Outcomes of surgical versus non-surgical treatment of resectable T4a laryngeal and hypopharyngeal carcinoma.

OBJECTIVE: Surgery is the recommended treatment for resectable T4a laryngeal and hypopharyngeal carcinoma. Non-surgical treatment is an option in a select few patients. METHOD: This retrospective study was undertaken to assess the treatment outcomes in patients with resectable T4a carcinoma of the larynx and hypopharynx who received either surgical or non-surgical treatment at our institute and to assess factors influencing these outcomes. RESULTS: A total of 120 patients were included in the study. They were divided into groups A, B and C based on the presence of extralaryngeal spread through laryngeal membrane, cartilage or both. The overall survival was better among patients who received surgery than those who received non-surgical treatment in the three groups. The factor influencing overall survival was the treatment given in the form of surgical versus non-surgical treatment. CONCLUSION: Surgery is the preferred treatment for T4a laryngeal and hypopharyngeal carcinoma, even in patients with extralaryngeal spread without cartilage erosion.

Revised recommendations from the CSO-HNS taskforce on performance of tracheotomy during the COVID-19 pandemic - what a difference a year makes.

BACKGROUND: During the early part of the COVID-19 pandemic, the Canadian Society of Otolaryngology - Head & Neck Surgery (CSO-HNS) task force published recommendations on performance of tracheotomy. Since then, our understanding of the virus has evolved with ongoing intensive research efforts. New literature has helped us better understand various aspects including patient outcomes and health care worker (HCW) risks associated with tracheotomy during the COVID-19 pandemic. Accordingly, the task force has re-evaluated and revised some of the previous recommendations. MAIN BODY: Based on recent evidence, a negative reverse transcription polymerase chain reaction (RT-PCR) COVID-19 swab status is no longer the main deciding factor in the timing of tracheotomy. Instead, tracheotomy may be considered as soon as COVID-19 swab positive patients are greater than 20 days beyond initial symptoms and 2 weeks of mechanical ventilation. Furthermore, both open and percutaneous surgical techniques may be considered with both techniques showing similar safety and outcome profiles. Additional recommendations with discussion of current evidence are presented. CONCLUSION: These revised recommendations apply new evidence in optimizing patient and health care system outcomes as well as minimizing risks of COVID-19 transmission during aerosol-generating tracheotomy procedures. As previously noted, additional evidence may lead to further evolution of these and other similar recommendations.

Role of α- and ß-adrenergic signaling in phenotypic targeting: significance in benign and malignant urologic disease.

The urinary tract is highly innervated by autonomic nerves which are essential in urinary tract development, the production of growth factors, and the control of homeostasis. These neural signals may become dysregulated in several genitourinary (GU) disease states, both benign and malignant. Accordingly, the autonomic nervous system is a therapeutic target for several genitourinary pathologies including cancer, voiding dysfunction, and obstructing nephrolithiasis. Adrenergic receptors (adrenoceptors) are G-Protein coupled-receptors that are distributed throughout the body. The major function of α1-adrenoceptors is signaling smooth muscle contractions through GPCR and intracellular calcium influx. Pharmacologic intervention of α-and ß-adrenoceptors is routinely and successfully implemented in the treatment of benign urologic illnesses, through the use of α-adrenoceptor antagonists. Furthermore, cell-based evidence recently established the antitumor effect of α1-adrenoceptor antagonists in prostate, bladder and renal tumors by reducing neovascularity and impairing growth within the tumor microenvironment via regulation of the phenotypic epithelial-mesenchymal transition (EMT). There has been a significant focus on repurposing the routinely used, Food and Drug Administration-approved α1-adrenoceptor antagonists to inhibit GU tumor growth and angiogenesis in patients with advanced prostate, bladder, and renal cancer. In this review we discuss the current evidence on (a) the signaling events of the autonomic nervous system mediated by its cognate α- and ß-adrenoceptors in regulating the phenotypic landscape (EMT) of genitourinary organs; and (b) the therapeutic significance of targeting this signaling pathway in benign and malignant urologic disease. Video abstract.

