Cancer stem cell mediated acquired chemoresistance in head and neck cancer can be abrogated by aldehyde dehydrogenase 1 A1 inhibition.

Chemoresistance leading to disease relapse is one of the major challenges to improve outcome in head and neck cancers. Cancer Stem Cells (CSCs) are increasingly being implicated in chemotherapy resistance, this study investigates the correlation between CSC behavior and acquired drug resistance in in vitro cell line models. Cell lines resistant to Cisplatin (Cal-27 CisR, Hep-2 CisR) and 5FU (Cal-27 5FUR) with high Resistance Indices (RI) were generated (RI ≥ 3) by short-term treatment of head and neck squamous cell carcinoma (HNSCC) cell lines with chemotherapeutic drugs (Cisplatin, Docetaxel, 5FU), using a dose-incremental strategy. The cell lines (Cal-27 DoxR, Hep-2 DoxR, Hep-2 5FUR) that showed low RI, nevertheless had a high cross resistance to Cisplatin/5FU (P < 0.05). Cal-27 CisR and DoxR showed 12-14% enrichment of CD44+ cells, while CisR/5FUR showed 4-6% increase in ALDH1A1+ cells as compared to parental cells (P < 0.05). Increased expression of stem cell markers (CD44, CD133, NOTCH1, ALDH1A1, OCT4, SOX2) in these cell lines, correlated with enhanced spheroid/colony formation, migratory potential, and increased in vivo tumor burden (P < 0.05). Inhibition of ALDH1A1 in Cal-27 CisR led to down regulation of the CSC markers, reduction in migratory, self-renewal and tumorigenic potential (P < 0.05) accompanied by an induction of sensitivity to Cisplatin (P < 0.05). Further, ex vivo treatment of explants (n = 4) from HNSCC patients with the inhibitor (NCT-501) in combination with Cisplatin showed a significant decrease in proliferating cells as compared to individual treatment (P = 0.001). This study hence suggests an ALDH1A1-driven, CSC-mediated mechanism in acquired drug resistance of HNSCC, which may have therapeutic implications. © 2016 Wiley Periodicals, Inc.

Rare presentation of solitary fibrous tumour in the floor of the mouth.

A male in his 20s, a tobacco chewer, presented to the outpatient department with a history of painless, slowly progressive swelling in the floor of the mouth. After a thorough history and clinical examination, MRI was done and the tumour was completely excised. Histopathological examination revealed the mass to be a solitary fibrous tumour, confirmed with immunohistochemical markers. On subsequent follow-ups, the patient was found to be asymptomatic with no clinical signs of recurrence.

Retained foreign body in nose following eye injury.

A man in his 60s presented with diminution of vision of the left eye with nasal bleeding after accidental fall. On examination his left upper eyelid was lacerated and left temporal sclera was punctured which was repaired under local anaesthesia after which he was discharged by ophthalmologists but continued to complain of pain and left nasal obstruction. A non-contrast CT of paranasal sinuses revealed fracture of medial wall of left orbit, left ethmoid haemosinus and a metallic foreign body (FB) in the septum and anterior face of sphenoid. Diagnostic nasal endoscopy performed to remove the metallic FB showed plastic splinters embedded in the mucosa of nasal cavity which was unexpected. Hence, the FB was removed in two sittings because of diagnostic dilemma.

Troubleshooting Cochlear Implant Malfunction Using Neural Response Telemetry and Normal Saline.

Cochlear implantation has become a standard of care for a child diagnosed with bilateral profound sensorineural hearing loss with a structured surgical standard operating procedure. A 3-year-old boy with bilateral profound prelingual sensorineural deafness underwent a Med-EL Sonata Ti100 implant. We faced a peculiar situation intraoperatively after inserting the electrodes and closing the wound. The impedance recording indicated high ground path impedance with short-circuiting of few electrodes. As a bionic implant, its electronic components may at times malfunction both intraoperatively and/or postoperatively; therefore, neural response telemetry (NRT) was invented to check it. By using NRT and a few milliliters of normal saline, we were able to diagnose as well as rectify the malfunctioning of the implant.

Treatment of congenital melanocytic naevi of nose using multiple flaps in single stage in a paediatric patient and literature review.

A girl in her middle childhood presented to the outpatient department (OPD) with a congenital melanocytic naevi (CMN) of the right nasal alar lobule. Her parents had aesthetic concerns and expressed their desire to get the lesion removed. The full-thickness excision of CMN was performed with the reconstruction of the defect using the nasolabial and dorsal nasal advancement flap with conchal cartilage to shape the contour of the ala.

Juvenile trabecular ossifying fibroma of the inferior turbinate.

Nasal obstruction is a commonly reported issue in the Otorhinolaryngology Outpatient Department. In this case, an early adolescent boy with a long-standing problem of right-sided nasal obstruction since childhood sought consultation. Diagnostic nasal endoscopy revealed a deviation of the nasal septum to the left, coupled with right inferior turbinate hypertrophy, all overlying healthy mucosa. A CT scan of the nose and paranasal sinuses further identified a bony hyperdense lesion with ground glass attenuation, confined to the right inferior turbinate. Subsequent biopsy confirmed juvenile trabecular ossifying fibroma (JTOF). The patient underwent endoscopic right medial maxillectomy, and the final histology affirmed the diagnosis of JTOF.

Kimura disease of naso-orbito-ethmoid region and review of surgical approaches to naso-orbito-ethmoid region.

