Parathyroid Hormone Resistance and Autoantibodies to the PTH1 Receptor.

We describe two cases of acquired parathyroid hormone (PTH) resistance consequent to the development of serum PTH type 1 receptor (PTH1R) autoantibodies, which block PTH binding and signaling. Both cases were associated with other autoimmune manifestations, and one case was associated with atypical membranous glomerulonephritis. In vitro binding and signaling assays identified the presence of PTH1R-blocking IgG autoantibodies, which were not present in serum samples from patients with other renal or autoimmune disorders. (Funded by the Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases and others.).

Is thyroid excision mandatory with laryngectomy in carcinoma larynx?

BACKGROUND: Advanced stage operable cancers of larynx are treated with total laryngectomy including thyroid resection in most of the cases, which may expose patient to hypothyroidism and hypoparathyroidism. The requirement of thyroidectomy during Total Laryngectomy is controversial. METHODS: A cross sectional observational study was set out to review preoperative clinical and radiological assessment; intraoperative and histopathological findings; and follow-up data to predict thyroid gland invasion in the setting of squamous cell carcinoma of the Larynx. RESULTS: 11 (16%) out of 69 patients had thyroid gland involvement on histopathological examination with mean age 63 years. Out of these 11 cases, 8 (72%) underwent primary total laryngectomy. 90% patients with thyroid gland involvement were male. 9 cases with thyroid gland involvement were staged as T4a preoperatively. CONCLUSION: Invasion of thyroid gland by laryngeal cancer is uncommon. Unnecessary hemithyroidectomies lead to hypothyroidism and hypoparathyroidism. The study points out the clear indications of thyroid excision in patients undergoing total laryngectomy. We can suggest that total thyroidectomy should be done with total laryngectomy in cases which have gross clinical, radiological or intraoperative thyroid gland involvement, subglottic extension and thyroid cartilage invasion. This can save the patients from the brunt of unnecessary morbid hypothyroidism and hypoparathyroidism.

GCM2-Activating Mutations in Familial Isolated Hyperparathyroidism.

Primary hyperparathyroidism (PHPT) is a common endocrine disease characterized by parathyroid hormone excess and hypercalcemia and caused by hypersecreting parathyroid glands. Familial PHPT occurs in an isolated nonsyndromal form, termed familial isolated hyperparathyroidism (FIHP), or as part of a syndrome, such as multiple endocrine neoplasia type 1 or hyperparathyroidism-jaw tumor syndrome. The specific genetic or other cause(s) of FIHP are unknown. We performed exome sequencing on germline DNA of eight index-case individuals from eight unrelated kindreds with FIHP. Selected rare variants were assessed for co-segregation in affected family members and screened for in an additional 32 kindreds with FIHP. In eight kindreds with FIHP, we identified three rare missense variants in GCM2, a gene encoding a transcription factor required for parathyroid development. Functional characterization of the GCM2 variants and deletion analyses revealed a small C-terminal conserved inhibitory domain (CCID) in GCM2. Two of the three rare variants were recurrent, located in the GCM2 CCID, and found in seven of the 40 (18%) kindreds with FIHP. These two rare variants acted as gain-of-function mutations that increased the transcriptional activity of GCM2, suggesting that GCM2 is a parathyroid proto-oncogene. Our results demonstrate that germline-activating mutations affecting the CCID of GCM2 can cause FIHP.

Transcriptional alterations in hereditary and sporadic nonfunctioning pancreatic neuroendocrine tumors according to genotype.

