Specific Subsites Research Articles

Reporting nasal pressure injuries in neonates receiving non-invasive ventilation: a scoping review.

Although neonates receiving Non-Invasive Ventilation (NIV) for respiratory support are at risk for nasal pressure injuries, efforts to standardize reporting are limited. A scoping review was conducted to identify the reporting systems used for describing these injuries. PubMed, Embase, and Web of Science were queried for papers reporting nasal injury with NIV usage in neonates. The primary outcome was reporting system usage. 705 titles and abstracts were screened. 40 papers met inclusion criteria. Most studies were Randomized Clinical Trials (37.5%) or cohort studies (37.5%). Most commonly, nasal injuries were reported using a unique, descriptive scale developed by the authors (10 studies, 25%). The Fischer et al 2010 scale, a three-stage reporting system, was used in 8 studies (20%). While 15 studies (38.0%) reported on specific anatomic subsite injury, only 2 studies (5.0%) employed endoscopy for assessment. Wide heterogeneity in pressure injury reporting secondary to NIV exists across specialties, institutions, and literature.

Concordance between head and neck MRI and histopathology in detecting laryngeal subsite invasion among patients with laryngeal cancer

BackgroundAccuracy of head and neck MRI (HN-MRI) in predicting tumor invasion of laryngeal site/subsites in patients with laryngeal cancer prior to laryngectomy is poorly evaluated in the literature. Therefore, we aim to evaluate the diagnostic value of HN-MRI in accurate pre-operative estimation of tumor invasion to laryngeal subsites in patients with laryngeal cancer.MethodsPatients with laryngeal cancer who underwent HN-MRI for cancer staging and underwent total laryngectomy between 2008 and 2021 were included. Sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy of HN-MRI in predicting tumor invasion of laryngeal subsites were calculated based on concordance between the HN-MRI and histopathological results.ResultsOne hundred and thirty-seven patients underwent total laryngectomy [primary: 82/137(60%), salvage 55/137(40%)]. The utilization of HN-MRI resulted in the downstaging of 16/137 (11.6%) patients and the upstaging of 8/137 (5.8%) patients. For the whole cohort, there was a significant discordance between HN-MRI and histopathology for T-category; out of 116 cT4a disease, 102(87.9%) were confirmed to have pT4a disease, and out of 17 cT3 disease, 9(52.9%) were confirmed to have pT3 disease, p < 0.001. The MRI overall diagnostic accuracy of predicting tumor invasion was 91%, 92%, 82%, 87%, 72%, 76%, 65% and 68% for base of tongue, arytenoid, vocal cord, posterior commissure, pre-epiglottic space, cricoid cartilage, inner thyroid cortex, and subglottis, respectively.ConclusionsIn patients with laryngeal cancer undergoing total laryngectomy, HN-MRI demonstrates promising accuracy in predicting tumor invasion of specific laryngeal subsites (e.g., base of tongue). Our findings showed the potential of HN-MRI as a valuable tool for pre-operative planning and treatment decision-making in this patient population.

Does Segmental Mandibulectomy Involving Critical Functional Sites Affect Quality of Life?

Segmental mandibulectomy (SM) is a morbid procedure, often indicated in the treatment of oral cavity pathology; however, the effect on quality of life resulting from resection of specific mandibular subsites has not previously been investigated. This study's primary aim was to evaluate differences in Health-Related Quality of Life (HRQoL) among patients who underwent segmental mandibulectomy with condylectomy (SMc+) or not (SMc-), and secondarily among patients who underwent SM with symphyseal resection (SMs+) or not (SMs-). A single-centre cross-sectional study was performed, identifying adults who had undergone SM over a 5-year period. Patients who had disease recurrence, further major head and neck surgery, or any surgery 3months prior to participating were excluded. Demographic, disease and treatment data were obtained via chart review. Participants completed the European Organisation for Treatment of Cancer 'General' and 'Head and Neck Specific' HRQoL modules. Condylectomy and midline-crossing resection were the primary and secondary predictor variables, while the primary outcome was HRQoL. Study variables were cross tabulated against predictor and outcome variables to identify potential confounders. The association between condylectomy and symphyseal resection on HRQoL was modelled using linear regression and subsequently with identified confounding factors. Forty-five enrolled participants completed questionnaires, of which 20 had undergone condylectomy and 14 symphyseal resection. Participants were majority male (68.9%) and on average 60.2±18years old, having undergone surgery 3.8±1.8years prior to participation. Prior to adjustment, Condylectomy patients reported significantly worse 'Emotional Function' (mean±standard deviation) (47.7±25.5 vs 68.4±26.6, P=.02), 'Social Function' (46.3±33.6 vs 61.4±28.9, P=.04) and 'Mouth Opening' (61.1±36.7 vs 29.8±38.3, P=.04) compared to the SMC- group. SMs+patients reported significantly worse scores in 'Social Function' (43.9±30.1 vs 48.3±32,1, P=.03), 'Dry Saliva' (65.1±35.3 vs 38.5±33.9, P<.01) and 'Social Eating' (48.5±45.6 vs 30.8±36.4, P<.01) compared to the SMs-group. Following adjustment only 'emotional function' in the SMc comparison retained significance (P=.04). SM causes anatomical distortion resulting in functional deficit. While the condyle and symphysis are theoretically functionally important, our findings suggest that morbidity associated with their resection may be the result of associated surgical and adjuvant treatment burden.

