Combined chemoradiotherapy showed improved outcome with early-stage HPV-positive oropharyngeal cancers.

BACKGROUND: The revised 8th Edition American Joint Committee on Cancer (AJCC) Head and Neck Staging Manual distinguishes HPV-mediated from non-HPV-mediated oropharyngeal cancer (OpSCC). The objective was to analyze OpSCC treatment modalities and outcomes. METHODS: A retrospective study of OpSCC patients treated with radiotherapy or chemoradiotherapy between January 1st, 2000, and December 31st, 2008, as identified from the BC Cancer Registry. All patients received treatment at cancer clinics and had at least 5 years follow-up post-treatment. A total of 1259 OpSCC patients were identified. After initial chart reviews, 288 patients were excluded from further analysis and the majority (n = 198) was due to not receiving curative treatment. Based on the availability of formalin-fixed, paraffin-embedded (FFPE) tissue, patients were divided into two cohorts: Study Cohort (FFPE available, n = 244) and General Cohort (FFPE unavailable, n = 727). The Study Cohort was restaged according to AJCC 8th Edition based on p16 immunohistochemistry status. Kaplan-Meier analysis was used to estimate the 5-year overall survival (OS), disease-specific survival (DSS), and locoregional recurrence-free survival (LFS). RESULTS: Among 971 patients, OpSCC age-adjusted incidence rate was observed to have increased from 2.1 to 3.5 per 100,000 between 2000 and 2008. The General Cohort was relatively older than the Study Cohort (60.1 ± 10.5 vs. 57.3 ± 9.4), but both cohorts were predominantly males (78.3% vs. 76.2%). Amongst the Study Cohort, 77.5% were p16-positive, of whom 98.4% were down staged in the 8th Edition. These early-stage patients showed OS improvement for those treated with chemoradiation, compared to radiation alone (85.8% vs. 73.1%, p = 0.05). CONCLUSIONS: OpSCC incidence is increasing in BC. The addition of chemotherapy to radiotherapy may portend a benefit in OS even for early-stage p16-positive OpSCC. Additional research is necessary to assess the safety of treatment de-escalation even among early-stage disease.

Therapeutic silencing of miR-652 restores heart function and attenuates adverse remodeling in a setting of established pathological hypertrophy.

Expression of microRNA-652 (miR-652) increases in the diseased heart, decreases in a setting of cardioprotection, and is inversely correlated with heart function. The aim of this study was to assess the therapeutic potential of inhibiting miR-652 in a mouse model with established pathological hypertrophy and cardiac dysfunction due to pressure overload. Mice were subjected to a sham operation or transverse aortic constriction (TAC) for 4 wk to induce hypertrophy and cardiac dysfunction, followed by administration of a locked nucleic acid (LNA)-antimiR-652 (miR-652 inhibitor) or LNA control. Cardiac function was assessed before and 8 wk post-treatment. Expression of miR-652 increased in hearts subjected to TAC compared to sham surgery (2.9-fold), and this was suppressed by ∼95% in LNA-antimiR-652-treated TAC mice. Inhibition of miR-652 improved cardiac function in TAC mice (fractional shortening:29±1% at 4 wk post-TAC compared to 35±1% post-treatment) and attenuated cardiac hypertrophy. Improvement in heart function was associated with reduced cardiac fibrosis, less apoptosis and B-type natriuretic peptide gene expression, and preserved angiogenesis. Mechanistically, we identified Jagged1 (a Notch1 ligand) as a novel direct target of miR-652. In summary, these studies provide the first evidence that silencing of miR-652 protects the heart against pathological remodeling and improves heart function.

MicroRNAs differentially regulated in cardiac and skeletal muscle in health and disease: potential drug targets?

The identification of non-coding RNA species, previously thought of as 'junk' DNA, adds a new dimension of complexity to the regulation of DNA, RNA and protein. MicroRNAs are short non-coding RNA species that control gene expression, are dysregulated in settings of cardiac and skeletal muscle disease and have emerged as promising therapeutic targets. MicroRNAs specifically enriched in cardiac and skeletal muscle are called myomiRs and play an important role in cardiac pathology and skeletal muscle biology. Moreover, microRNA profiles are altered in response to exercise and disease; thus, their potential as therapeutic drug targets is being widely explored. In the cardiovascular field, therapeutic inhibition of microRNAs has been shown to be effective in improving cardiac outcome in preclinical cardiac disease models. MicroRNAs that promote skeletal muscle regeneration are attractive therapeutic targets in muscle wasting conditions where regenerative capacity is compromised.

