Neurotrophin signaling is a central mechanism of salivary dysfunction after irradiation that disrupts myoepithelial cells.

The mechanisms that prevent regeneration of irradiated (IR) salivary glands remain elusive. Bulk RNAseq of IR versus non-IR human salivary glands showed that neurotrophin signaling is highly disrupted post-radiation. Neurotrophin receptors (NTRs) were significantly upregulated in myoepithelial cells (MECs) post-IR, and single cell RNAseq revealed that MECs pericytes, and duct cells are the main sources of neurotrophin ligands. Using two ex vivo models, we show that nerve growth factor (NGF) induces expression of MEC genes during development, and upregulation of NTRs in adult MECs is associated with stress-induced plasticity and morphological abnormalities in IR human glands. As MECs are epithelial progenitors after gland damage and are required for proper acinar cell contraction and secretion, we propose that MEC-specific upregulation of NTRs post-IR disrupts MEC differentiation and potentially impedes the ability of the gland to regenerate.

Placement technique impacts gastrostomy tube-related complications amongst head and neck cancer patients.

OBJECTIVES: Percutaneous endoscopic gastrostomy (PEG) placement is essential for the provision of enteral nutrition in select head and neck cancer (HNC) patients. Minimally invasive tube placement is facilitated through one of two techniques, push or pull, but there have been conflicting results regarding safety profiles of these procedures. The objectives of this study were to determine the association of PEG insertion technique with gastrostomy tube complications, including stomal metastases. METHODS: A multi-institutional retrospective cohort study of patients with HNC undergoing PEG insertion by either the pull (gastroscope assisted) or push (fluoroscopy assisted) technique was performed. Tube-related complications included infection, dislodgement, deterioration, leak, and other. Adjusted analysis was performed via a multivariable logistic regression model. RESULTS: 1,575 patients were included across three institutions. Tube-related complications occurred in 36% of patients, the most common being peristomal leak (13%) and infection (16%). The push technique (OR 2.66, 95% CI: 1.42-4.97), and the presence of T4 disease (OR 4.62, 95% CI: 1.58-13.51), were associated with a greater risk of developing any tube-related complication. Infection rates were similar between pull and push cohorts. All detected stoma metastases occurred with the pull technique, with an overall prevalence of 0.32% amongst the cohort. CONCLUSIONS: The push technique is associated with a greater risk of developing any tube-related complication, but the rate of stomal metastases may be higher with the pull technique. There is potential for quality improvement measures to improve tube-related complications associated with either technique.

Out-of-pocket costs associated with head and neck cancer treatment.

BACKGROUND: Out-of-pocket costs (OOPC) associated with treatment have significant implications on quality of life and survival in cancer patients. Head and neck cancer patients face unique treatment-related challenges, but to date OOPC have been understudied in this population. AIMS: This study aims to identify and measure OOPC for patients with head and neck cancer (HNC) in Ontario. METHODS: HNC patients between 2015 and 2018 at Princess Margaret Cancer Centre in Toronto were recruited. Participants completed OOPC questionnaires and lost income questions during radiation, post-surgery, and 3, 6, 12, and 24 months after completion of treatment. Associations between OOPC and treatment modality and disease site were tested with multivariable hurdle regression. RESULTS: A total of 1545 questionnaires were completed by 657 patients. Median estimated OOPC for the total duration of treatment for participants undergoing chemoradiation was $1452 [$0-14 616], for surgery with adjuvant radiation or chemoradiation (C/RT) was $1626, for radiation therapy alone was $635, and for surgery alone was $360. The major expenses for participants at the mid-treatment time-point was travel (mean $424, standard error of the mean [SEM] $34) and meals, parking, and accommodations (mean $617, SEM $67). In multivariable analysis, chemoradiation, surgery with C/RT, and radiation were associated with significantly higher OOPC than surgery alone during treatment (791% higher, p < .001; 539% higher, p < .001; 370% higher, p < .001 respectively) among patients with non-zero OOPC. Participants with non-zero OOPC in the laryngeal cancer group paid 49% lower OOPC than those with oropharyngeal cancers in adjusted analysis (p = .025). CONCLUSIONS: Patients undergoing treatment for HNC pay significant OOPC. These costs are highest during treatment and gradually decrease over time. OOPC vary by patient demographics, clinical factors, and, in particular, treatment modality.