Differential activation of NOTCH1 pathway in HNSCC cell lines of different anatomical sites

Head and neck squamous cell carcinoma (HNSCC) is one of the most frequent types of cancers and the role of NOTCH1 pathway during development of HNSCC is debatable. Here, we have made an attempt to evaluate the NOTCH1 pathway status in HNSCC cell lines from different anatomical subsites. At first, mRNA expression status of NOTCH1 pathway associated genes (NOTCH1/JAG1/JAG2/HES1/HEY1/CD44/FBXW7/HIF1α/VEGF) was analysed in two HNSCC cell lines: FaDu (hypopharyngeal carcinoma) and SCC9 (tongue carcinoma) and was compared with publicly available database. Then, molecular profiling (RNA/protein) of the genes and cell cycle phase distribution analysis were done after DAPT (γ-secretase inhibitor) administration at different concentrations on the cell lines to see the differential effect, if any. High NOTCH1 pathway activation was noted in FaDu cell line than the SCC9. In cytotoxicity assay with DAPT, FaDu showed more sensitivity than SCC9. Therefore, gradual decline of the expression of NOTCH1 pathway associated genes was noted in FaDu with the increasing DAPT concentrations, leading to high S/G2-M arrest of the cell population. Contrastingly, SCC9 showed significant reduced expression of the genes at higher concentration of DAPT with comparatively low S/G2-M arrest of the cell population. The study demonstrates distinct NOTCH1 pathway signature in the HNSCC cell lines of specific sub-sites of head and neck.

Postburn Reconstruction of the Face and Neck.

After studying this article, the participant should be able to: 1. Understand the cardinal principles in the management of postburn deformities in the face and neck. 2. Understand reconstruction of specific subsites in the face and neck affected by burn contracture. 3. Acquire knowledge about the various techniques of burn reconstruction of the face and neck. 4. Grasp technical nuances and select appropriate surgical options for individual cases. Postburn contractures in the face and neck region are multifactorial in origin and difficult to prevent in extensive burns. Facial burns lead to distortion of anatomical landmarks, causing aesthetic, functional, and psychological problems. Each subunit of the face is unique in structure; thus, the surgeon needs to adjust the timing of surgery and the technique according to region and the severity of contracture. Contracture of one unit, especially that of the neck and forehead, can exaggerate the contracture in neighboring subunits. The role of these extrinsic influences must be considered while sequencing surgical procedures. The burn surgeon must be adept in all reconstructive surgery techniques from skin grafting to tissue expanders to microsurgery to obtain the best outcomes. Surgery must be followed up with long-term physical therapy and psychological rehabilitation to help burn survivors with head and neck contractures to integrate back into society.