A systematic review of reports of quality improvement for bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is the most common morbidity of preterm infants, and its incidence has not responded to research and intervention efforts to the same degree as other major morbidities associated with prematurity. The complexity of neonatal respiratory care as well as persistent inter-institutional variability in BPD rates suggest that BPD may be amenable to quality improvement (QI) efforts. We present a systematic review of QI for BPD in preterm infants. We identified 22 reports from single centers and seven from collaborative efforts published over the past two decades. In almost all of the reports, respiratory QI interventions successfully reduced BPD or other key respiratory measures, particularly for infants with birth weight over 1000 g. Several themes and lessons from existing reports may help inform future efforts in both research and QI to impact the burden of BPD.

Relationship of depth of invasion to survival outcomes and patterns of recurrence for T3 oral tongue squamous cell carcinoma.

INTRODUCTION: Current research is elucidating how the addition of depth of invasion (DOI) to the 8th edition of the American Joint Committee on Cancer (AJCC) TNM staging for oral cavity squamous cell carcinoma influences its prognostic accuracy. However, there is limited research on survival in pT3N0M0 oral tongue SCC (OTSCC) patients when stratifying by DOI. OBJECTIVES: Determine 5-year overall survival (OS), and cancer-specific survival (CSS) for patients with pT3N0M0 oral OTSCC based on shallow DOI (<10 mm) and deep DOI (10-20 mm). METHODS: Retrospective review involving three tertiary care cancer centers in North America. cT3N0M0 OTSCC patients receiving primary surgical treatment from 2004 to 2018 were identified. Inclusion: age > 18 years old and confirmation of pT3N0M0 OTSCC on surgical pathology. Exclusion: patients undergoing palliative treatment or previous head and neck surgery/radiotherapy. Analysis comprised two groups: shallow pT3 (tumor diameter > 4 cm, DOI < 10 mm) and deep pT3 (DOI 10 mm-20 mm). RESULTS: One hundred and four patients with pT3N0M0 OTSCC were included. Mean age was 59.1 years (range: 18-80.74). Age, gender, and Charlson Comorbidity Index were similar between the two groups (p > 0.05). Recurrence, LVI, PNI, and positive margins were more common in deep T3 tumors (P < 0.05). 5-year OS (50% vs 26%, p = 0.006) and CSS (72% vs 24%, p = 0.005) were worse in deep pT3 tumors. Deep pT3 disease was an independent predictor of OS (p = 0.004) and CSS (p = 0.01) on Cox-Regression analysis. CONCLUSION: DOI is an independent predictor of poor survival in pT3N0M0 OTSCC patients. Consideration should be given to escalating adjuvant therapy for deep pT3N0M0 OTSCC patients.

Transcriptional and translational abundance of visfatin (NAMPT) in buffalo ovary during estrous cycle and its in vitro effect on steroidogenesis.

Visfatin is a highly conserved adipokine protein having multiple biological effects, including regulation of reproduction. Evidence in recent years has shown a pivotal role of visfatin in ovarian functions. The present study was conducted to evaluate the mRNA and protein abundance of visfatin in ovarian follicles and corpora lutea (CL) during different stages of their development in the ovary of water buffalo (Bubalus bubalis) and to investigate the role of visfatin on estradiol (E2) and progesterone (P4) secretion. Ovarian follicles were categorized in to small (F1), medium (F2), large (F3), and preovulatory (F4) follicles, whereas the CL were categorized into early (CL1), mid (CL2), late (CL3), and regressing (CL4) CL stage. In follicles, the mRNA and protein abundance of visfatin increased with an increase in follicle size in granulosa cells (GCs) and theca interna (TI) cells. In CL, the transcript of visfatin was significantly (P < 0.05) higher in the late luteal phase (CL3) than that in other phases. The translational abundance of visfatin was significantly higher in the mid and late luteal phase. Visfatin was localized in the cytoplasm of GC and TI of ovarian follicles and small and large luteal cells of CL. GCs were cultured in vitro and treated at 0, 1, and 10 ng/mL visfatin either alone or in the presence of FSH (30 ng/mL) or IGF-I (10 ng/mL) for 48 h. The luteal cells were treated with visfatin at 0, 1, and 10 ng/mL dose for 48h. There was significant (P < 0.05) increase in estradiol (E2) secretion from GCs at 10 ng/mL dose of visfatin and visfatin (10 ng/mL) +IGF-I (10 ng/mL). Visfatin also increased (P < 0.05) progesterone (P4) secretion from cultured luteal cells at both 1 and 10 ng/mL dose. In GCs, visfatin in the presence of IGF-I increased the transcriptional abundance of cytochrome P45019A1 (CYP19A1), the gene for key enzyme aromatase. In luteal cells, the visfatin increased mRNA abundance of factors involved in progesterone synthesis viz. steroidogenic acute regulatory protein (StAR), cytochrome P45011A1 (CYP11A1), 3beta-hydroxysteroid dehydrogenase (HSD3B1). The present study provided evidence that visfatin is expressed in ovarian follicles and CL of buffalo ovary and visfatin has a stimulatory effect on estradiol and progesterone secretion in ovarian cells of water buffalo.

