Synthesis and Biological Evaluation of a Carbamate-Containing Tubulysin Antibody-Drug Conjugate.

Antibody-drug conjugates (ADCs) use antibodies to deliver cytotoxic payloads directly into tumor cells via specifically binding to the target cell surface antigens. ADCs can enhance the anti-tumor effects of antibodies, and increase the delivery of cytotoxic payloads to cancer cells with a better therapeutic index. An ADC was prepared with a potent carbamate-containing tubulysin analogue attached to an anti-mesothelin antibody via a Cit-Val dipeptide linker. An aniline functionality in the tubulysin analogue was created to provide a site of linker attachment via an amide bond that would be stable in systemic circulation. Upon ADC internalization into antigen-positive cancer cells, the Cit-Val dipeptide linker was cleaved by lysosomal proteases, and the drug was released inside the tumor cells. The naturally occurring acetate of tubulysin was modified to a carbamate to reduce acetate hydrolysis of the ADC in circulation and to increase the hydrophilicity of the drug. The ADC bearing the monoclonal anti-mesothelin antibody and the carbamate-containing tubulysin was highly potent and immunologically specific to H226 human lung carcinoma cells in vitro, and efficacious at well-tolerated doses in a mesothelin-positive OVCAR3 ovarian cancer xenograft mouse model.

Innovative Use of Tympanometry and Scintigraphy in Preoperative Assessment of the Patients with Chronic Otitis Media.

Normal middle ear volume indicates the well ventilated middle ear and subsequently the normal function of the Eustachian tube. We carried out preoperative assessment of the middle ear volume by tympanometry and scintigraphic evaluation of Eustachian tube patency in patients with unilateral otitis media. We correlated the middle ear volume and Eustachian tube patency in these patients. Prospective. A total of 58 patients with unilateral otitis media were studied. All patients underwent Eustachian tube scintigraphy. We categorized the patients as Group A with patent Eustachian tube and Group B with blocked Eustachian tube (ET). We assessed the equivalent middle ear volume (VeqME) in all patients and correlated it with ET patency. We also correlated the degree of hearing loss and intraoperative middle ear pathology in two groups. There is strong linear correlation between the ET patency and VeqME of the patients. Degree of hearing loss and the middle ear pathology is also found to be severe in patients with blocked ET and low VeqME. Preoperative assessment of patients with chronic otitis media should include the objective evaluation of middle ear volume and ET patency, as it is the reliable predictor of middle ear pathology.

Comparison between clinical and audiological results of tympanoplasty with modified sandwich technique and underlay technique / Comparação entre os resultados clínicos e audiológicos de timpanoplastia com a técnica "sanduíche" modificada e a técnica underlay

Abstract Introduction: Surgical repair of the tympanic membrane, termed a type one tympanoplasty is a tried and tested treatment modality. Overlay or underlay technique of tympanoplasty is common. Sandwich tympanoplasty is the combined overlay and underlay grafting of tympanic membrane. Objective: To describe and evaluate the modified sandwich graft (mediolateral graft) tympanoplasty using temporalis fascia and areolar fascia. To compare the clinical and audiological outcome of modified sandwich tympanoplasty with underlay tympanoplasty. Methods: A total of 88 patients of chronic otitis media were studied. 48 patients (Group A) underwent type one tympanoplasty with modified sandwich graft. Temporalis fascia was underlaid and the areolar fascia was overlaid. 48 patients (Group B) underwent type one tympanoplasty with underlay technique. We assessed the healing and hearing results. Results: Successful graft take up was accomplished in 47 patients (97.9%) in Group A and in 40 patients (83.3%) Group B. The average Air-Bone gap closure achieved in Group A was 24.4 ± 1.7 dB while in Group B; it was 22.5 ± 3.5 dB. Statistically significant difference was found in graft healing rate. Difference in hearing improvement was not statistically significant. Conclusion: Double layered graft with drum-malleus as a 'meat' of sandwich maintains a perfect balance between sufficient stability and adequate acoustic sensitivity.