Association of Tumor Microbiome and Hypoxia Expression Signatures in Different Anatomic Subsites of Head and Neck Cancer

<h3>Purpose/Objective(s)</h3> Tumor response to radiation is dependent on the presence of oxygen with hypoxic tumors requiring a two to three-fold higher dose of radiation to achieve clinical equipoise. Head and neck squamous cell cancers (HNSCC) are the most hypoxic among various cancers, as observed in the The Cancer Genome Atlas (TCGA) dataset of 10,700 samples. Potentially related to this, tumor microenvironment (TME) in specific subsites has more anaerobes compared to the normal oral mucosa. The purpose of our study was to analyze the relationship between tumor subsite, hypoxia, and the local tumor microbiome in HNSCC using data from TCGA. <h3>Materials/Methods</h3> Tumor RNAseq samples from TCGA were processed through the exoTIC (exogenous sequencing in tumors and immune cells) pipeline to identify and count exogenous sequences, filter contaminants, and normalize expression values. The software ‘tmesig' was used to calculate gene expression signatures of the TME, including the Buffa hypoxia (BH) score, a validated gene signature that uses 52 hypoxia-regulated genes. Microbe relative abundances were modeled as the response variable with primary tumor location and a high vs low tertile BH score as predictor variables using a gamma-distributed generalized linear regression via the "stats'' package in R. Adjusted p-value of <0.05 was considered significant. <h3>Results</h3> A total of 357 patients were included [Oral cavity (OC) = 226, Oropharynx (OPx) = 53 and Larynx/Hypopharynx (LHPx) = 78] out of which HPV was present in 12.8%, 71.7% and 10.3% patients respectively in OC, OPx and LHPx tumors. The mean (SD) BH scores were 2.38 (18.17), -3.38 (20.45) and -4.97 (16.74) in OC, OPx and LHPx tumors, respectively, with higher values indicating greater hypoxia. The hypoxia signature was significantly higher for OC tumors compared to OPx (p= 0.044) and LHPx (p = 0.002), but was not statistically different between OPx and LHPx tumors (p= 0.625). Patients with upper tertile of BH scores had 395 microbes significantly enriched in tumors vs 307 microbes in patients with lower tertile of BH. The hypoxia expression signature was significantly associated with 413, 206 and 130 microbes in the OC, OPx and LHPx, respectively. Different strains of microbes were significantly associated with hypoxia depending on the tumor location, specifically, <i>Pseudomonas sp</i> in OC, <i>Actinomyces sp</i> and <i>Sulfurimonas sp</i> in OPx, and <i>Filifactor sp</i> in LHPx. In OPx cancer, there were no microbes significantly associated with hypoxia conditional in the presence of HPV. <h3>Conclusion</h3> Oral cavity tumors were associated with the greatest degree of hypoxia among HNSCC subsites, suggesting a potential mechanism for radiation resistance. In this study, we were able to identify an association between specific anaerobic microbes and relative hypoxia in different tumor subsites. Further investigation is required to determine if this is a causal relationship and whether modification of the microbiome in the TME can lead to reduced hypoxia and improved radiosensitivity and outcomes.

Melanoma predilection for the lower limbs of women compared with men.

The lower limb is a common site for melanoma in women, but the reason for this is not fully understood. To investigate this phenomenon in more detail, we assessed the specific subsites of primary melanoma occurring on the lower limbs of females compared with males across age groups. In a records-based study at an oncology hospital in north-west of England, among an unselected sample of patients with primary invasive melanoma treated between 2002-2015, information was collected on patient age at diagnosis, sex, and co-morbidities, and the tumor thickness and anatomical subsite (thigh, lower leg, foot for lower limb). Of a total sample of 1,522 patients, 316 (227, 72% female) had lower limb melanoma. The most common subsite was lower leg (142 cases with F:M ratio =3.74), followed by thigh (55 cases with F:M = 1.83) and feet (30 cases with F:M = 1.15). At ages<40 years the odds of thigh to foot melanoma was 20 times higher in females than in males (OR 20.0, 95% CI 2.6-152.6) and 7.5 times higher on the lower limb (OR 7.5, 95% CI 1.1-49.2). For ages 40+ years, the odds of females developing thigh melanoma compared to foot melanoma was similar in males versus females (OR 0.8), while the corresponding odds of lower leg melanoma in females versus males remained significantly increased at ages 40-59 and 60+ (OR 4.2 and 2.8 respectively). Our study demonstrates the female predilection for lower limb melanoma persists over most but not all subsites.However, there is heterogeneity in the female to male occurence of lower limb melanoma across subsites and at different ages, which may be linked to relative influence of genetic and environmental risk factors.

Risk factors for head and neck cancer in more and less developed countries: Analysis from the INHANCE consortium.