BACKGROUND: Nonfunctioning pancreatic neuroendocrine tumors (NFPanNETs) may be sporadic or inherited because of germline mutations associated with von Hippel-Lindau disease (VHL) or multiple endocrine neoplasia type 1 (MEN1). The clinical behavior of NFPanNETs is difficult to predict, even in tumors of the same stage and grade. The authors analyzed genotype-specific patterns of transcriptional messenger RNA (mRNA) levels of NFPanNETs to understand the molecular features that determine PanNET phenotype. METHODS: Thirty-two samples were included for genome-wide mRNA gene expression analysis (9 VHL-associated, 10 MEN1-associated, and 9 sporadic NFPanNETs and 4 purified normal islet cell [NIC] samples). Validation of genes was performed by real-time polymerase chain reaction analysis and immunohistochemistry. Gene expression profiles were analyzed by tumor genotype, and pathway analysis was curated. RESULTS: Consensus clustering of mRNA expression revealed separate clustering of NICs, VHL-associated NFPanNETs, and MEN1-associated NFPanNETs; whereas some sporadic tumors clustered with MEN1. Four of 5 MEN1-like sporadic PanNET subtypes had loss of heterozygosity at the MEN1 gene locus. Pathway analysis demonstrated subtype-specific pathway activation, comprising angiogenesis and immune response in VHL; neuronal development in MEN1; protein ubiquitination in the new MEN1/sporadic subtype; and cytokinesis and cilium/microtubule development in sporadic NFPanNETs. Among many genes, platelet-derived growth factor receptor ß (PDGFRB), lymphoid enhancer-binding factor-1 (Lef-1), cyclin-dependent kinase 4 (CDK4), and CDK6 were upregulated in VHL or MEN1 NFPanNETs, providing potential subtype-specific treatment targets. CONCLUSIONS: Distinct mRNA expression patterns were identified in sporadic-associated, VHL-associated, and MEN1-associated NFPanNETs. The current results uncover new pathways involved in NFPanNETs that are subtype-specific and provide potential new diagnostic or therapeutic targets based on tumor subtype. Cancer 2018;124:636-47. © 2017 American Cancer Society.

Germline HABP2 Mutation Causing Familial Nonmedullary Thyroid Cancer.

Familial nonmedullary thyroid cancer accounts for 3 to 9% of all cases of thyroid cancer, but the susceptibility genes are not known. Here, we report a germline variant of HABP2 in seven affected members of a kindred with familial nonmedullary thyroid cancer and in 4.7% of 423 patients with thyroid cancer. This variant was associated with increased HABP2 protein expression in tumor samples from affected family members, as compared with normal adjacent thyroid tissue and samples from sporadic cancers. Functional studies showed that HABP2 has a tumor-suppressive effect, whereas the G534E variant results in loss of function.

Pro-oncogenic Roles of HLXB9 Protein in Insulinoma Cells through Interaction with Nono Protein and Down-regulation of the c-Met Inhibitor Cblb (Casitas B-lineage Lymphoma b).

Pancreatic islet ß-cells that lack the MEN1-encoded protein menin develop into tumors. Such tumors express the phosphorylated isoform of the ß-cell differentiation transcription factor HLXB9. It is not known how phospho-HLXB9 acts as an oncogenic factor in insulin-secreting ß-cell tumors (insulinomas). In this study we investigated the binding partners and target genes of phospho-HLXB9 in mouse insulinoma MIN6 ß-cells. Co-immunoprecipitation coupled with mass spectrometry showed a significant association of phospho-HLXB9 with the survival factor p54nrb/Nono (54-kDa nuclear RNA-binding protein, non-POU-domain-containing octamer). Endogenous phospho-HLXB9 co-localized with endogenous Nono in the nucleus. Overexpression of HLXB9 decreased the level of overexpressed Nono but not endogenous Nono. Anti-phospho-HLXB9 chromatin immunoprecipitation followed by deep sequencing (ChIP-Seq) identified the c-Met inhibitor, Cblb, as a direct phospho-HLXB9 target gene. Phospho-HLXB9 occupied the promoter of Cblb and reduced the expression of Cblb mRNA. Cblb overexpression or HLXB9 knockdown decreased c-Met protein and reduced cell migration. Also, increased phospho-HLXB9 coincided with reduced Cblb and increased c-Met in insulinomas of two mouse models of menin loss. These data provide mechanistic insights into the role of phospho-HLXB9 as a pro-oncogenic factor by interacting with a survival factor and by promoting the oncogenic c-Met pathway. These mechanisms have therapeutic implications for reducing ß-cell proliferation in insulinomas by inhibiting phospho-HLXB9 or its interaction with Nono and modulating the expression of its direct (Cblb) or indirect (c-Met) targets. Our data also implicate the use of pro-oncogenic activities of phospho-HLXB9 in ß-cell expansion strategies to alleviate ß-cell loss in diabetes.

Reoperative Surgery in Patients with Multiple Endocrine Neoplasia Type 1 Associated Primary Hyperparathyroidism.