SummaryA man in 30s had complaints of glabellar and upper nasal swelling for 8 years. It was insidious in onset and gradually progressive causing epiphora and restriction of nasal visual field. Fine-needle aspiration cytology and biopsy revealed features which were suggestive of Kimura's disease (KD). CT scans showed a well-defined subcutaneous swelling in the naso-orbito-ethmoid (NOE) region. KD presents as lymphoglandular swelling; however, NOE region is an uncommon site of occurrence. A thyroid-shaped tumour was excised by H-shaped incision approach to the NOE region.

BCA101 Is a Tumor-Targeted Bifunctional Fusion Antibody That Simultaneously Inhibits EGFR and TGFß Signaling to Durably Suppress Tumor Growth.

The EGFR and TGFß signaling pathways are important mediators of tumorigenesis, and cross-talk between them contributes to cancer progression and drug resistance. Therapies capable of simultaneously targeting EGFR and TGFß could help improve patient outcomes across various cancer types. Here, we developed BCA101, an anti-EGFR IgG1 mAb linked to an extracellular domain of human TGFßRII. The TGFß "trap" fused to the light chain in BCA101 did not sterically interfere with its ability to bind EGFR, inhibit cell proliferation, or mediate antibody-dependent cellular cytotoxicity. Functional neutralization of TGFß by BCA101 was demonstrated by several in vitro assays. BCA101 increased production of proinflammatory cytokines and key markers associated with T-cell and natural killer-cell activation, while suppressing VEGF secretion. In addition, BCA101 inhibited differentiation of naïve CD4+ T cells to inducible regulatory T cells (iTreg) more strongly than the anti-EGFR antibody cetuximab. BCA101 localized to tumor tissues in xenograft mouse models with comparable kinetics to cetuximab, both having better tumor tissue retention over TGFß "trap." TGFß in tumors was neutralized by approximately 90% in animals dosed with 10 mg/kg of BCA101 compared with 54% in animals dosed with equimolar TGFßRII-Fc. In patient-derived xenograft mouse models of head and neck squamous cell carcinoma, BCA101 showed durable response after dose cessation. The combination of BCA101 and anti-PD1 antibody improved tumor inhibition in both B16-hEGFR-expressing syngeneic mouse models and in humanized HuNOG-EXL mice bearing human PC-3 xenografts. Together, these results support the clinical development of BCA101 as a monotherapy and in combination with immune checkpoint therapy. SIGNIFICANCE: The bifunctional mAb fusion design of BCA101 targets it to the tumor microenvironment where it inhibits EGFR and neutralizes TGFß to induce immune activation and to suppress tumor growth.

The concatenation of association between gastroesophageal reflux and obstructive adenotonsillar hypertrophy.

OBJECTIVES: Gastroesophageal reflux (GER) is frequently seen in patients with adenotonsillar hypertrophy. However, the sequential association between GER and adenotonsillar hypertrophy is unknown. This leads to unpredictable outcomes while treating patients of adenotonsillar hypertrophy with GER. The objective of this study is to evaluate the prevalence of GER and gastroesophageal reflux disease (GERD) in paediatric patients with obstructive adenotonsillar hypertrophy (OATH), and to assess the effect of adenotonsillectomy (AT) on GER as well as GERD. METHODS: In this prospective cohort study, consecutive pediatric patients with grade III/IV hypertrophy of adenoid or/and tonsillar tissue who were planned for AT were recruited after excluding comorbidities predisposing to GER. Symptoms of GERD using Gastro Esophageal Reflux Questionnaire for Young Children (GERQ-YC) and Reflux Indices (RI) obtained from 24-h ambulatory esophageal pH monitoring were evaluated in all patients pre-operatively and 12 weeks following AT. RESULTS: A total of 49 patients with OATH with average age of 6 years were included in this study. With a RI of >4.3% as the threshold for making the diagnosis of GER on esophageal pH monitoring, the prevalence of GER was 20.4%. The average RI preoperatively was 15.7% which reduced to 1.7% following AT (p = 0.004). Among the 10 patients with preoperative GER, 80% of the patients had no evidence of GER after surgery. New incidences of GER was not observed post operatively in this cohort. As per the GER symptom scoring system, 31% of the parents reported GERD pre-operatively which resolved completely in all patients following surgery. CONCLUSIONS: - In this study, the prevalence of GER proven by 24 h ambulatory esophageal pH monitoring is 20% in pediatric patients with OATH. Following AT, GER resolved in 80% of cases and was reduced substantially in the remaining cases in the subset of patients with pre-operative GER. The symptoms of GERD based on parents' recall of child's previous symptoms may not accurately represent presence of GER. Our results suggest that OATH can result in GER due to increased negative intra-thoracic pressure as a result of breathing against an obstructed upper airway and hence, GER subsides following surgical removal of the obstructive pathology. To establish this concatenational association of OATH and GER, larger studies are mandated.

Discovery and Development of SPR519 as a Potent, Selective, and Orally Bioavailable Inhibitor of PI3Kα and mTOR Kinases for the Treatment of Solid Tumors.

Herein, we report the identification and preclinical profile of a lead compound 10, (SPR519) as an equally potent dual inhibitor of PI3Kα and mTOR kinases. SPR519 exhibits an EC50 of low sub-micromolar range among various tested cancer cell lines such as A2780 (0.23 µM), PC3 (0.48 µM), and SKOV3 (0.50 µM). When administrated orally, it shows a considerably high plasma exposure (area under curve: 26,858 nM/h at 1 mg/kg) in mice. Moreover, it is found to be safe in animals with a dose of 30 mg/kg BID for 12 days in the dose tolerance study. SPR519 did not show any CYP or hERG liability. The identified lead compound demonstrates significant efficacy and bioavailability in ovarian and colon cancer xenograft models when evaluated for dose-ranging efficacy studies, at a dose as low as 2.5 mg/kg.