Tumor Bed Margins Versus Specimen Margins in Oral Cavity Cancer: Too Close to Call?

INTRODUCTION: The routine assessment of intraoperative margins has long been the standard of care for oral cavity cancers. However, there is a controversy surrounding the best method for sampling surgical margins. The aim of our study is to determine the precision of a new technique for sampling tumor bed margins (TBMs), to evaluate the impact on survival and the rate of free flap reconstructions. METHODS: This retrospective cohort study involved 156 patients with primary cancer of the tongue or floor of the mouth who underwent surgery as initial curative treatment. Patients were separated into 2 groups: one using an oriented TBM derived from Mohs' technique, where the margins are taken from the tumor bed and identified with Vicryl sutures on both the specimen and the tumor bed, and the other using a specimen margins (SMs) driven technique, where the margins are taken from the specimen after the initial resection. Clinicopathologic features, including margin status, were compared for both groups and correlated with locoregional control. Precision of per-operative TBM sampling method was obtained. RESULTS: A total of 156 patients were included in the study, of which 80 were in TBM group and 76 were in SM group. Precision analysis showed that the oriented TBM technique pertained a 50% sensitivity, 96.6% specificity, 80% positive predictive value, and an 87.5% negative predictive value. Survival analysis revealed nonstatistically significant differences in both local control (86.88% vs 83.50%; P = .81) as well as local-regional control (82.57% vs 72.32%; P = .21). There was a significant difference in the rate of free flap-surgeries between the 2 groups (30% vs 64.5%; P < .001). CONCLUSION: Our described oriented TBM technique has demonstrated reduced risk of free flap reconstructive surgery, increased precision, and similar prognostic in terms of local control, locoregional control, and disease-free survival when compared to the SM method.

Synchrony in head and neck surgery: Feasibility and outcomes of simultaneous scapular free flap reconstruction.

BACKGROUND: The scapula free flap is a versatile option in head and neck reconstruction but is less amenable to simultaneous harvest and ablation. METHODS: Retrospective series (2015-2021) of consecutive scapula flaps. Cases categorized as simultaneous versus sequential, compared for operative time, oncological and patient-reported outcomes. RESULTS: Seventy consecutive scapula free flaps were performed (n = 21 simultaneous, n = 49 sequential). Mandible reconstruction was performed in 51.0% and 61.9% of sequential and simultaneous cases, respectively; 49.0% and 38.1% addressed bony maxillary defects. Simultaneous surgery reduced operative time by 37.9% (151 min, p < 0.00001) and there were fewer tracheostomies performed (p < 0.005). Rates of positive margins and free flap compromise were equivalent (n = 1, 4.8% vs. n = 2, 4.1%). There was no difference in patient-reported outcomes. CONCLUSIONS: This series demonstrates feasibility, efficacy, and outcomes of bony scapula reconstruction of maxillofacial defects comparing simultaneous and sequential approaches. Benefits of the two-team approach are highlighted including decreased operative time.

A Unique Case of Primary EBV-Positive, HPV-Negative Nasopharyngeal Carcinoma Located in the Tonsil.

Nasopharyngeal carcinomas (NPC) are non-keratinizing squamous cell carcinomas of the nasopharynx associated with Epstein-Barr virus (EBV). When occurring outside of the nasopharynx, they are referred to as lymphoepithelioma-like carcinomas (LELCs) and present the same morphology as NPC. LELC have been described in other head and neck regions such as the salivary glands and the soft palate. LELC can also occur in the oropharynx, are associated with human papillomavirus (HPV) and are typically negative for EBV. We herein present a unique case of a 78-year-old Chinese male with EBV-positive, HPV-negative NPC of the left tonsil. His presenting symptom was a left-sided lymph node. There was no evidence of nasopharyngeal lesion seen on physical examination, PET and MRI. The patient was treated with curative-intent external beam radiotherapy which delivered 70 Gy (Gy) to the gross tumour and lymph nodes, and 56 Gy electively to the ipsilateral neck using a volumetric modulated arc therapy technique. This is the first case of primary tonsil EBV-positive NPC described in the literature.

Maxillectomy defects: Virtually comparing fibular and scapular free flap reconstructions.