BACKGROUND: Persistent/recurrent primary hyperparathyroidism (pHPT) occurs frequently in multiple endocrine neoplasia type 1 (MEN1). We assessed the usefulness of intraoperative PTH (IOPTH) and preoperative localizing studies based on the outcome of patients with MEN1-associated pHPT undergoing reoperative surgery. METHODS: A retrospective analysis identified MEN1 patients with persistent/recurrent pHPT. Patient outcome was defined as postoperative serum calcium and PTH levels (cured, persistent or recurrent) at last follow-up. Positive predictive value (PPV) was calculated for imaging studies and IOPTH. RESULTS: Thirty patients with MEN1-associated recurrent/persistent pHPT underwent 69 reoperative parathyroidectomies. Median follow-up time was 33 months. Persistent pHPT occurred in four (13 %) patients. IOPTH had a 92 % PPV for postoperative eucalcemia. Ultrasound and Tc99m-sestamibi had sensitivities of 100 and 85 % for localizing an enlarged parathyroid gland. However, five (17 %) patients had additional enlarged glands, not visualized preoperatively that were removed after IOPTH did not drop appropriately. Bone mineral density scores did not improve after reoperation (p = 0.60), but the rate of postoperative nephrocalcinosis did (p = 0.046). Patients with pancreatic neuroendocrine tumors had significantly higher rates of persistent/recurrent pHPT compared with those without (40 vs. 0 %, p = 0.021). Intraoperative and delayed parathyroid autotransplantation was performed in nine (30 %) and four (14 %) patients, respectively. CONCLUSIONS: Although preoperative localizing studies are helpful for guiding reoperative strategy in MEN1 with persistent/recurrent pHPT, additional enlarged glands may be missed by conventional imaging. IOPTH should therefore be employed routinely in this setting. Routine cryopreservation should be considered in all patients. Pancreatic manifestation may be associated with earlier recurrence or persistent disease.

GSK-3ß protein phosphorylates and stabilizes HLXB9 protein in insulinoma cells to form a targetable mechanism of controlling insulinoma cell proliferation.

Insulinomas (pancreatic islet ß cell tumors) are the most common type of functioning pancreatic neuroendocrine tumors that occur sporadically or as a part of the MEN1 syndrome that is caused by germ line mutations in MEN1. Tissue-specific tumor predisposition from germ line mutations in ubiquitously expressed genes such as MEN1 could occur because of functional consequences on tissue-specific factors. We previously reported the proapoptotic ß cell differentiation factor HLXB9 as a downstream target of menin (encoded by MEN1). Here we show that GSK-3ß inactivates the proapoptotic activity of HLXB9 by phosphorylating HLXB9 at Ser-78/Ser-80 (pHLXB9). Although HLXB9 is found in the nucleus and cytoplasm, pHLXB9 is predominantly nuclear. Both pHLXB9 and active GSK-3ß are elevated in ß cells with menin knockdown, in MEN1-associated ß cell tumors (insulinomas), and also in human sporadic insulinomas. Pharmacologic inhibition of GSK-3ß blocked cell proliferation in three different rodent insulinoma cell lines by arresting the cells in G2/M phase and caused apoptosis. Taken together, these data suggest that the combination of GSK-3ß and pHLXB9 forms a therapeutically targetable mechanism of insulinoma pathogenesis. Our results reveal that GSK-3ß and pHLXB9 can serve as novel targets for insulinoma treatment and have implications for understanding the pathways associated with ß cell proliferation.

A Germline ZFX Missense Variant in a Patient With Primary Hyperparathyroidism.

A 51-year-old woman with a history of primary hyperparathyroidism (PHPT) with prior parathyroidectomy, osteoporosis, and learning disability was referred for hypercalcemia discovered after a fall. Family history was negative for PHPT, pituitary, enteropancreatic neuroendocrine, or jaw tumors. Dysmorphic facies, multiple cutaneous melanocytic nevi, café au lait macules, long fingers, and scoliosis were observed. Laboratory evaluation showed an elevated parathyroid hormone (PTH) level, hypercalcemia, and hypophosphatemia, all consistent with PHPT. Preoperative imaging revealed a right inferior candidate parathyroid lesion. The patient underwent right inferior parathyroidectomy with normalization of PTH, calcium, and phosphorus. Genetic testing showed a likely pathogenic de novo heterozygous germline missense variant p.R764W in the ZFX gene that encodes a zinc-finger transcription factor previously shown to harbor somatic missense variants in a subset of sporadic parathyroid tumors. Germline variants in ZFX have been reported in patients with an X-linked intellectual disability syndrome with an increased risk for congenital anomalies and PHPT. Further research may determine if genetic testing for ZFX could be of potential benefit for patients with PHPT and developmental anomalies, even in the absence of a family history of parathyroid disease.