A 4-gene signature from histologically normal surgical margins predicts local recurrence in patients with oral carcinoma: clinical validation.

Prognostic biomarkers for recurrence of Oral Squamous Cell Carcinoma (OSCC) are urgently needed. We aimed to independently validate a 4-gene expression signature (MMP1, COL4A1, P4HA2, THBS2) predictive of OSCC recurrence risk. Gene expression was measured using Nanostring nCounter® in 245 histologically normal surgical resection margins from 62 patients. Association between risk scores for individual patients and recurrence was assessed by Kaplan-Meier analysis. Signature performance was quantified by concordance index (CI), hazard ratio (HR) and the area under receiver operating characteristics (AUC). Risk scores for recurrence were significantly higher than recurrence-free patients (p = 9.58e-7, Welch's t-test). A solid performance of the 4-gene signature was determined: CI = 0.64, HR = 3.38 (p = 1.4E-4; log-rank test), AUC = 0.71. We showed that three margins per patient are sufficient to preserve predictive performance (CI = 0.65; HR = 2.92; p = 2.94e-3; AUC = 0.71). Association between the predicted risk scores and recurrence was assessed and showed HR = 2.44 (p = 9.6E-3; log-rank test, N = 62). Signature performance analysis was repeated using an optimized threshold (70th percentile of risks), resulting in HR = 3.38 (p = 1.4E-4; log-rank test, N = 62). The 4-gene signature was validated as predictive of recurrence risk in an independent cohort of patients with resected OSCC and histologically negative margins, and is potentially applicable for clinical decision making on adjuvant treatment and disease monitoring.

What Touched Your Heart? Collaborative Story Analysis Emerging From an Apsáalooke Cultural Context.

Community-based participatory research and decolonizing research share some recommendations for best practices for conducting research. One commonality is partnering on all stages of research; co-developing methods of data analysis is one stage with a deficit of partnering examples. We present a novel community-based and developed method for analyzing qualitative data within an Indigenous health study and explain incompatibilities of existing methods for our purposes and community needs. We describe how we explored available literature, received counsel from community Elders and experts in the field, and collaboratively developed a data analysis method consonant with community values. The method of analysis, in which interview/story remained intact, team members received story, made meaning through discussion, and generated a conceptual framework to inform intervention development, is detailed. We offer the development process and method as an example for researchers working with communities who want to keep stories intact during qualitative data analysis.

Comorbidity and performance status as independent prognostic factors in patients with head and neck squamous cell carcinoma.

BACKGROUND: The purpose of this study was to evaluate the individual and combined relationship of comorbidity and performance status (PS) on head and neck squamous cell carcinoma (HNSCC) survival. METHODS: Six hundred patients with HNSCC were prospectively recruited. Comorbidity and PS were measured using the Charlson Comorbidity Index (CCI) and the Eastern Cooperative Oncology Group (ECOG) Scale. Outcomes were overall survival (OS) and cancer-specific survival (CSS). RESULTS: A total of 48.3% of the patients had at least 1 comorbidity, and 42.3% had impaired PS at baseline. There was no correlation between CCI and ECOG (Spearman's ρ = 0.033; p = .42). In multivariate analysis, CCI score was significantly associated with OS (p = .01). ECOG was not associated with OS, but seems to act as an effect modifier in the association between comorbidity and OS. CCI and ECOG were not associated with CSS. CONCLUSION: CCI and ECOG scores both provide prognostic information in predicting OS in HNSCC, but a significant association with CSS was not observed.

Comparison of Health State Utility Measures in Patients With Head and Neck Cancer.