Two-Point versus Three-Point Fixation in the Management of Zygomaticomaxillary Complex Fractures: A Comparative Study.

Introduction: The zygoma plays an important role in the facial contour for both cosmetic and functional reasons; therefore, zygomatic bone injuries should be properly diagnosed and adequately treated. Comparison of various surgical approaches and their complications can only be done objectively using outcome measurements that require a protocol for management and long-term follow-up. The objectives of this study were to compare the efficacy of zygomatic bone after treatment with open reduction internal fixation (ORIF) using two-point fixation and ORIF using three-point fixation and compare the outcome of two procedures. Materials and Methods: Twenty patients were randomly divided equally into two groups. In Group A, ten patients were treated by ORIF using two-point fixation by miniplates and in Group B, ten patients were treated by ORIF using three-point fixation by miniplates. They were evaluated with their advantages and disadvantages and the difference between the two groups was observed. Results: We found that postoperative facial and neurological complications are minimum in two-point fixation group. Based on this study, open reduction and internal fixation using two-point fixation by miniplates is sufficient and the best available treatment of choice for the management of zygomaticomaxillary complex fractures. Discussion: Alignment of the fracture at three points and fixation at two stable points provide the most accurate and satisfactory postoperative results. Two-point interosseous fixation at the "buttress" fracture and the frontozygomatic (FZ) fracture is suitable for routine surgery. The results of these studies confirm with the present study that two-point fixation provided better stability in patients with clinical and radiological evidence of fracture in FZ and zygomaticomaxillary buttress area.

An outlook on procedures of conjugating folate to (co)polymers and drugs for effective cancer targeting.

Folate receptors (FRs) are expressed in vast majority of cancers. Selective targeting of the FRs is, therefore, one of the most popular and sought-after strategies for improving the efficacy of cancer therapeutics. Variety of approaches involving folate conjugation to several well-known and novel, nontoxic, biodegradable, and biocompatible (co)polymers have been attempted and successfully applied to a large number of nanoparticulate drug delivery systems (micelles, liposomes, nanoparticles, quantum dots, mesoporous silica-based materials, and others) in the last decade-and-a-half. Standard and novel synthetic approaches were utilized for the conjugation, followed by the formulation of the drug delivery modality. In most of the cases, the targeted system lived up to its reputation, validating its usefulness in targeted cancer therapeutics. The present review summarizes the progress and state-of-the-art synthetic methodologies for folate conjugation to (co)polymers, drugs, and nucleic acids. The limitations of the FR targeting are discussed in brief to give the reader the other side of the story. Finally, the information on marketed folic acid conjugates highlight their industrial applications.

Quality by design (QbD) approach in processing polymeric nanoparticles loading anticancer drugs by high pressure homogenizer.

Polymeric nanoparticles prepared using high pressure homogenizer (HPH) present some unique challenges during manufacturing which can be better understood by application of quality by design (QbD) approaches. The present review highlights the ways to identify the critical material attributes which includes the anticancer drugs, polymers, surfactants, solvent system and dispersion system. A comprehensive understanding of the critical processing parameters like pressure and number of cycles during the working of HPH used in putting forward the critical quality attributes such as size, shape, surface charge or droplet stabilization. Such QbD approach will involve development of an effective control strategy for would ensure safe encapsulation of anticancer drugs for successful product development. Proper addressing of the issues related to scaling-up would lead to successful commercialization of the nano-sized formulations loaded with anticancer drugs.