Go-Brown, Go-Green and smart initiatives implemented by the University of Delhi for environmental sustainability towards futuristic smart universities: Observational study.

Go-Brown are brown agendas that focus on protecting the environment and health of the current students yielding immediate results. Go-Green are green agendas that aim to protect the environment and health of the future students yielding long-lasting results. Smart initiatives are implemented on the university infrastructure to preserve our ecosystem. It is important to create sustainability awareness in the students and implement these initiatives in universities' infrastructure. There are limited studies on these initiatives' implementation, which creates a research gap. The research question is whether the University of Delhi (DU) is implementing these initiatives for creating sustainability awareness among students to put them on a sustainable path. The research objectives are to assess whether the DU colleges are implementing these initiatives; highlight new definitions of sustainability agendas into Go-Brown, Go-Green, and Smart categories pertinent to the education system and study them step-wise; study sustainable environment indicators: water, waste, air, land and energy; and conceptualize the "Educational Institutional Environmental Sustainability Stars" Theory and Rating System. This study selected Go-Brown, Go-Green and Smart parameters from water, waste, air, land and energy and conducted an assessment survey in 30 colleges on their sustainability compliance and evaluated them through a statistical analysis. It recommends implementation of these initiatives by the Government of India to develop futuristic smart universities, inculcate the "Educational Institutions Environmental Sustainability Stars" Theory and Rating System in the Indian educational system and to frame regulatory sustainability laws. Limitations are whether the outcome of this study conducted on 15 parameters in 30 DU colleges can be applied to all India's educational institutions; and whether the implemented initiatives have influenced the students to take them forward. The smart university modelling features inclusive of smart environment, smart infrastructure and smart education solutions with their interdependent relationship and various stakeholders can lead to future research.

Phenotypic Profiling and Molecular Mechanisms in Hyperparathyroidism-jaw Tumor Syndrome.

CONTEXT: Hyperparathyroidism-jaw tumor (HPT-JT) syndrome is a heritable form of primary hyperparathyroidism caused by germline inactivating mutations in CDC73 encoding parafibromin and is associated with an increased risk of parathyroid cancer. There is little evidence to guide the management of patients with the disease. OBJECTIVE: (1) Characterize the natural history of HPT-JT, (2) correlate genotype and histology of parathyroid tumors with parafibromin immunostaining, (3) understand molecular changes downstream to CDC73 loss. DESIGN: Retrospective study of patients with HPT-JT syndrome (genetically confirmed or affected first-degree relatives). Independent review of uterine tumor from 2 patients and staining for parafibromin on parathyroid tumors from 19 patients (13 adenomas, 6 carcinomas) was performed. RNA-sequencing was performed in 21 parathyroid samples (8 HPT-JT-related adenomas, 6 HPT-JT-related carcinomas, and 7 sporadic carcinomas with wild-type CDC73). RESULTS: We identified 68 patients from 29 kindreds with HPT-JT with median age at last follow-up of 39 [interquartile range, 29-53] years. A total of 55/68 (81%) developed primary hyperparathyroidism; 17/55 (31%) had parathyroid carcinoma. Twelve of 32 (38%) females developed uterine tumors. Of the 11 patients who had surgical resection for uterine tumors, 12/24 (50%) tumors were rare mixed epithelial mesenchymal polypoid lesions. Four of 68 patients (6%) developed solid kidney tumors; 3/4 had a CDC73 variant at p.M1 residue. Parafibromin staining of parathyroid tumors did not correlate with tumor histology or genotype. RNA-sequencing showed a significant association of HPT-JT-related parathyroid tumors with transmembrane receptor protein tyrosine kinase signaling pathway, mesodermal commitment pathway, and cell-cell adhesion. CONCLUSIONS: Multiple, recurrent atypical adenomyomatous uterine polyps appear to be enriched in women with HPT-JT and appear characteristic of the disease. Patients with CDC73 variants at p.M1 residue appear predisposed to kidney tumors. CLINICAL TRIAL NUMBER: NCT04969926.

A Knock-In Mouse Model of the Gcm2 Variant p.Y392S Develops Normal Parathyroid Glands.