Resumo Introdução: O reparo cirúrgico da membrana timpânica, denominado timpanoplastia tipo 1, é uma modalidade de tratamento já bem estabelecida. As técnicas overlay ou underlay de timpanoplastia são comuns. A timpanoplastia "sanduíche" é a técnica de enxerto de membrana timpânica overlay e underlay combinadas. Objetivo: Descrever e avaliar a timpanoplastia com a técnica "sanduíche" modificada (timpanoplastia mediolateral) utilizando fáscia temporal e fáscia aureolar. Comparar o desfecho clínico e audiológico da timpanoplastia com a técnica "sanduíche" modificada com o da timpanoplastia com a técnica underlay. Método: Foram estudados 88 pacientes com otite média crônica, 48 (Grupo A) foram submetidos à timpanoplastia tipo 1 com enxerto "sanduíche" modificado. A fáscia temporal foi utilizada na técnica underlay e a fáscia areolar na técnica overlay. 48 pacientes (Grupo B) foram submetidos à timpanoplastia tipo 1 com a técnica underlay. Foram avaliados os resultados da cicatrização e da audição. Resultados: O sucesso do enxerto ocorreu em 47 pacientes (97,9%) no Grupo A e em 40 (83,3%) do Grupo B. O fechamento médio do gap aéreo-ósseo no Grupo A foi de 24,4 ± 1,7 dB, enquanto no Grupo B foi de 22,5 ± 3,5 dB. Houve diferença estatisticamente significativa na taxa de cicatrização do enxerto. A diferença na melhora auditiva não foi estatisticamente significante. Conclusão: O enxerto de camada dupla e o tímpano-martelo posicionados como o "recheio" do sanduíche mantém um equilíbrio perfeito entre a estabilidade necessária e adequada sensibilidade acústica.

Comparison between clinical and audiological results of tympanoplasty with modified sandwich technique and underlay technique.

INTRODUCTION: Surgical repair of the tympanic membrane, termed a type one tympanoplasty is a tried and tested treatment modality. Overlay or underlay technique of tympanoplasty is common. Sandwich tympanoplasty is the combined overlay and underlay grafting of tympanic membrane. OBJECTIVE: To describe and evaluate the modified sandwich graft (mediolateral graft) tympanoplasty using temporalis fascia and areolar fascia. To compare the clinical and audiological outcome of modified sandwich tympanoplasty with underlay tympanoplasty. METHODS: A total of 88 patients of chronic otitis media were studied. 48 patients (Group A) underwent type one tympanoplasty with modified sandwich graft. Temporalis fascia was underlaid and the areolar fascia was overlaid. 48 patients (Group B) underwent type one tympanoplasty with underlay technique. We assessed the healing and hearing results. RESULTS: Successful graft take up was accomplished in 47 patients (97.9%) in Group A and in 40 patients (83.3%) Group B. The average Air-Bone gap closure achieved in Group A was 24.4±1.7dB while in Group B; it was 22.5±3.5dB. Statistically significant difference was found in graft healing rate. Difference in hearing improvement was not statistically significant. CONCLUSION: Double layered graft with drum-malleus as a 'meat' of sandwich maintains a perfect balance between sufficient stability and adequate acoustic sensitivity.

Endoscopic stapedotomy: our view point.