We analyzed the pooled case-control data from the International Head and Neck Cancer Epidemiology (INHANCE) consortium to compare cigarette smoking and alcohol consumption risk factors for head and neck cancer between less developed and more developed countries. The location of each study was categorized as either a less developed or more developed country. We compared the risk of overall head and neck cancer and cancer of specific anatomic subsites associated with cigarette smoking and alcohol consumption. Additionally, age and sex distribution between categories was compared. The odds ratios for head and neck cancer sites associated with smoking duration differed between less developed and more developed countries. Smoking greater than 20years conferred a higher risk for oral cavity and laryngeal cancer in more developed countries, whereas the risk was greater for oropharynx and hypopharynx cancer in less developed countries. Alcohol consumed for more than 20years conferred a higher risk for oropharynx, hypopharynx, and larynx cancer in less developed countries. The proportion of cases that were young (<45years) or female differed by country type for some HNC subsites. These findings suggest the degree of industrialization and economic development affects the relationship between smoking and alcohol with head and neck cancer.

Allosteric regulation by membranes and hydrophobic subsites in phospholipase A2 enzymes determine their substrate specificity

Lipids play critical roles in several major chronic diseases of our times, including those that involve inflammatory sequelae such as metabolic syndrome including obesity, insulin sensitivity, and cardiovascular diseases. However, defining the substrate specificity of enzymes of lipid metabolism is a challenging task. For example, phospholipase A2 (PLA2) enzymes constitute a superfamily of degradative, biosynthetic, and signaling enzymes that all act stereospecifically to hydrolyze and release the fatty acids of membrane phospholipids. This review focuses on how membranes interact allosterically with enzymes to regulate cell signaling and metabolic pathways leading to inflammation and other diseases. Our group has developed “substrate lipidomics” to quantify the substrate phospholipid specificity of each PLA2 and coupled this with molecular dynamics simulations to reveal that enzyme specificity is linked to specific hydrophobic binding subsites for membrane phospholipid substrates. We have also defined unexpected headgroup and acyl chain specificity for each of the major human PLA2 enzymes, which explains the observed specificity at a structural level. Finally, we discovered that a unique hydrophobic binding site—and not each enzyme’s catalytic residues or polar headgroup binding site—predominantly determines enzyme specificity. We also discuss how PLA2s release specific fatty acids after allosteric enzyme association with membranes and extraction of the phospholipid substrate, which can be blocked by stereospecific inhibitors. After decades of work, we can now correlate PLA2 specificity and inhibition potency with molecular structure and physiological function.

Colorectal cancer among farmers in the AGRICAN cohort study

ObjectivesSpecific farming types and tasks have rarely been studied in relation to colorectal cancer (CRC). We evaluated associations between 5 types of livestock and 13 types of crops in relation to CRC and its subsites within the Agriculture and Cancer (AGRICAN) study. MethodsAGRICAN cohort includes 181,842 agricultural workers living in 11 French geographical areas. Data on farming types and tasks was collected by self-administered questionnaires. We identified 2 609 CRC, 972 right colon, 689 left colon and 898 rectal incident cancer cases during follow-up from 2005 to 2015. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI). ResultsSignificantly increased CRC risk was observed for farmers producing horses (HR=1.18, 95% CI 1.06–1.31), sunflower (HR=1.23, 95% CI 1.03–1.45) and field vegetables (HR=1.18, 95% CI 1.02–1.36). Positive associations were also observed for pig, poultry and wheat/barley. Some associations were observed only for specific subsites: left colon cancer was associated with fruit growing (HR=1.36, 95% CI 1.09–1.70) and potato (HR=1.28, 95% CI 1.05–1.57). Tasks related to livestock (animal care, insecticide treatment, disinfection of milking equipment and building) or to crop (haymaking, sowing, pesticide treatment, seed treatment, harvesting) were also associated with CRC. Duration and size of farming types/task increased the risk for some of the associations. Analysis stratified by sex suggested an interaction with several farming types/task. ConclusionsThe current study showed original and positive findings for several farming types and tasks and CRC risk, overall and by subsites.

Association of TP53 and CDKN2A Mutation Profile with Tumor Mutation Burden in Head and Neck Cancer.