Context: The glial cells missing 2 (GCM2) gene functions as a transcription factor that is essential for parathyroid gland development, and variants in this gene have been associated with 2 parathyroid diseases: isolated hypoparathyroidism in patients with homozygous germline inactivating variants and primary hyperparathyroidism in patients with heterozygous germline activating variants. A recurrent germline activating missense variant of GCM2, p.Y394S, has been reported in patients with familial primary hyperparathyroidism. Objective: To determine whether the GCM2 p.Y394S missense variant causes overactive and enlarged parathyroid glands in a mouse model. Methods: CRISPR/Cas9 gene editing technology was used to generate a mouse model with the germline heterozygous Gcm2 variant p.Y392S that corresponds to the human GCM2 p.Y394S variant. Wild-type (Gcm2+/+) and germline heterozygous (Gcm2+/Y392S) mice were evaluated for serum biochemistry and parathyroid gland morphology. Results: Gcm2 +/Y392S mice did not show any change compared to Gcm2+/+ mice in serum calcium and parathyroid hormone levels, parathyroid gland histology, cell proliferation, or parathyroid gland size. Conclusion: The mouse model of the p.Y392S variant of Gcm2 shows that this variant is tolerated in mice, as it does not increase parathyroid gland cell proliferation and circulating calcium or PTH levels. Further investigation of Gcm2+/Y392S mice to study the effect of this variant of Gcm2 on early events in parathyroid gland development will be of interest.

Long-Term Outcomes of Parathyroid Autografts in Primary Hyperparathyroidism.

Context: Autologous implantation of parathyroid tissue is frequently utilized after parathyroidectomy in patients with heritable forms of primary hyperparathyroidism (PHPT). Data on long-term functional outcome of these grafts is sparse. Objective: To investigate long-term outcomes of parathyroid autografts. Methods: Retrospective study of patients with PHPT who underwent parathyroid autografts from 1991 to 2020. Results: We identified 115 patients with PHPT who underwent 135 parathyroid autografts. Median follow-up duration since graft was 10 (4-20) years. Of the 111 grafts with known functional outcome, 54 (49%) were fully functional, 13 (12%) partially functional, and 44 (40%) nonfunctional at last follow-up. Age at time of graft, thymectomy prior to autograft, graft type (delayed vs immediate), or duration of cryopreservation did not predict functional outcome. There were 45 (83%) post-graft PHPT recurrences among 54 fully functional grafts at a median duration of 8 (4-15) years after grafting. Surgery was performed in 42/45 recurrences, but cure was attained in 18/42 (43%) only. Twelve of 18 (67%) recurrences were graft-related while remaining 6 (33%) had a neck or mediastinal source. Median time to recurrence was 16 (11-25) years in neck or mediastinal source vs 7 (2-13) years in graft-related recurrences. Median parathyroid hormone (PTH) gradient was significantly higher at 23 (20-27) in graft-related recurrence vs 1.3 (1.2-2.5) in neck or mediastinal source (P = .03). Conclusions: Post-graft recurrence of PHPT occurs frequently within the first decade after graft and is challenging to localize. Time to recurrence after graft is significantly shorter and PTH gradient higher for graft-related recurrence. Clinical Trial Number: NCT04969926.

Germline- and Somatic-Inactivating FLCN Variants in Parathyroid Cancer and Atypical Parathyroid Tumors.

CONTEXT: Parathyroid cancer (PC) is a rare endocrine neoplasm with high mortality. While surgery is the treatment for patients with the disease, recurrence rates are high, and patients usually succumb to severe hypercalcemia. There is no effective systemic therapy for the disease. OBJECTIVE: To investigate for novel genes causing parathyroid cancer. METHODS: We analyzed the germline DNA of 17 patients with "sporadic" PC and 3 with atypical parathyroid tumors (APTs) who did not have germline CDC73 or MEN1 pathogenic variants. Sequencing of available tumor tissue from 14 patients with PC and 2 with APT was also performed (including 2 patients with no available germline DNA). In addition, sporadic parathyroid adenomas from 74 patients were analyzed for FLCN variants. RESULTS: We identified germline FLCN variants in 3 unrelated patients with PC. The 2 frameshift variants have been described in patients with Birt-Hogg-Dubé (BHD) syndrome, while the pathogenicity of the missense variant c.124G > C (p.G42R) has not been definitively established. Functional analysis of the missense variant showed a potential effect on posttranslational modification. All 3 patients with germline FLCN variants were noted to have renal cysts and 2 had lung cysts, features associated with BHD syndrome. Somatic FLCN variants were identified in tumors from 2 (1 APT) of 16 patients with PC/APT and in none of the 74 sporadic parathyroid adenomas. No second hits in FLCN were noted on sequencing; however, loss of heterozygosity at the locus was demonstrated in 2 of 3 patients with the identified germline FLCN variant. CONCLUSION: The finding of FLCN variants associated with PC may provide the foundation for the development of therapy for this malignancy.