Use of endoscope in middle ear surgery is not new, yet there is resistance to its use in stapedotomy. This is due to perceived long learning curve in shifting from conventional microscope to the endoscope and fear of one-handed work. (1) to present a case series of endoscopic stapedotomies and analyze the operative findings. (2) Discuss the merits and demerits of same. 20 patients with otosclerosis underwent stapedotomy over 5 years using 0°, 4 mm nasal endoscope of 18 cm length. Visualization of middle ear structures, surgical steps, operative time, hearing results and complications were analyzed. In all 20 cases, (13 males, 7 females, age: 32.7 years) manipulation of endoscope within the canal was easy facilitating endomeatal incision and elevation of tympanomeatal flap. An optimum exposure of incudo-stapedial joint was obtained in 88.24 % cases. Adequate exposure of crura was obtained in 82.35 % and the footplate in 95 %. The removal of postero-superior bony wall was required in 30 % and chorda tympani mobilization in 25 % of cases. The average operative time was 31 min. Audiometry done at 6 weeks showed, complete air-bone gap closure in 55 %, mild conductive hearing loss (up to 20 dB) in 30 % and mixed hearing loss in 2 cases (BC up to 30 dB and air-bone gap up to 20 dB). In one patient who initially had hearing improvement post operatively, developed moderate conductive hearing loss at 10 weeks. Performing fully endoscopic stapedotomy using a 4 mm nasal endoscope is a feasible option giving excellent visualization with good results.

Randomized, double-blind, placebo-controlled study to investigate the pharmacodynamic interaction of 5-HT3 antagonist ondansetron and paracetamol in postoperative patients operated in an ENT department under local anesthesia.

BACKGROUND: The preclinical incision pain models and clinical studies in healthy volunteers have demonstrated the central serotonergic analgesic mechanism, paracetamol analgesia. This has been evidenced by raised serotonin concentrations in the brain following paracetamol administration in a few studies. The inhibition of paracetamol analgesia by 5-HT3 antagonists suggests that this analgesia is 5-HT3 mediated. However, in a few studies, 5-HT3 antagonists themselves exhibited an analgesic action. Various studies in this context stated intricate results. The present study was intended to understand the pharmacodynamic interaction between paracetamol and ondansetron in postoperative patients. METHODS: This randomized clinical trial included 32 postoperative cases of either sex, ages between 18 and 70 years. The patients were randomly allocated into the placebo and test groups and received respective treatment at the end of surgery. The pain score was recorded using Visual Analogue Scale (VAS) and Face, Legs, Activity, Cry, Consolability (FLACC) behavioral scale at awakening and every 30 min for the next 3 h. The postoperative rescue analgesic consumption for 24 h was recorded. The data were analyzed using OpenEpi and SciStatCalc statistical software. RESULTS: A significantly higher pain score was observed in the placebo group postoperatively for 60 min on VAS (p<0.05 and p<0.01), whereas the FLACC behavior scale score was significantly higher at 120 and 150 min (p<0.05). The test group patients were more comfortable throughout the study, and the postoperative analgesic requirement was significantly lesser (p<0.05). CONCLUSIONS: The pharmacodynamic interaction between paracetamol and ondansetron coadministration does not block but instead increase paracetamol analgesia, reduce the postoperative analgesic requirement, and improve the postoperative comfort level.

Microfollicular adenoma of ectopic thyroid gland masquerading as salivary gland tumor - a diagnostic and therapeutic challenge: a case report.

INTRODUCTION: Ectopic thyroid tissue may appear in any location along the trajectory of the thyroglossal duct from the foramen cecum to the mediastinum. Rarely, there is incomplete descent of the gland where the final resting point may be high resulting in sublingual ectopic thyroid tissue. Ectopic thyroid tissue carries a low risk of malignancy. Most recently reported neoplasms in ectopic thyroid tissue have been papillary carcinoma of thyroid. Individual case reports of clear cell type of follicular adenoma within the ectopic thyroid tissue have been described in the literature. CASE PRESENTATION: We present a rare case of microfollicular follicular adenoma in an ectopic sublingual thyroid tissue presenting as submental swelling in a euthyroid 24-year-old Dravidian woman. CONCLUSION: Findings in this case emphasize that when confronted with a submental/sublingual mass lesion, the evaluation of thyroid function tests and ultrasonography of the neck should be included in a pre-operative workup.

Treatment of auricular seroma: a conservative, innovative, and effective approach.

