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.

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.

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.

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.

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.

Lateral Skull Base Lesions: Our Experience of 15 Years.

To analyse and report various aspects of lateral skull base surgery by describing the incidence and demographic variables, diagnostic and management challenges, surgical choices along with complications and their management and the long term morbidity and survival outcomes in our experience of 15 years. Retrospective review of complete records of all cases operated for lateral skull base tumors at a tertiary care teaching institution in India between timespan of 15 years from 2003 to 2018 was undertaken. 53 cases were selected and analysed. Those having follow up of less than 6 months were excluded. Outcomes were assessed in terms of incidence of types of tumors, benign or malignant, age and sex variation of the patients, staging status at presentation, status of facial and other lower cranial nerves pre-operatively, surgical techniques with complications if any, recurrences and survival. Of 35 benign tumors, tympanojugular paragangliomas were most common. Average age for these was 53 years with 19 females and 14 males. All were non-functional. Tinnitus and hearing loss were most common presentations. Class B2 and C1 tumors were most commonly encountered and the ITF A approach was most commonly used. Hearing loss and Facial palsy were commonest complication post-operatively. There were 2 recurrences. 18 malignancies were observed. Most were stage IV at presentation. Otorrhea and otalgia were most common presenting symptoms followed by hearing loss. 5 year survival was 55%. Successful treatment of lateral skull base lesions requires a multimodality therapy with team approach. Surgical resection is the primary management choice with variable approaches. ICA status related to the tumor is the most important consideration. Malignancies require more aggressive treatment for obtaining clear margins along with pre/post-op chemoradiation. Good results with acceptable complications can be obtained even with advanced tumors.

Assessment of Accuracy of Fine Needle Aspiration Cytology and Ultrasonography in Relation to Histopathology in Cases of Solitary Thyroid Nodule.

The thyroid gland is an endocrine gland situated in the lower part of front and the sides of the neck. Thyroid nodules are very common with estimated prevalence that ranges from 4% by palpation to 67% by Ultrasonography. The main purpose of our study was to detect cases of thyroid carcinoma preoperatively in patients with solitary thyroid nodules and subsequently advise surgery in these selected patients only, without missing any malignancy. The goal of the investigating modalities used was that they should detect maximum (ideally all) cases of carcinoma and minimize the number of patients who might end up with unnecessary surgery. The present study was to be undertaken for assessment of accuracy of FNAC & USG in relation to Histopathology in cases of solitary thyroid nodule (accuracy in terms of sensitivity, specificity, positive predictive value, negative predictive value). In our series of total 102 pateints, 90 patients were females (88.2%) and 12 cases were males (11.8%). The overall incidence of malignancy in solitary thyroid nodules is 15.68%. In our series the sensitivity and specificity of Fine needle aspiration cytology and Ultrasonography was 81.25% & 98.84% and 75% and 77.91% respectively. The closest method to ideal was fine needle aspiration cytology. However, a combination of techniques, rather than a single technique, give optimum results & avoid unnecessary surgery in a greater number of patients without missing any malignancy.

Kimura Disease: A Case Report and Review of Literature.

Kimura disease is a rare benign chronic inflammatory disorder characterised by multiple subcutaneous nodules and lymphadenopathy most commonly in head and neck region. It is seen in Asian men in their 2nd and 3rd decade. Kimura disease is usually confused for Angiolymphoid hyperplasia with eosinophilia and associated with eosinophilia and increased serum IgE. Kimura disease is also known for its recurrence. Diagnosis is by histopathological examination. Treatment is mainly surgical excision for cosmetic purposes.

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.

Diagnostic Efficacy of Thyrotropin to Thyroglobulin Ratio in Correlation with Histopathology of Euthyroid Patient Having Solitary Thyroid Nodule.