Blood-based Proteomic Signatures Associated With MEN1-related Duodenopancreatic Neuroendocrine Tumor Progression.

PURPOSE: Patients with multiple endocrine neoplasia type 1 (MEN1) are predisposed to develop duodenopancreatic neuroendocrine tumors (dpNETs), and metastatic dpNET is the primary cause of disease-related mortality. Presently, there is a paucity of prognostic factors that can reliably identify patients with MEN1-related dpNETS who are at high risk of distant metastasis. In the current study, we aimed to establish novel circulating molecular protein signatures associated with disease progression. EXPERIMENTAL DESIGN: Mass spectrometry-based proteomic profiling was conducted on plasmas procured through an international collaboration between MD Anderson Cancer Center, the National Institutes of Health, and the University Medical Center Utrecht from a cohort of 56 patients with MEN1 [14 with distant metastasis dpNETs (cases) and 42 with either indolent dpNETs or no dpNETs (controls)]. Findings were compared to proteomic profiles generated from serially collected plasmas from a mouse model of Men1-pancreatic neuroendocrine tumors (Men1fl/flPdx1-CreTg) and control mice (Men1fl/fl). RESULTS: A total of 187 proteins were found to be elevated in MEN1 patients with distant metastasis compared to controls, including 9 proteins previously associated with pancreatic cancer and other neuronal proteins. Analyses of mouse plasmas revealed 196 proteins enriched for transcriptional targets of oncogenic MYCN, YAP1, POU5F1, and SMAD that were associated with disease progression in Men1fl/flPdx1-CreTg mice. Cross-species intersection revealed 19 proteins positively associated with disease progression in both human patients and in Men1fl/flPdx1-CreTg mice. CONCLUSIONS: Our integrated analyses identified novel circulating protein markers associated with disease progression in MEN1-related dpNET.

The Effect of Age at Cochlear Implantation on Speech and Auditory Performances in Prelingually Deaf Children.

To understand the effect of age at implantation on speech and auditory performances of 74 prelingually deaf Indian children after using cochlear implants for 3, 6 and 12 months. We also evaluate the causes of late implantation in this population. Seventy four children who underwent cochlear implantation from December 2013 to December 2015 in the Department of Otorhinolaryngology and Head Neck Cancer in SMS Medical College, Jaipur were participated in this study. To compare the efficacy of cochlear implant, candidates are classified into 2 groups according to the age at the time of implantation: 1-4 years and 4.1-7 years. The sample size is 37 in both age groups. Their auditory performance and speech intelligibility were rated using the Revised Categories of Auditory Perception scales, Speech Intelligibility Rating scales and Meaningful Auditory Integration Scale. The evaluations were made before implantation and 3, 6 and 12 months after implantation. The scores when compared in both the groups revealed that the results were comparable and significant after 12 months of follow up while the scores were not significant after 3 and 6 months. The results were statistically significant when baseline is compared with different postoperative stages. The children implanted before the age of 4 years had significantly better auditory and linguistic performances. At least 12 months of audio-verbal rehabilitation and speech and language therapy are required to compare the effects of cochlear implant in any set of children. Our study shows that hearing impaired children who receive cochlear implantation below 4 years of age acquires better auditory ability for developing language skills.

Outcomes of Acoustic and Linguistic Performances Following Cochlear Implantation in Large Vestibular Aqueduct Syndrome (LVAS).