Recommendations from the CSO-HNS taskforce on performance of tracheotomy during the COVID-19 pandemic.

INTRODUCTION: The performance of tracheotomy is a common procedural request by critical care departments to the surgical services of general surgery, thoracic surgery and otolaryngology - head & neck surgery. A Canadian Society of Otolaryngology - Head & Neck Surgery (CSO-HNS) task force was convened with multi-specialty involvement from otolaryngology-head & neck surgery, general surgery, critical care and anesthesiology to develop a set of recommendations for the performance of tracheotomies during the COVID-19 pandemic. MAIN BODY: The tracheotomy procedure is highly aerosol generating and directly exposes the entire surgical team to the viral aerosol plume and secretions, thereby increasing the risk of transmission to healthcare providers. As such, we believe extended endotracheal intubation should be the standard of care for the entire duration of ventilation in the vast majority of patients. Pre-operative COVID-19 testing is highly recommended for any non-emergent procedure. CONCLUSION: The set of recommendations in this document highlight the importance of avoiding tracheotomy procedures in patients who are COVID-19 positive if at all possible. Recommendations for appropriate PPE and environment are made for COVID-19 positive, negative and unknown patients requiring consideration of tracheotomy. The safety of healthcare professionals who care for ill patients and who keep critical infrastructure operating is paramount.

Reduced risk of suicidal behaviours associated with the treatment of hidradenitis suppurativa with tumour necrosis factor alpha antagonists: results from the US FDA Adverse Events Reporting System pharmacovigilance database.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic, recurrent condition that presents as painful, suppurating lesions in the apocrine gland-bearing skin regions. HS has been associated with increased suicidal behaviours (SB), independent of any treatment. TNF-alpha antagonists are used to treat moderate-to-severe HS and have also been associated with SB, a factor that could confound the decision to use the TNF-α antagonists in the moderately to severely affected HS patients, who may already be experiencing increased SB risk. OBJECTIVES: To determine presence or absence of a safety signal for SB when HS is treated with TNF-α antagonists. METHODS: We calculated the reporting odds ratios (ROR) with 95% CI of SB associated with treatment for HS with TNF-α antagonists vs. the reference group of all other treatments for HS in the US Food and Drug Administration pharmacovigilance database from 1 January 2004 to 31 March 2019. A second analysis excluded isotretinoin (which has been used to treat HS and has also been associated with SB) from the reference group. RESULTS: There was a signal for decreased risk of SB with TNF-α antagonists (ROR = 0.1959, 95% CI 0.1247-0.3079; z = 7.071, P < 0.0001] vs. all other HS treatments; the ROR did not change significantly after isotretinoin was excluded from the reference group. CONCLUSIONS: Treatment of HS with TNF-α antagonists is associated with a decreased risk of SB.

Cytokine gene variants and treatment outcome of cisplatin-based concomitant chemoradiotherapy in cervical cancer.

Background: Cervical cancer is the second most common cancer among women after breast cancer. Its standard treatment is cisplatin-based concomitant chemoradiotherapy. Chronic inflammation in uterine cervix triggers both pro- and anti-inflammatory pathways. The unpredictability in toxicity and efficacy of treatment is a major challenge. We hypothesized a link between IL-1, IL-6 and TNF gene variants and treatment response.Material & Methods: We genotyped 246 cervical cancer cases and 246 controls by PCR, PCR-RFLP and ARMS-PCR. Treatment and response were evaluated by RECIST criteria. Chemotherapy and radiation doses were same for all patients, whilst 48 were followed-up for 36 months after treatment.Results: SNPs in IL-1RN, IL-1ß, IL-6 and TNFα were linked with cervical cancer. Cases with certain allele combinations in IL-1RN, IL-1ß, IL-6(-597A/G) and TNF-α showed odds ratios (95% CI) of up to 17.54 (2.7-24.08) for the presence of cervical cancer. Variant IL-1ß (-511T/C) was linked to vital status but none were linked to overall survival.Conclusion: Certain cytokine gene variants may help detect susceptibility to cervical cancer and predict response to chemoradiotherapy.

Genotypic analysis of XRCC4 and susceptibility to cervical cancer.