In patients with solitary thyroid nodules, the first course of action is to determine whether the nodule is benign or malignant. Many investigations are used to differentiate between benign and malignant nodules so as to avoid surgery in those who don't need it. Among these, FNAC and USG are commonly used in association with clinical features but there are drawbacks of each technique. The present study was undertaken to assess the diagnostic effectivity of thyrotropin (also known as TSH) to thyroglobulin ratio in correlation with histopathology in euthyroid patients having solitary thyroid nodule. This is a prospective study carried out on 48 euthyroid cases of solitary thyroid nodule. All patients subjected to FNAC, USG, thyrotropin and thyroglobulin assay. Then, they underwent surgery and histopathological examination (HPE) of the specimens done. Finally, the histopathology reports were correlated with the thyrotropin to thyroglobulin ratio in order to evaluate their sensitivity and specificity by statistical methods. The sensitivity and specificity of thyrotropin to thyroglobulin ratio was 100% and 100% respectively. All malignant lesions according to thyrotropin to thyroglobulin ratio were confirmed by histopathology indicating its excellence. Therefore, TSH to thyroglobulin ratio helps in planning the correct management and avoids second surgery. It was found that serum TSH:Tg is a safe, reliable and effective diagnostic modality with a high sensitivity and specificity and is the single best investigation for preoperative evaluation of solitary thyroid nodule to differentiate between benign and malignant nodules.

An Observational Study Depicting Role of p16 in Detecting Human Papilloma Virus in Oral and Oropharyngeal Cancer and Associated Factors.

The longstanding phrase, traditional risk factors like-smoking, tobacco and alcohol are the only causative agents of oral and oropharyngeal squamous cell carcinoma (SCC) is changing now. Etiological divergence is taking place which we have to know to reach upon an exact cause of the disease. Human papilloma virus (HPV) infection is a well-established cause of oral cancer. Escalating incidence of HPV associated cancer has a strong impact on its management. So, a concern clinician needs to get aware for it. Among various types of HPV, HPV-16 is more frequently associated with oral cancers. HPV detection will become a game changer in management of oral cancers. HPV infection and p16 protein expression has a strong and consistent correlation. Therefore, immunohistochemical analysis of p16 protein can be a surrogate biomarker in high risk groups. This hospital based prospective observational study recruited 180 subjects of oral and oropharyngeal SCC. We underwent immunohistochemical analysis of p16 in biopsy specimen of subjects and studied HPV status and associated environmental, clinical and behavioral factors. We observed 9.4% (17/180) incidence of p16 positivity with female predominance. Our observations showed that its prevalence was higher in urban patients who were non tobacco users, had sexually transmitted disease, early stage (T1-T2), poorly differentiated SCC with nodal metastasis. We conclude that keeping in mind HPV as a cause of oral and oropharyngeal SCC, p16 should be use as a biomarker for its detection in high risk cases.

A Study of Pulmonary Function Tests in Patients with Chronic Rhinosinusitis Following Endoscopic Sinus Surgery.

Chronic inflammatory disorders of the upper airways are extremely prevalent and they have a major impact on public health.To assess the change in pulmonary function tests in patients of chronic rhinosinusitis undergoing functional endoscopic sinus surgery pre operatively and post operatively.To evaluate the difference in mean of FEV1, FEV1%, FVC, FVC%, FEV1/FVC in patients of chronic rhinosinusitis undergoing functional endoscopic sinus surgery.Prospective observational study.From July 2019 to September 2020 in Department of ENT and Head & Neck surgery, SMS Medical College, Jaipur.There was a significant improvement in the mean FEV1, FEV1%, FVC, and FVC% values post-surgically (p < 0.05). In our study, there was also a significant improvement in the FEV1/FVC value at one month postoperatively, reflecting the effect of FESS on relieving the symptomatic lower airway obstruction.Our study concludes that following Functional Endoscopic Sinus Surgery there is significant improvement in pulmonary function tests reflecting the improvement of asymptomatic lower airway disease in cases of chronic rhinosinusitis.

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.

