroscopic swallow-studies (VFSS) testing for OPCF were recorded. For the patients that were noted to develop OPCF, the length of time to diagnosis of fistula and subsequent mode of management were examined. Results: Of the 93 patients in this study, 25 (26.9%) developed OPCF. Advanced T-classification (T3/T4) was the only significant predisposing risk factor (p = 0.013). The sensitivity and specificity of the bedside blue dye testing was found to be 36.4% and 100%, respectively. The test positive patients were diagnosed with OPCF at a median of postoperative day (POD) 9.5 as compared to POD 13 for the test negative patients (p = 0.001). Early diagnosis was associated with faster fistula resolution with treatment. Conclusion: Blue dye testing is a simple bedside test that can assist in the early diagnosis of OPCF in patients, allowing treatment to be instituted earlier with improved outcomes. Level of Evidence: 3.

Mutational landscapes of tongue carcinoma reveal recurrent mutations in genes of therapeutic and prognostic relevance.

BACKGROUND: Carcinoma of the oral tongue (OTSCC) is the most common malignancy of the oral cavity, characterized by frequent recurrence and poor survival. The last three decades has witnessed a change in the OTSCC epidemiological profile, with increasing incidence in younger patients, females and never-smokers. Here, we sought to characterize the OTSCC genomic landscape and to determine factors that may delineate the genetic basis of this disease, inform prognosis and identify targets for therapeutic intervention. METHODS: Seventy-eight cases were subjected to whole-exome (n = 18) and targeted deep sequencing (n = 60). RESULTS: While the most common mutation was in TP53, the OTSCC genetic landscape differed from previously described cohorts of patients with head and neck tumors: OTSCCs demonstrated frequent mutations in DST and RNF213, while alterations in CDKN2A and NOTCH1 were significantly less frequent. Despite a lack of previously reported NOTCH1 mutations, integrated analysis showed enrichments of alterations affecting Notch signaling in OTSCC. Importantly, these Notch pathway alterations were prognostic on multivariate analyses. A high proportion of OTSCCs also presented with alterations in drug targetable and chromatin remodeling genes. Patients harboring mutations in actionable pathways were more likely to succumb from recurrent disease compared with those who did not, suggesting that the former should be considered for treatment with targeted compounds in future trials. CONCLUSIONS: Our study defines the Asian OTSCC mutational landscape, highlighting the key role of Notch signaling in oral tongue tumorigenesis. We also observed somatic mutations in multiple therapeutically relevant genes, which may represent candidate drug targets in this highly lethal tumor type.

Transaxillary thyroidectomies: a comparative learning experience of robotic vs endoscopic thyroidectomies.

OBJECTIVE: Robotic and endoscopic approaches have become more accepted in thyroid surgery, with current literature documenting the experience of high-volume centers. We adopted both approaches concurrently, and this series presents our initial experience to assess the more practical option for low- to moderate-volume centers starting out with transaxillary thyroidectomies. STUDY DESIGN: Case series with chart review. SETTING: Tertiary academic center. SUBJECTS AND METHODS: Over a period of 4 years, 101 patients underwent transaxillary thyroidectomies, of whom 48 underwent robotic thyroidectomy and 53 underwent endoscopic thyroidectomy. Data analysis includes patient characteristics, procedure time, thyroid pathology, and postoperative complications. A survey was conducted among surgeons to assess the subjective experience. RESULTS: Endoscopic hemithyroidectomies had a significantly shorter duration of operation (145.8 minutes) vs that of robotic hemithyroidectomies (193.6 minutes), P < .001. The mean time taken for the first 5 hemithyroidectomies vs the last 5 hemithyroidectomies showed a greater drop in the endoscopic group (49.1%) vs the robotic group (18.6%). There were 2 cases of transient recurrent laryngeal nerve injury. In the surgeon survey, the endoscopic technique was perceived to have less need for peripheral support, while the robotic technique was preferred for its shorter learning curve. CONCLUSION: In terms of outcome, both techniques are comparable at least in the initial phase. Based on our early experience, the endoscopic technique may be less intuitive with a longer learning curve, although at steady state, it may be the quicker procedure. This is relevant for low- to moderate-volume centers starting their transaxillary thyroidectomy program.