BACKGROUND: This study virtually compares patient-specific fibular and scapular reconstructions for maxillectomies. METHODS: Nine maxillectomy defects were created on 10 maxillas and virtually reconstructed with patient-specific fibulas and scapulas. Reconstructions were compared for restoring midface cephalometrics, dental implantability, and pedicle length. RESULTS: Of 90 maxillectomy defects, the vertically oriented scapula provided improved orbital floor and maxillary height reconstructions (p < 0.001), albeit at the cost of dental implantability compared to the fibula (p < 0.001). In two defects crossing the midline, the fibula, allowing for more osteotomies, provided improved maxillary projection. In the remaining three defects crossing the midline, the horizontally oriented scapula was comparable to the fibula. Fibular and scapular reconstructions were amenable for dental implantation and had similar pedicle lengths, although favoring scapula in extensive defects. CONCLUSION: Fibular and scapular reconstructions of maxillectomy defects provide unique strengths. This virtual analysis can guide a goal-oriented reconstruction based on defect type and patient-specific goals.

Giant Frontal Sinus Osteomas: Demographic, Clinical Presentation, and Management of 10 Cases.

BACKGROUND: Osteomas are rare benign and slow-growing osteogenic tumors mainly involving frontal and ethmoid sinuses. OBJECTIVES: The primary objective of our study is to present the management of cases of giant frontal sinus osteomas. Secondarily, we describe our modified unilateral osteoplastic flap approach without obliteration to remove these osteomas. METHODS: Retrospective chart review at a tertiary academic center ("Hôpital de l'Enfant-Jésus") from July 2006 to October 2016. Demographics characteristics, tumor characteristics, presenting symptoms, frontal sinus surgery technique (osteoplastic flap, endoscopic surgery, or a combination of both), and outcomes of giant frontal sinus osteomas (≥30 mm) were recorded. For laterally placed osteomas, tumors with posterior wall involvement, orbital roof involvement, or intracranial extension, the modified unilateral osteoplastic flap approach was used. A decision-making algorithm is proposed for the choice of surgical approach. RESULTS: Ten giant frontal osteomas were analyzed (7 men and 3 women). The mean age at diagnosis was 38 years old (range, 24-55 years; median, 39 years; standard deviation, 11 years). The most common presenting symptom was headache (43% of symptomatic patients). Five patients had complications preoperatively due to tumoral extension (sinusitis, cellulitis, mucocele, optic nerve compression, and convulsions). One patient was treated endoscopically, 3 patients had an open approach and 6 patients had a combined technique. One patient experienced a postoperative complication (local infection treated with oral antibiotics). Six patients had minimal residual tumor with one patient needing reoperation. CONCLUSION: Osteomas are rare paranasal sinus tumors. Due to the proximity to noble structures, a giant frontal osteoma should be managed surgically. The modified unilateral osteoplastic flap without obliteration offers good long-term surgical and aesthetic results. Osteomas are not known for malignant transformation and recurrences are rare; thus, subtotal resection is warranted and safe when a cleavage plan is not found.

Juvenile psammomatoid ossifying fibroma: A radiolucent lesion to suspect preoperatively.

We present the cases of 2 expansive juvenile psammomatoid ossifying fibromas from sinonasal origin. Our first patient presented with a fronto-ethmoidal mass invading the orbit and the cranial base and had a bicoronal approach for tumor removal. The second patient also had orbital involvement and underwent an endoscopic surgery. Complete resection of juvenile psammomatoid ossifying fibromas is paramount to avoid recurrence, thus preoperative recognition of their characteristic thick outer mantle and radiolucent core on imaging is key, but can be challenging. We herein discuss and propose a novel algorithm of differential diagnoses of facial bone lesions based on radiologic appearance.

Epithelial Myoepithelial Carcinoma of the Nasal Cavity: Clinical, Histopathological, and Immunohistochemical Distinction of a Case Report.

BACKGROUND: Epithelial myoepithelial carcinomas (EMCs) are rare low-grade salivary gland tumors. Here, we report the case of a 75-year-old man presenting with an oncocytic variant of EMC of the nasal cavity, initially diagnosed as an oncocytoma. METHODS: Our patient underwent functional sinus surgery in 2012. On pathology, an oncocytic neoplasm was found in the right nasal cavity, characterized by fragments of uniform bland oncocytic cells with bilayered arrangement of nuclei. Immunohistochemical stains demonstrated biphasic cells: luminal epithelial and basal cell-type myoepithelial cells. The tumor was best diagnosed as an oncocytoma. In 2015, the patient presented with a recurrent right inferior turbinate lesion, compatible with oncocytic EMC. RESULTS: The patient underwent oncological surgery and received adjuvant radiotherapy. He had no disease recurrence. CONCLUSION: Different variants of EMCs exist, such as oncocytic EMC. EMCs should be treated aggressively because they can be locally invasive, recur, and give rise to distant metastases.