Metastatic Grade 3 Neuroendocrine Tumor in Multiple Endocrine Neoplasia Type 1 Expressing Somatostatin Receptors.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) may occur in 30% to 90% of patients with multiple endocrine neoplasia type 1 (MEN1). However, only 1% of GEP-NETs are grade 3 (G3). Given the rarity of these aggressive tumors, treatment of advanced G3 GEP-NETs in MEN1 is based on the treatment guidelines for sporadic GEP-NETs. We report a 43-year-old male with germline MEN1 followed at our institution, with clinical features including hyperparathyroidism, a nonfunctional pancreatic NET, and Zollinger-Ellison syndrome. On routine surveillance imaging at age 40, computed tomography/positron emission tomography imaging showed 2 arterially enhancing intraluminal masses on the medial aspect of the gastric wall. Anatomical imaging confirmed 2 enhancing masses within the pancreas and a rounded mass-like thickening along the lesser curvature of the stomach. The gastric mass was resected, and pathology reported a well-differentiated G3 NET with a Ki-67 >20%. The patient continued active surveillance. Eighteen months later cross-sectional imaging studies showed findings consistent with metastatic disease within the right hepatic lobe and bland embolization was done. On follow-up scans, including 68Ga-DOTATATE (68Ga-DOTA(0)-Tyr(3)-octreotate) imaging, interval increase in number and avidity of metastatic lesions were compatible with disease progression. Given a paucity of treatment recommendations for G3 tumors in MEN1, the patient was counseled based on standard NET treatment guidelines and recommended 177Lu-DOTATATE treatment. PRRT (peptide receptor radionuclide therapy) with 177Lu-DOTATATE (177Lu-tetraazacyclododecanetetraacetic acid-octreotide) is an important therapeutic modality for patients with somatostatin receptor-positive NETs. However, prospective studies are needed to understand the role of PRRT in G3 NETs.

Invasive Fungal Infections in Dengue Recovered Patients: A New Phenomenon in the Covid-19 Era.

Invasive fungal rhinosinusitis was seen to rise to epidemic levels after the 2nd wave of ongoing Covid pandemic, especially in tropical countries, maximally in India. A similar trend is being observed for cases who have recently recovered from dengue virus infection. Post dengue invasive fungal infection is a new presentation and any associations between it and Covid pandemic need to be studied in detail to help prepare for any complications. 3 patients presented to the out-patient department of E.N.T at a tertiary level teaching hospital in East India with complains similar to rhinosinusitis. These patients were then evaluated and diagnosed to be infected from Mucormycosis and Aspergillosis fungal sinusitis after which they were managed with surgical debridement and systemic antifungal therapy. All had a recent history of recovery from Dengue virus infection and a possible association could be suspected. 3 patients presented with complains of pain over upper jaw with orbital swelling and loss of vision developing over a period of 24 days. Two of them had ulceration of hard palate. They were then subjected to Contrast MRI along with CT scan of the Paranasal sinuses which depicted pansinus involvement with intracranial extension in two patients. These were then planned for diagnostic nasal endoscopies along with biopsies which turned out to be Invasive fungal sinusitis in the form of Aspergillosis and Mucormycosis. All the 3 patients had recent history of recovery from Dengue virus infection and did not have any other co-morbidities. Covid Associated Mucormycosis (CAM) is a well-known entity now but no reports of Dengue associated Invasive fungal sinusitis are yet reported. Whether this new phenomenon has anything to do with the interactions between dengue virus and coronavirus is not known at present and needs to be studied in detail so appropriate management protocols can be formulated.

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.

Novel GLCCI1-BRAF fusion drives kinase signaling in a case of pheochromocytomatosis.