OBJECTIVE: Auricular seroma is a cystic swelling filled with serous fluid. It occurs spontaneously or following trauma. Successful treatment of the seroma remains a challenge because this disease has a high propensity for recurrence. The aim was to study the results of the Plaster of Paris (POP) cast in treatment of seroma in terms of complete resolution of swelling, recurrence, and auricular aesthesis. STUDY DESIGN: Prospective. SETTING: Smt. Kashibai Navale Medical College and General Hospital. MATERIALS AND METHODS: A total of 48 patients with auricular seroma were studied. They were treated with aspiration of the cyst followed by compression dressing with a POP cast, taking the contour of the pinna. The POP cast was kept for 3 days. The patients were followed up for 6 months for recurrence. RESULTS: Out of 48 patients, 43 patients had complete resolution of the swelling in a single application of the POP cast. Five patients needed 2 applications of the POP cast. Not a single patient had recurrence. Temporary discoloration or thickening of the pinna was noted in 8 patients. No major complications like perichondritis were noted. CONCLUSION: Aspiration and contour dressing using POP is an innovative and effective treatment for management of auricular seroma as it prevents surgical trauma and recurrence and gives cosmetically excellent results.

A unique case of dystrophic calcification in masseter: a diagnostic challenge.

The objective of this study was to present an unusual case of isolated dystrophic calcification in masseter and the diagnostic challenge it posed. A case report on a 14-year-old boy presented with swelling in left parotid region along with the review of literature was reported. Histopathological and biochemical analyses of the excised mass diagnosed this affliction as dystrophic calcification. Dystrophic calcification is deposition of calcium salt in degenerated tissues in the presence of normal calcium and phosphorous metabolism. It usually occurs in injured tissues. This is different from systemic mineral imbalance causing metastatic calcification and needs to be differentiated. On reviewing the literature, this appears to be the second reported case in the world wide literature. The unique presentation, diagnosis, and surgical management of dystrophic calcification have been described.

Qualitative and quantitative representation of taste disturbances: how we do it by pentagon chart.

Taste is a chemical sense responding to chemical stimuli. In our daily practice as ENT practitioners or Neurologists we do come across patients complaining of taste disturbances. Tests for taste have to be performed regularly in the clinical centres as well as in neurological labs as a part of complete work up for neurotology cases. Assessment of taste sensation can be easily done in a neurological clinic by chemogustometry as described by Claussen. The stimuli used are chemicals, representative substances for the four qualities of sweet, salty, sour and bitter, in graded solutions. These semi-quantitative results are plotted on a pentagon scheme devised by Claussen. The points of the best results for glucose, sodium chloride, citric acid, phenylthio-urea and quinine then are connected with a coloured line. That gives a linked graphic structure, which can be read by the physician at one glance. Different patterns are obtained for normal taste, taste-blindness for phenylthio-urea, ageusia, partial ageusias for glucose, or sodium chloride or citric acid or quinine or their combinations and parageusias. In this article we present different patterns of taste disturbances depicted on the pentagon chart highlighting the easy interpretation of chemogustometry.

A nonfucosylated human antibody to CD19 with potent B-cell depletive activity for therapy of B-cell malignancies.

A human anti-CD19 antibody was expressed in fucosyltransferase-deficient CHO cells to generate nonfucosylated MDX-1342. Binding of MDX-1342 to human CD19-expressing cells was similar to its fucosylated parental antibody. However, MDX-1342 exhibited increased affinity for FcγRIIIa-Phe158 and FcγRIIIa-Val158 receptors as well as enhanced effector cell function, as demonstrated by increased potency and efficacy in antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis assays. MDX-1342 showed dose-dependent improvement in survival using a murine B-cell lymphoma model in which Ramos cells were administered systemically. In addition, low nanomolar binding to cynomolgus monkey CD19 and increased affinity for cynomolgus monkey FcγRIIIa was observed. In vivo administration of MDX-1342 in cynomolgus monkeys revealed potent B-cell depletion, suggesting its potential utility as a B-lymphocyte depletive therapy for malignancies and autoimmune indications.