Background: XRCC4 encodes a DNA repair protein which maintains genome stability by repairing double-strand breaks by the error-prone method. Defects in the protein-encoding gene lead to impairment of DNA repair process and accumulation of DNA damage, a hallmark of cancer development. We hypothesised that variants in XRCC4 are linked to cervical cancer.Material and methods: Genotyping of XRCC4 variants viz. intron3 DIP (rs28360071), intron7 DIP (rs28360017), G-1394T(rs6869366) and G-652T (rs2075685) was carried out in 246 women with cervical cancer cases and 246 control women.Results: There were several links to cervical cancer: intron3 DIP (rs28360071) II genotype (p = 0.002) and I allele (odds ratio is 0.54-0.89) (p = 0.004), intron7 DIP (rs28360017) II genotype (p = 0.003) and I allele (odds ratio 0.68 [0.53-0.88]) (p = 0.004), and G-652T (rs2075685) genotype (p = 0.044) and the T allele (odds ratio 1.35 [1.03-1.77]) (p = 0.032). In combining data into haploviews, the DDGG allele combination had an odds ratio of 0.12 (0.04-0.39) (p= 0.029) and the IIGT combination an odds ratio of 3.08 (1.25-7.55) (p = 0.01) for cervical cancer.Conclusion: Our results suggested that homozygous 'I' and 'T' genotypes in certain XRCC4 sequences may be associated with the development of cervical cancer and so may be a useful biomarker to predict cervical cancer susceptibility.

HPV E6 oncoproteins and nucleic acids in neck lymph node fine needle aspirates and oral samples from patients with oropharyngeal squamous cell carcinoma.

Commercial assays measuring HPV E6 viral oncoproteins, E6/E7 mRNA or DNA were used to test neck lymph node fine needle aspirates (FNA) and oropharyngeal samples (saliva and oral swabs) from 59 Canadian patients with oropharyngeal squamous cell carcinomas (OPSCC). Overall agreements of p16 antigen staining of tumors to FNA tested for OncoE6™, Aptima HPV E6/E7 mRNA and cobas HPV DNA were 81.4% (k 0.53), 94.9% (k 0.83) and 91.1% (k 0.73) respectively. Using HPV presence in a subset of 25 tumors as the comparator, overall agreement was 64.0% (k 0.08) with OncoE6™, 88.0% (k 0.65) with Aptima HPV E6/E7 mRNA and 91.7% (k 0.70) with cobas HPV DNA. HPV testing of oropharyngeal samples yielded lower agreements with tumor markers; 23.7-24.0% (k 0.02), 55.9-68.0% (k 0.24-0.37) and 78.9-86.9% (k 0.49-0.58) in the 3 respective tests. HPV 16 was present in 93.7-100% of the samples tested and showed 100% genotype agreement between FNA and tumors. The high rates for HPV E6 oncoproteins and E6/E7 mRNA suggests most patients were experiencing transcriptionally active HPV-related OPSCC. Results from these commercial assays performed on FNA but not oropharyngeal samples showed moderate to very good agreements with p16 and HPV testing of tumors.

Improvement in sperm functional competence through modified low-dose packaging in French mini straws of bull semen.

To achieve the targeted artificial insemination coverage with the current rate of semen production, without affecting the conception rate, it needs to reduce the number of spermatozoa per insemination dose in India as per international practice. Therefore, this study was planned to perform different levels of semen dilution, compare in vitro post-thaw semen quality and develop a modified low-dose semen packaging method in French mini straw to minimise semen dilution effect. Sixteen ejaculates were collected from Karan Fries bulls (n = 4). The mean percentage post-thaw motility, viability, membrane integrity, acrosome integrity, lipid peroxidation and capacitation status were estimated as post-thaw sperm function assays in semen sample diluted to 20, 15, 10 and 5 million spermatozoa per 0.25 ml and filled in the French mini straw by conventional packaging. No significant (p > .05) difference in post-thaw sperm quality was observed between 15 and 20 million doses; however, below 15 million sperm quality get reduced. There was no significant difference in post-thaw semen quality traits between 20 million conventional packaging and 5 million spermatozoa/dose in modified packaging. In conclusions, the modified packaging is a very effective method for low-dose cryopreservation with acceptable post-thaw semen quality.