Head and neck squamous cell carcinoma (HNSCC) is a frequently devastating cancer that affects more than a half million people annually worldwide. Although some cases arise from infection with human papillomavirus (HPV), HPV-negative HNSCC is more common, and associated with worse outcome. Advanced HPV-negative HNSCC may be treated with surgery, chemoradiation, targeted therapy, or immune checkpoint inhibition (ICI). There is considerable need for predictive biomarkers for these treatments. Defects in DNA repair capacity and loss of cell-cycle checkpoints sensitize tumors to cytotoxic therapies, and can contribute to phenotypes such as elevated tumor mutation burden (TMB), associated with response to ICI. Mutation of the tumor suppressors and checkpoint mediators TP53 and CDKN2A is common in HPV-negative HNSCC. To gain insight into the relation of the interaction of TP53 and CDKN2A mutations with TMB in HNSCC, we have analyzed genomic data from 1,669 HPV-negative HNSCC tumors with multiple criteria proposed for assessing the damaging effect of TP53 mutations. Data analysis established the TP53 and CDKN2A mutation profiles in specific anatomic subsites and suggested that specific categories of TP53 mutations are more likely to associate with CDKN2A mutation or high TMB based on tumor subsite. Intriguingly, the pattern of hotspot mutations in TP53 differed depending on the presence or absence of a cooccurring CDKN2A mutation. These data emphasize the role of tumor subsite in evaluation of mutational profiles in HNSCC, and link defects in TP53 and CDKN2A to elevated TMB levels in some tumor subgroups.

Transcriptome-Wide Association Study for Inflammatory Bowel Disease Reveals Novel Candidate Susceptibility Genes in Specific Colon Subsites and Tissue Categories

Genome-wide association studies [GWAS] for inflammatory bowel disease [IBD] have identified 240 risk variants. However, the benefit of understanding the genetic architecture of IBD remains to be exploited. Transcriptome-wide association studies [TWAS] associate gene expression with genetic susceptibility to disease, providing functional insight into risk loci. In this study, we integrate relevant datasets for IBD and perform a TWAS to nominate novel genes implicated in IBD genetic susceptibility. We applied elastic net regression to generate gene expression prediction models for the University of Barcelona and University of Virginia RNA sequencing project [BarcUVa-Seq] and correlated expression and disease association research [CEDAR] datasets. Together with Genotype-Tissue Expression project [GTEx] data, and GWAS results from about 60 000 individuals, we employed Summary-PrediXcan and Summary-MultiXcan for single and joint analyses of TWAS results, respectively. BarcUVa-Seq TWAS revealed 39 novel genes whose expression in the colon is associated with IBD genetic susceptibility. They included expression markers for specific colon cell types. TWAS meta-analysis including all tissues/cell types provided 186 novel candidate susceptibility genes. Additionally, we identified 78 novel susceptibility genes whose expression is associated with IBD exclusively in immune (N = 19), epithelial (N = 25), mesenchymal (N = 22) and neural (N = 12) tissue categories. Associated genes were involved in relevant molecular pathways, including pathways related to known IBD therapeutics, such as tumour necrosis factor signalling. These findings provide insight into tissue-specific molecular processes underlying IBD genetic susceptibility. Associated genes could be candidate targets for new therapeutics and should be prioritized in functional studies.

Prognostic significance of lymph node ratio in patients with squamous cell carcinoma of the floor of the mouth

The lymph node ratio (LNR) has been proposed as an independent prognostic factor for survival in patients with oral squamous cell carcinoma (OSCC). However, little attention has been paid to its role in the specific subsite of the floor of the mouth (FOM). The purpose of this study was to evaluate the prognostic significance of the LNR in patients with FOM SCC. A retrospective analysis of 92 patients with FOM SCC who were treated with primary curative resection and neck dissection was conducted. Overall survival (OS) and disease-free survival (DFS) were used to evaluate the prognostic significance of the LNR. Both of these parameters were significantly worse (P < 0.001) in patients with neck metastases. The mean LNR was 0.145 in patients with positive lymph nodes. A LNR <0.145 was predictive of longer DFS, while the receiver operating characteristic curve analysis demonstrated that a LNR ≥0.175 indicated a significantly lower OS. This study confirms that metastatic cervical lymph nodes correlate with an adverse prognosis in patients with FOM SCC, and specifically, a LNR ≥0.145 is predictive. Therefore, the LNR in patients with FOM SCC may be a predictor of survival in these patients.