IMPORTANCE: Accurate measurement of health state utilities (HU) is the cornerstone for cost-utility analyses and the valuation of quality of life for given health states. Current indirect methods of HU derivation lack face validity for patients with head and neck cancer. The appropriateness of these measures compared with direct methods, such as the standard gamble (SG), time trade-off (TTO), and visual analog scale (VAS), have not been assessed in this patient population. OBJECTIVE: To assess the convergent and construct validities of 5 different HU derivation methods in patients with head and neck cancer. DESIGN, SETTING, AND PARTICIPANTS: In a cross-sectional study, we recruited 100 consecutive patients with squamous cell carcinoma of the upper aerodigestive tract treated in the outpatient surgical oncology clinics of the Princess Margaret Cancer Centre from August 1 through October 31, 2014. We enrolled patients with a minimum of 3 months of follow-up after completion of treatment and no evidence of recurrent or metastatic disease. Participants completed SG, TTO, and VAS exercises, the EuroQoL instrument (EQ-5D), and the Health Utilities Index Mark 3 (HUI3) questionnaire. Data analysis was performed November 1 through December 15, 2014. EXPOSURES: Head and neck cancer and HU measures. MAIN OUTCOMES AND MEASURES: We assessed convergent validity of the 5 HU instruments through Spearman rank order correlation assessment. We determined construct validity through a priori hypotheses relating HU scores with clinical indexes of disease severity. RESULTS: The SG and TTO measures generated higher mean (SD) utility scores (0.91 [0.17] and 0.94 [0.14], respectively) than the VAS, EQ-5D, and HUI3 (0.76 [0.19], 0.82 [0.18], and 0.75 [025], respectively) (P < .001). The maximum score of 1.0 was reported in 60 of 99 cases (61%) for the SG and 75 of 99 cases (76%) for the TTO (a significant ceiling effect), in contrast to 5 of 99 cases (5%) for the VAS, 29 of 99 cases (29%) for the EQ-5D, and 6 of 99 cases (6%) for the HUI3. The VAS showed strong correlations with the EQ-5D (ρ = 0.63 [P < .001]) and HUI3 (ρ = 0.50 [P < .001]), and the HUI3 strongly correlated with the EQ-5D (ρ = 0.67 [P < .001]), whereas the SG and TTO generally correlated poorly with other HU measures (ρ range, 0.19-0.29) and with one another (ρ = 0.21 [P < .001]). The VAS, EQ-5D, and HUI3 were able to discriminate between participants who underwent salvage surgery compared with those who underwent primary surgery (mean [SD] utility scores, 0.48 [0.13] vs 0.76 [0.20] [P = .006], 0.62 [0.17] vs 0.83 [0.19] [P = .004], and 0.37 [0.29] vs 0.78 [0.22] [P = .004], respectively). Mean EQ-5D utility scores monotonically increased over time since completion of treatment (0.26 [P = .01]). The HUI3 yielded lower utility values for participants with laryngeal cancer (mean [SD], 0.59 [0.29]). The SG and TTO measures frequently generated utility scores that contradicted our hypothesized expectations. CONCLUSIONS AND RELEVANCE: Indirect HU measures may be more reflective of the health status of patients with head and neck cancer than direct measures. Current instruments lack face validity for attributes germane to this population.

Association of two BRM promoter polymorphisms with head and neck squamous cell carcinoma risk.

The SWI/SNF chromatin remodeling complex is an important regulator of gene expression that has been linked to cancer development. Expression of Brahma (BRM), a critical catalytic subunit of SWI/SNF, is lost in a variety of solid tumors. Two novel BRM promoter polymorphisms (BRM-741 and BRM-1321) have been correlated with BRM loss and elevated cancer risk. The aim(s) of this study were to examine BRM expression in head and neck squamous cell carcinoma (HNSCC) and to correlate BRM polymorphisms with HNSCC risk. BRM expression studies were performed on eight HNSCC cell lines and 76 surgically resected tumor samples. A case-control study was conducted on 668 HNSCC patients (oral cavity, oropharynx, larynx and hypopharynx) and 700 healthy matched controls. BRM expression was lost in 25% of cell lines and 16% of tumors. The homozygous genotype of each polymorphism was significantly associated with increased HNSCC risk [BRM-741: adjusted odds ratio (aOR) 1.75, 95% CI 1.2-2.3, P < 0.001; BRM-1321: aOR 1.65, 95% CI 1.2-2.2, P < 0.001]. Individuals that were homozygous for both BRM polymorphisms had a more than 2-fold increase in the risk of HNSCC (aOR 2.23, 95% CI 1.5-3.4, P < 0.001). A particularly elevated risk was seen within the oropharynx, human papillomavirus-positive subgroup for carriers of both homozygous variants (aOR 3.09, 95% CI 1.5-6.8, P = 0.004). BRM promoter polymorphisms appear to act as susceptibility markers of HNSCC with potential utility in screening, prevention and treatment.