AIM: This study aims to collate the outcomes in acoustic and linguistic performances after cochlear implantation in LVAS. METHODS: In a hospital-based prospective interventional study, seven prelingual children with bilateral profound sensorineural hearing loss (SNHL) with LVAS were recruited. They underwent unilateral cochlear implantation between December 2013 and December 2015 in the Department of Otorhinolaryngology and Head Neck Surgery at a tertiary care center. Outcomes of auditory and speech performances were assessed in the form of revised categories of auditory perception (CAP), infant toddler meaningful auditory integration scale (IT-MAIS) and speech intelligibility rating (SIR) scores preoperatively, at one and two years follow up. RESULTS: The mean age of implantation was 4 years. The median revised CAP, IT-MAIS, and SIR scores after one and two years of follow-up were 6, 27, 3, and 11, 36, 5 respectively. The mean follow-up duration was 21.3 months. CONCLUSION: Pre op median revised CAP, IT-MAIS, and SIR scores of 0, 1, 1 showed improvement to 11, 36, 5 at two years follow up which was statistically significant. Hence, we conclude that good functional outcomes post-operatively advocate the significance of cochlear implantation in LVAS.

Olfactory Neuroblastoma: A Novel Site of Presentation.

Olfactory neuroblastoma (ONB) or esthesioneuroblastoma is a rare malignant intranasal tumor, commonly originated from upper part of nasal cavity. Majority of cases presented with nasal obstruction or epistaxis. ONB is rarely reported in ectopic locations. Here we present the first-ever documented case of an olfactory neuroblastoma situated anterior to body of maxilla, presented as left sided facial swelling. This case report is aimed at achieving the consideration of this rare tumour as a differential diagnosis in the lesions of the anatomical region surrounding the commonly known site of origin i.e. the sinonasal cavity.

Role of Vimentin and E-cadherin Expression in Premalignant and Malignant Lesions of Oral Cavity.

To determine the role of Vimentin and E-cadherin expression in oral premalignant and malignant lesions. 68 histopathologically confirmed cases of premalignant and malignant oral cavity lesions enrolled. Biopsy specimens were taken from lesion of all cases and subjected to immunohistochemical evaluation of expression of E-cadherin and Vimentin. We examined the relationships between the expression of these markers and specific clinicopathological features were analyzed. Out of 68 cases 28 showed high vimentin expression (3 + and 4 + grade) and 40 showed low vimentin expression (1 + and 2 + grade). 20 cases out of 68 presented with high E-cadherin expression (3 + and 4 +) and rest 48 with low expression (1 + and 2 +) of the same. Smoking and tobacco chewing reflected non-significant association with their expression. In this study all 28 patients (100%) with high vimentin expression had malignant lesions and 17 (60.7%) presented with metastatic lymph nodes Out of 20 patients with high E-cadherin expression 8(40.0%) had malignant lesions and 12 (60.0%) had pre malignant lesions and 4 (20%) showed nodal metastasis. As tumor stage (TNM) progresses, it showed increased vimentin and decreased E-cadherin expression and vice versa. We concluded that increased vimentin and decreased E-cadherin expression in oral cancers are associated with metastasis and disease progression in terms of upstaging of disease. We can use cellular expression of vimentin and E-cadherin for early diagnosis of disease.

An Observational Study on Association of Clinical Outcome of Diphtheria Cases with Immunization Status: A Tertiary Care Hospital, Jaipur.

BACKGROUND: Diphtheria is an important vaccine preventable disease with varied outcome from mild to death. It was observed that the outcome also gets affected with status of immunization. The outcome is relatively milder in immunized children. OBJECTIVE: To find out the clinical presentation and outcome of diphtheria cases and its association with the immunization status. METHODS: A descriptive analysis of 64 diphtheria cases admitted from January 2019 to May 2020 at SMS hospital, a tertiary care referral hospital in Jaipur. RESULTS: Half of (51.56%, 33/60) patients were in the age group of 6-10 years. The peak load (48.44%) of diphtheria cases was seen in the monsoon season. Around 60% of the patients were fully immunized and around 10% partially immunized, every third case was un-immunized. The most common complication was neurological in 13 cases (20.31%), followed by cardiac complications in 11 cases (17.19%), and respiratory (7.81%). The proportion of complication was much lower (26.3%) in immunized cases as compare to partially immunized and un immunized. The proportion of myocarditis was significantly higher in un immunized cases (40%) than partially immunized (16.7%) and filly immunized group (5.3%). Similarly, Bronchopneumonia was also significantly higher (20%) in unimmunized. CONCLUSION: Our study depicted that there has been a shift of age above 5 years for diphtheria which suggests the need for the booster dose. Also high chances of complications are seen in unimmunized and partially immunized calling for public awareness regarding complete immunization.