Lower disease control rates and survival outcomes among Blacks with pharyngeal squamous cell carcinomas compared with Whites: a retrospective analysis at the University of Florida

Disparate clinical outcomes for pharyngeal squamous cell carcinoma (PSCC) of the oropharynx (OPSCC) and hypopharynx (HPSCC) have been observed in Black compared with White patients. Higher tobacco and alcohol use has been associated with decreased survival in Black patients with PSCC. Higher human papilloma virus (HPV) infection rates, associated with specific subsites of the oropharynx, are linked to improved overall survival (OS). Using an institutional cohort of Black and White patients with PSCC, we performed a retrospective analysis using multiple disease endpoints including local control (LC), local-regional control (LRC), freedom from distant metastases (DMFS), OS,cause-specific survival (CSS), and recorded tobacco and alcohol use. 1419 patients [Black (n = 111) and White (n = 1,308)] treated for PSCC from 1973 to 2013 were evaluated. PSCC 5- and 10-year LC, LRC, and DMFS and CSS rates were lower for Blacks. Notably, Black patients with OPSCC had higher stage cancers, higher percentage of soft palate tumors, and lower percentage of base of tongue cancers, were more likely to receive radiotherapy, and hadhigher tobacco and alcohol use. OS was significantly lower in Black patients at both anatomic sites, with the greatest difference observed for OPSCC. Multivariate analysis showed race and tobacco independently predicted DMFS, OS, and CSS; however, tobacco use had a greater impact on DMFS (HR 2.5, p = 0.021) than race (HR 1.9, p = 0.027). Overall, we propose that the higher burden of tobacco use along with a lower rate of tumors arising from traditional HPV-related subsites were important contributors to disparate disease outcomes seen in our Black patients.

Validation of Selected Head and Neck Cancer Prognostic Markers from the Pathology Atlas in an Oral Tongue Cancer Cohort.

Simple SummaryPrognostic markers are used to predict the aggressiveness of a cancer and to help decide the best treatment for individual patients. Despite intense research, reliable prognostic markers for oral cancer are still few. The aim of the present study was to validate selected prognostic markers for head and neck cancer identified by unbiased approaches in oral tongue cancer, a specific subsite of head and neck cancer. From a list of 790 markers, we selected three based on reported prognostic value as well as expression pattern and availability of validated antibodies. These were analyzed on transcriptional and protein level in a cohort of 121 oral tongue cancers. Only one of the markers showed significant prognostic value when controlling for established prognostic parameters. Our study highlights the need to evaluate prognostic markers in homogeneous groups of cancers and to control for established prognostic parameters.The Pathology Atlas is an open-access database that reports the prognostic value of protein-coding transcripts in 17 cancers, including head and neck cancer. However, cancers of the various head and neck anatomical sites are specific biological entities. Thus, the aim of the present study was to validate promising prognostic markers for head and neck cancer reported in the Pathology Atlas in oral tongue squamous cell carcinoma (OTSCC). We selected three promising markers from the Pathology Atlas (CALML5, CD59, LIMA1), and analyzed their prognostic value in a Norwegian OTSCC cohort comprising 121 patients. We correlated target protein and mRNA expression in formalin-fixed, paraffin-embedded cancer tissue to five-year disease-specific survival (DSS) in univariate and multivariate analyses. Protein expression of CALML5 and LIMA1 were significantly associated with five-year DSS in the OTSCC cohort in univariate analyses (p = 0.016 and p = 0.043, respectively). In multivariate analyses, lymph node metastases, tumor differentiation, and CALML5 were independent prognosticators. The prognostic role of the other selected markers for head and neck cancer patients identified through unbiased approaches could not be validated in our OTSCC cohort. This underlines the need for subsite-specific analyses for head and neck cancer.

Molecular landscape of head and neck cancer and implications for therapy.