A gene signature in histologically normal surgical margins is predictive of oral carcinoma recurrence.

BACKGROUND: Oral Squamous Cell Carcinoma (OSCC) is a major cause of cancer death worldwide, which is mainly due to recurrence leading to treatment failure and patient death. Histological status of surgical margins is a currently available assessment for recurrence risk in OSCC; however histological status does not predict recurrence, even in patients with histologically negative margins. Therefore, molecular analysis of histologically normal resection margins and the corresponding OSCC may aid in identifying a gene signature predictive of recurrence. METHODS: We used a meta-analysis of 199 samples (OSCCs and normal oral tissues) from five public microarray datasets, in addition to our microarray analysis of 96 OSCCs and histologically normal margins from 24 patients, to train a gene signature for recurrence. Validation was performed by quantitative real-time PCR using 136 samples from an independent cohort of 30 patients. RESULTS: We identified 138 significantly over-expressed genes (> 2-fold, false discovery rate of 0.01) in OSCC. By penalized likelihood Cox regression, we identified a 4-gene signature with prognostic value for recurrence in our training set. This signature comprised the invasion-related genes MMP1, COL4A1, P4HA2, and THBS2. Over-expression of this 4-gene signature in histologically normal margins was associated with recurrence in our training cohort (p = 0.0003, logrank test) and in our independent validation cohort (p = 0.04, HR = 6.8, logrank test). CONCLUSION: Gene expression alterations occur in histologically normal margins in OSCC. Over-expression of the 4-gene signature in histologically normal surgical margins was validated and highly predictive of recurrence in an independent patient cohort. Our findings may be applied to develop a molecular test, which would be clinically useful to help predict which patients are at a higher risk of local recurrence.

Low prevalence of human papillomavirus in oral cavity carcinomas.

BACKGROUND: Increasing evidence shows that Human Papillomavirus (HPV) is preferentially associated with some head and neck squamous cell carcinomas (HNSCCs), with variable infection rates reported. METHODS: We assessed HPV involvement in HNSCC using the Roche Linear Array HPV Genotyping Test, which can detect 37 different HPV types. We examined the prevalence of HPV infection in 92 HNSCCs (oropharynx, oral cavity, and other HNSCC sites). RESULTS: HPV was frequently detected in oropharyngeal cancers (OPCs) (16/22, 73%), but was uncommon in oral cavity cancers (2/53, 4%), and in other HNSCC subsites (1/17, 6%). HPV positive tumors were associated with patients that were 40-60 years old (p = 0.02), and node positive (p = < 0.0001). HPV 16 was the most prevalent type, but other types detected included 6, 18, 33, 35, 45, and 52/58. CONCLUSION: Our results show that in contrast to oropharyngeal cancers, oral cancers and other HNSCCs infrequently harbor HPV.

Quality of life in patients with maxillectomy prostheses.

BACKGROUND: This cross-sectional study sought to determine patient quality of life and function after prosthetic rehabilitation for maxillary and palate defects following cancer resection. METHODS: Sixty-nine patients were identified, 42 participated in the study (61%). The Obturator Functioning Scale (OFS) and 4 general quality of life measures (Mental Health Inventory [MHI], Impact of Events Scale [IES], Illness Intrusiveness Ratings Scale [IIRS], and Centre for Epidemiologic Studies Depression Scale [CES-D]) were correlated with clinical parameters. RESULTS: Leakage when swallowing foods was the most frequently reported problem with the obturator (29%). Positive correlation was noted between the OFS and both the IES subscales (p < .01) and CES-D (p < .001). Difficulty with speech and eating was associated with increased avoidance of social situations. The surgical approach had a significant effect on the OFS, IES, and MHI subscales (p < .01). CONCLUSION: These results support the findings that good obturator function is associated with a better quality of life.