Functional outcomes of fasciocutaneous free flap and pectoralis major flap for salvage total laryngectomy.

BACKGROUND: Pectoralis major muscle flaps (PMMFs) and fasciocutaneous free flaps (FFFs) are commonly used for reconstruction of the surgical defect after salvage total laryngectomy. This study compared swallowing function in patients who underwent reconstruction with either PMMF or FFF. METHODS: This study was based on a retrospective cohort of patients treated at the CHU de Québec between January 2000 and March 2015. Demographics, chemoradiation data, surgical protocol, pathologic results, complications, evolution, esophageal dilation, diet intake, and feeding tube dependence were documented. RESULTS: A total of 126 patients were analyzed (93 PMMFs and 33 FFFs). Of the patients who received PMMFs, 38.7% had a limited oral intake compared to 15.2% of patients who received FFFs (odds ratio [OR] 3.54; 95% confidence interval [CI] 1.25-9.99; P = .02). The need for esophageal dilation tended to be greater for PMMF patients (25% vs 9%; OR 3.38; 95% CI 0.94-12.13; P = .06). Complication rates were similar. CONCLUSION: The FFF reconstruction led to better results in terms of swallowing function than PMMF reconstruction.

Physical Activity Programs with Post-Intervention Follow-Up in Children: A Comprehensive Review According to Categories of Intervention.

Only 9% of Canadian children meet the National Guidelines of 60 min of daily moderate-to-vigorous intensity physical activity. The aim of this review is to assess the mid- and long-term effectiveness of physical activity interventions and their impact on cardiovascular risk factors in children. We assessed the success of interventions within three different categories: those using a behavioural and social approach, an informational approach or an environmental approach. The average number of children included in these studies was 860 (range of 30-5106); the age range was from 2 to 18 years; and the mean intervention duration was 1607 min (range of 12-8160 min). The length of follow-up post-intervention averaged 13 months (ranging from 0.25 to 96 months). A positive impact on physical activity was found in 74% and on any measured outcomes in 90% of the studies reviewed. However, the benefits of physical activity interventions decreased with longer follow-up. Regardless of the approaches, physical activity interventions improved cardiovascular risk factors. However, the challenge of any program is to maintain beneficial effects once the intervention is completed. These findings will inform the development of future intervention programs in order to optimize sustained cardiovascular benefits.

Outcomes review of modern hearing preservation technique in cochlear implant.

INTRODUCTION: Preservation of residual hearing in cochlear implantation is a main concern for patients and otologists. New electrode arrays as well as development of minimally invasive technique have allowed the expansion of indication criteria for cochlear implantation. The loss of residual low-frequency hearing is thought to be the result of many factors. Opinions differ in regards with the electrodes array characteristics, the surgical implantation technique and the pharmacological therapy used. OBJECTIVE: The aim of this research is to analyze the available information pertaining to hearing preservation with cochlear implantation. RESULTS: Both cochleostomy and round window approaches are adequate, but should rely on the anatomic position of the round window membrane. No electrode design had a higher rate of hearing preservation, either a standard or shorter length was used, or a straight or contoured array. The speed of insertion has a significant impact on hearing preservation and vestibular function. A slow insertion should be used for all cochlear implant insertion, hearing preservation or not. However, the optimal speed of insertion is still unclear. Moreover, the use of steroids regardless of the route or the timing, along with intraoperative topical steroids, had a positive impact on hearing preservation. CONCLUSION: Classic atraumatic insertion maneuvers, very slow and delicate insertion and the use of intraoperative corticosteroids improve hearing outcomes. Whichever the surgeon's preferences, all surgical modifications are aimed at the same goal: protection of the delicate intracochlear structures with preservation of residual low-frequency hearing to improve speech perception abilities.

Inhibition of miR-154 Protects Against Cardiac Dysfunction and Fibrosis in a Mouse Model of Pressure Overload.