Head and neck squamous cell carcinomas (HNSCC) arising from the oral cavity, pharynx, and larynx constitute the 6th most common human cancer. Human papillomavirus (HPV)-positive tumours are distinct from HPV-negative counterparts, with HPV status affording clear clinical utility, prognostic benefit and better treatment outcomes. In contrast to their HPV-positive counterparts, HPV-negative tumours are characterized by high mutational load and chromosomal aberrations, with varying copy number alteration (CNA) profiles. HNSCC are distinct tumours at the chromosomal, gene and expression levels, with additional insight gained from immune profiling. Based on mutational analyses, HNSCC are categorized as HPV-positive, HPV-negative CNA-silent, and HPV-negative CNA-high tumours. Furthermore, gene expression profiling segregates these tumours into atypical, classical, basal, and mesenchymal, with clear differences observed between tumours of the oral cavity, oropharynx, hypopharynx and larynx. Additional immune profiling further classifies tumours as either immune-active or immune-exhausted. The clinical utility and impact of these tumour molecular subtypes however remains to be determined. HNSCC harbor high levels of somatic mutations. They display loss at 3p and 18q and gain at 3q and 8q, with mutations in CDKN2A, TP53, CCND1, EGFR, PIK3CA, PTEN, NOTCH1, NSD1, FAT1, AJUBA and KMT2D. Important pathways include the p53 and RB pathways which are involved in cell cycle control and are frequently lost in HPV-negative tumours, the WNT-β-catenin pathway related to the mesenchymal subtype and smoking etiology, and the PI3K pathway which includes the most common genetic alteration in HPV-positive HNSCC. Understanding the mutational, genomic and transcriptomic landscape of HNSCC has leveraged better therapeutic approaches to manage this group of diseases, and it is hoped that additional insight into the molecular subtypes of HNSCC and its specific subsites will further drive improved strategies to stratify and treat patients with this debilitating disease.

Head and Neck Cancer Clinical Research on ClinicalTrials.gov: An Opportunity for Radiation Oncologists

PurposeMany improvements in head and neck cancer (HNC) outcomes are related to optimization of radiation therapy (RT) dose, fractionation, normal-tissue sparing, and technology. However, prior work has shown that the literature of randomized controlled trials is dominated by industry-sponsored trials that have lower rates of incorporating RT. We characterized HNC clinical trials, hypothesizing that RT-specific research questions may be relatively underrepresented among HNC randomized controlled trials. Methods and MaterialsA web query of all open interventional trials on www.ClinicalTrials.gov was performed using search terms “head and neck cancer” and specific HNC subsites. Trial details were captured including the modality used, principal investigator (PI) specialty, funding, and whether the study tested a RT-modality specific hypothesis. Chi-square testing and logistic regression were used to compare groups. ResultsThere were 841 open HNC trials, including definitive (47.6%) and recurrent/metastatic (41.9%) populations. Most trials (71.7%) were phase I or nonrandomized phase II studies, rather than phase III or randomized phase II (28.3%). Among single-arm studies, most (79.6%) incorporated systemic therapy (ST), and fewer (25.2%) incorporated RT. Even fewer phase III and randomized phase II trials tested an RT-specific hypothesis (11.1%), compared with ST-related hypotheses (77.1%; P < .001); trials were more likely to test an RT-hypothesis if the study PI was a radiation oncologist (20.9% vs 6.0%; P < .001). Among RT trials, most early-phase studies tested novel modalities (eg, stereotactic body radiation therapy, proton therapy), whereas most later-phase studies tested dose and fractionation. RT-focused trials had low rates of federal (10.4%) or industry (2.6%) funding. ConclusionsRT-specific research hypotheses are a minority of phase II-III HNC trials, which mostly focus on incorporating ST in the definitive or recurrent/metastatic setting and have higher rates of industry funding. Radiation oncologist PI leadership and increased nonindustry funding access may ensure that RT-specific hypotheses are incorporated into trial design.