I-125 versus Pd-103 for low-risk prostate cancer: morbidity outcomes from a prospective randomized multicenter trial.

PURPOSE: The purpose of this study was to test the hypothesis that the shorter half-life of Pd-103 versus I-125 results in a shorter duration of radiation-related symptoms after prostate brachytherapy. METHODS: As of February 2000, 110 of a planned total of 380 patients with 1997 American Joint Commission clinical stage T1c-T2a prostatic carcinoma (Gleason grade 2-6, prostate-specific antigen, 4-10 ng/mL) had been randomly assigned to implantation with I-125 (144 Gy, TG-43) or Pd-103 (125 Gy, NIST-99). Isotope implantation was performed by standard techniques, using a modified peripheral loading pattern. Treatment-related morbidity was monitored by mailed questionnaires, using standard American Urologic Association (AUA) and Radiation Therapy Oncology Group criteria at 1, 3, 6, 12, and 24 months. Use of alpha-blockers to relieve obstructive symptoms was not controlled for but was noted at each follow-up point. All patients reported here have a minimum 1-year follow-up. Randomization was carried out at a central enrollment office where eligibility criteria were confirmed and the patient assigned by computerized random number generator to one of the two treatment arms. Patients were assigned to 95 blocks of four. Most statistical comparisons shown here are by Student's unpaired t-test at specific follow-up times, as indicated in the figure legends. Additionally, considering the patients' scores change overtime, repeated measures were incorporated in a mixed model assuming an unstructured covariance matrix. RESULTS: Patients in each arm were well matched by preimplant prostate volume, AUA score, and age. The AUA scores peaked at the 1-month point for both isotopes and then gradually declined. The difference was greatest at 6 months, when I-125 patients had a mean AUA score of 16 (+/- 8), compared with 11 (+/- 10) for the Pd-103 patients. By 12 months, mean AUA scores for the Pd-103 patients had decreased to 12 (+/- 9), compared with 13 (+/- 8) for the I-125 patients. At 6 months after implantation, 41% of Pd-103 patients were still taking alpha-blockers, versus 44% of I-125 patients. The differences between isotopes were more marked in patients with a low pretreatment AUA score or smaller preimplant transrectal ultrasonography volume. Results of the mixed model, incorporating repeated measures for each patient, showed that the effect of isotope choice on AUA score depended on time. This effect was further dependent on baseline AUA score, but not on transrectal ultrasonography volume or on age. Urinary and rectal morbidity was generally low, typically grade 1 or 2. There was a trend to greater morbidity with I-125 than with Pd-103, most markedly at the 6-month time point. DISCUSSION: Patients treated with Pd-103 recovered from their radiation-induced prostatitis sooner than I-125 patients. It appears that patients with minimal pretreatment urinary obstructive symptoms are the most likely to experience implant-related exacerbations of their symptoms and are the most likely to benefit from the more rapid half-life of Pd-103 rather than I-125.

Prostate brachytherapy in obese patients.

PURPOSE: To identify and illustrate the potential problems with brachytherapy in obese patients. METHODS AND MATERIALS: Three patients with body mass index greater than 30 were treated with prostate brachytherapy. Transrectal ultrasound (TRUS) was performed using a 6.0-MHz Siemens Sonoline Prima ultrasound machine and a Barzell-Whitmore stepper unit. The patients' weight required use of an accessory table support. RESULTS: Once set up, there was ample room to maneuver, providing that the patient's legs were abducted fully. TRUS imaging of the prostate was unaffected by patients' obesity. The amount of periprostate adipose tissue visualized on TRUS appeared to be no different than that noted in nonobese patients. Similarly, there was no increased distance between the prostate and rectal surface, either on preimplant CT or transverse TRUS. To date, our experience is that the perineal skin to prostate distance was not so great that standard 20-cm applicator needles could not be used. For the 2 sub-350-pound patients who could be imaged on our CT scanner, postimplant target coverage (V100) was 88% and 95%. CONCLUSIONS: Standard TRUS and brachytherapy needles are sufficient to implant even the largest patients.