Expression of miR-154 is upregulated in the diseased heart and was previously shown to be upregulated in the lungs of patients with pulmonary fibrosis. However, the role of miR-154 in a model of sustained pressure overload-induced cardiac hypertrophy and fibrosis had not been assessed. To examine the role of miR-154 in the diseased heart, adult male mice were subjected to transverse aortic constriction for four weeks, and echocardiography was performed to confirm left ventricular hypertrophy and cardiac dysfunction. Mice were then subcutaneously administered a locked nucleic acid antimiR-154 or control over three consecutive days (25 mg/kg/day) and cardiac function was assessed 8 weeks later. Here, we demonstrate that therapeutic inhibition of miR-154 in mice with pathological hypertrophy was able to protect against cardiac dysfunction and attenuate adverse cardiac remodelling. The improved cardiac phenotype was associated with attenuation of heart and cardiomyocyte size, less cardiac fibrosis, lower expression of atrial and B-type natriuretic peptide genes, attenuation of profibrotic markers, and increased expression of p15 (a miR-154 target and cell cycle inhibitor). In summary, this study suggests that miR-154 may represent a novel target for the treatment of cardiac pathologies associated with cardiac fibrosis, hypertrophy and dysfunction.

Novel hyperactive glucocorticoid receptor isoform identified within a human population.

Glucocorticoids serve as important therapeutic agents in diseases of inflammation, but clinical use, especially in advanced septic shock, remains controversial because of the unpredictable response. Prior studies correlate human glucocorticoid receptor (hGR) isoforms with a decreased response to steroid therapy. Further analysis of additional hGR isoforms may improve the understanding of the steroid response. Ninety-seven human volunteers' blood samples were surveyed for hGR isoforms. An isoform matching National Center for Biotechnology Informatics (NCBI) hGRα (hGR NCBI) served as a reference. Two isoforms were of particular interest-one isoform had three nonsynonymous single-nucleotide polymorphisms (SNPs) (hGR NS-1), and the second had a single-nucleotide deletion (hGR DL-1) resulting in a truncated protein. Transactivation potentials were measured using a luciferase reporter assay. Human glucocorticoid receptor NS-1 had activity more than twice of hGR NCBI, whereas hGR DL-1 demonstrated less than 10% of the activity of hGR NCBI. Cotransfection of two isoforms revealed that the presence of hGR NS-1 increased transactivation potential, whereas hGR DL-1 decreased activity. Synthetic constructs isolating individual and paired SNPs of hGR NS-1 were created to identify the SNP responsible for hyperactivity. Transactivation studies revealed a SNP within the ligand-binding domain exerted the greatest influence over hyperactivity. In evaluating the response to hydrocortisone, hGR NCBI and hGR NS-1 displayed an increased dose-dependent response, but hGR NS-1 had a response more than twice hGR NCBI. Characterization of the novel hyperactive hGR NS-1 provides insight into a possible mechanism underlying the unpredictable response to steroid treatment.

Identification of putative endogenous retroviruses actively transcribed in the brain.

Remnant proviral sequences in the genome resulting from the ancient germline infection of exogenous retroviruses are called endogenous retroviruses (ERVs). The transcriptional activation of human ERVs (HERVs) in the brain of patients with some neurologic diseases suggests that ERVs may participate in certain disease processes in the central nervous system. In this study, we identified putative murine ERVs (MuERVs) which are transcriptionally active in the brain and characterized their biological properties to better understand the ERVs' roles in the brain pathophysiology. The brain and selective non-nervous tissues (heart, muscle, adrenal gland, and salivary gland) of female C57BL/6J mice were subjected to RT-PCR analyses of MuERV expression by amplifying the 3'-end U3 regions and full-length/subgenomic transcripts. The expression patterns of the U3 regions and subgenomic transcripts in the brain were unique compared to the other tissues as well as the genomic MuERV profile. Two putative MuERVs (8,027 and 5,668 bp) were mapped on the mouse genome (chromosome 10, and chromosomes 4 and 8, respectively) using the MuERV U3 sequences, which were evidently expressed in the brain, as probes. Biological properties of these putative MuERVs, such as transcription potential, primer binding site, coding potential, integration age, recombination, and flanking host genes, were characterized. In particular, one of the two putative MuERV isolates had coding potentials for intact group specific antigen (gag), and truncated polymerase (pol) and envelope (env) polypeptides, while the other was defective for all three polypeptides. The findings from this study suggest that a specific group of MuERVs are constitutively expressed in the brain and they may participate in normal and pathogenic events pertaining to the brain through their replication gene products (e.g., gag and env polypeptides) as well as interactions with flanking host genes.