Phase III Radiation Oncology Clinical Trials: A Snapshot of the Last Two Decades

Modern radiation therapy is an integral modality in the treatment of cancer, yet data on the current state of Phase III radiation therapy trials remains scarce. We sought to characterize the landscape of radiation oncology phase III clinical trials in the last two decades. We searched ClinicalTrials.gov for phase III randomized controlled trials (RCTs) between 2003 and 2018. Randomized, multi-arm trials assessing a therapeutic intervention in adult cancer patients were included. Trials where radiation therapy was a main intervention were identified and grouped according to specific disease subsites and other trial information. Differences in trial factors between radiotherapy and other oncologic interventional trials were analyzed. Out of the 600 phase III RCTs identified, 15 trials were solely radiation therapy trials (2.5%). By disease subsite, we identified 3 (20%) breast cancer trials, 2 (13.3%) gastrointestinal cancer trials, 2 (13.3%) genitourinary cancer trials, 2 (13.3%) colorectal cancer trials, and 2 (13.3%) head and neck cancer trials. Radiation trials were less likely to be industry funded when compared to other oncological trials (20.0% vs 79.3% respectively, p<0.001). Furthermore, 73.3% of radiation trials had cooperative group sponsorship (vs 30.3% for other oncologic trials, p<0.001). Radiotherapy trials had less restrictions on including healthier patients (ECOG score 0 to 1) when compared to trials of systemic therapy (p<0.001). Even though radiation therapy is currently recognized as an integral modality in treating cancer patients, radiation therapy trials remain scarce and largely underfunded. Lastly, while cooperative groups seem to play an important role in radiation therapy trials, stakeholders are encouraged to assess and address ways to increase quality radiotherapy research.

Annual malignant transformation rate of oral leukoplakia remains consistent: A long-term follow-up study.

Numerous clinical and histopathological characteristics have been associated with malignant transformation (MT) of oral leukoplakia (OL), including classic and differentiated epithelial dysplasia, but MT predictions remain suboptimal. The objective of this study was to determine the annual MT rate of OL and to identify clinicopathological risk factors associated with MT. 170 patients with OL were included in this retrospective cohort study, 117 females and 53 males. Follow-up ranged from 12 to 219months (median 54). The analyzed variables included age, gender, smoking habits, clinical presentation, subsite, size and treatment. In a subgroup of 140 patients, histopathological diagnoses were reviewed with regard to the presence of dysplasia, discerning both classic dysplasia and differentiated dysplasia. MT occurred in 23% of the patients, resulting in an annual MT rate of 4.9% (95% CI: 3.5 - 6.6) which remained consistent. High-risk subsite (tongue and floor of mouth) was the only clinical predictor for MT (Hazard Ratio=2.7, 95% CI: 1.3 - 5.5, p=0.007). In 140 patients, classic dysplasia (Hazard Ratio=7.2, 95% CI: 1.6 - 33.1, p=0.012) and differentiated dysplasia (Hazard Ratio=6.6, 95% CI: 1.2 - 25.4, p=0.026) were predictors for MT. Binary grading between dysplasia and no dysplasia was significant for predicting MT (Hazard Ratio=6.4, 95% CI: 1.5 - 27.5, p=0.013). Since annual MT rate of OL remains stable during follow-up, regular long-term or even life-long follow-up is advocated. Specific oral subsites and epithelial dysplasia are predictors for MT of OL.

The contribution of specific subsites to catalytic activities in active site architecture of a GH11 xylanase.

Xylanase with high specific activity plays a crucial role in hemicellulose biodegradation and has important industrial application. The amino acids located in the active site determine the enzyme biological characterization. In this study, structure bioinformatics analysis and alanine screening experiments were performed to explore the roles of amino acids at each subsite of the GH11 xylanase active site. There are highly conserved amino acids at - 2 to + 1 subsites, and the network of the interactions is concentrated near the catalytic sites (E86, E178). However, the amino acids at relatively distal subsites, especially at the + 2 and + 3 subsites, are few but diverse. Alanine substitution of amino acids in the active site architecture exerted different impacts on catalytic efficiency. Interestingly, mutants Y180A at the + 2 subsite and Y96A at the + 3 subsite had reduced enzymatic activities by almost 95%, which indicate that these two aromatic residues are necessary for the catalysis of substrates in addition to the highly conserved residues at the - 2 and + 1 subsites. Moreover, in these two subsites, aromatic amino acids with different side-chain properties also affected enzyme activity. The mutants Y180W and Y96W showed 6.2% and 12.8% increase in specific activities by comparison with wild-type enzyme at 50°C, respectively. We elucidated the interaction between amino acids and substrates in the active site, which will aid understanding of the protein-ligand interaction in enzyme engineering. • Xylanase of GH11 family is a good industrial candidate. • The roles of residues at each subsite of GH11 xylanase active site are explored. • The two aromatic residues at the + 2 and + 3 subsites are necessary for the catalysis. • Y180W and Y96W increased the enzymatic activity by 6.2% and 12.8% at low temperature.