Introduction: Recurrent and metastatic pheochromocytoma (PCC) are rare advanced endocrine neoplasms with limited treatment options. Insight into the pathogenic molecular alterations in patients with advanced PCC can provide therapeutic options for precisely targeting dysregulated pathways. Objective: We report the discovery and characterization of a novel BRAF-containing fusion transcript and its downstream molecular alterations in a patient with recurrent PCC with peritoneal seeding (pheochromocytomatosis). Methods: We reviewed the medical record of a patient with pheochromocytomatosis. A comprehensive pan-cancer molecular profiling using next-generation sequencing (NGS) as well as confirmatory real-time-quantitative PCR were performed on surgical specimens. BRAF rearrangement and downstream molecular changes were assayed using fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC), respectively. Western blot was used to assess the in vitro activation of the mitogen-activated protein kinase (MAPK) signaling pathway and the EMT markers in transfected HEK-293 cells. Results: The NGS analysis of a specimen from a 72-year-old female patient with pheochromocytomatosis showed an in-frame fusion of exon 3 of Glucocorticoid Induced 1 (GLCCI1) to exon 9 of BRAF. The upstream auto-inhibitory domain of BRAF was excluded from the GLCCI1-BRAF fusion; however, the downstream BRAF kinase domain was intact. A BRAF rearrangement was confirmed via a BRAF-specific break-apart FISH assay. Four separate tumor foci harbored GLCCI1-BRAF fusion. IHC demonstrated increased phosphorylated MEK. HEK-293 cells transfected with the GLCCI1-BRAF fusion demonstrated increased phosphorylated MEK as well as higher expression of EMT markers SNAI1 and ZEB1 in vitro. Conclusion: We demonstrate a novel pathogenic gene fusion of GLCCI1 with the oncogenic kinase domain of BRAF, resulting in an activation of the MAPK signaling pathway and EMT markers. Thus, this patient may benefit from clinically available MEK and/or BRAF inhibitors when systemic therapy is indicated. Summary Statement: This report is the first of GLCCI1 fused to BRAF in a human neoplasm and only the second BRAF-containing fusion transcript in PCC. Detailed molecular characterization of PCC can be a valuable tool in managing patients with recurrent PCC and pheochromocytomatosis that represents a significant clinical challenge.

Orbital magnetic resonance imaging profile and clinicoradiological correlation in COVID-19-associated rhino-orbital-cerebral mucormycosis: A single-center study of 270 patients from North India.

PURPOSE: To study the clinical profile and magnetic resonance imaging (MRI) features in patients of COVID-19-associated rhino-orbital-cerebral mucormycosis (CA-ROCM) with orbital involvement and perform a clinicoradiological correlation. METHODS: A cross-sectional study was performed at a tertiary care center in north India from May 2021 to June 2021. Consecutive patients with clinical, nasal endoscopic, and/or microbiological evidence of CA-ROCM underwent MRI of paranasal sinuses, orbit, and brain as per the study protocol. Orbital MRI findings were studied in detail and were correlated with clinical signs. RESULTS: Two hundred and seventy patients were studied. The mean age was 48.4 (± 16.82) years. A male predilection was noted (male:female = 1.77). Orbital involvement was seen in 146 (54%) patients on clinical evaluation and in 184 (68%) patients on MRI. Unilateral orbital involvement was more common (134; 92%). The most common presenting symptom was periorbital and/or facial pain (141; 52.2%) and the most common clinical sign was periorbital edema (116; 43%). The most common MRI finding was suggestive of orbital cellulitis (160; 59%). Orbital compartment syndrome was found in 17 (6.3%) patients. The inter-rater agreement between clinical and radiological assessments to detect the involvement of infraorbital nerve and frontal nerve was found to be 85.56%, (κ 0.621) and 93.70% (κ 0.776), respectively. The diagnostic accuracy, sensitivity, and specificity of MRI to detect medial orbital wall defect were found to be 87.9%, 65%, and 97%, respectively. CONCLUSION: Orbital imaging features of a cohort of ROCM patients have been presented with clinicoradiological correlation.

COVID-19, Diabetes and Steroids: The Demonic Trident for Mucormycosis.

Coronavirus disease 2019 (COVID-19) has been found to be associated with mucormycosis in few parts of the world, especially India. It is important to look for reasons for this upsurge of cases so that other countries may take proper steps to prevent it. A prospective clinico-demographic study was conducted in SMS Medical College, Jaipur, India from April to May 2021. All patients (235) with COVID associated mucormycosis (CAM) were studied in detail with reference to their diabetic status and steroid intake during treatment of COVID-19. Steroid usage was in 84.3% of patients with methylprednisolone being the most commonly used steroid (66.8%). Majority of the patients had taken steroids for 7-14 days. Diabetes was found in 204 patients and 42.1% of patients were newly diagnosed during/after COVID-19 treatment. The HbA1c levels of diabetic patients ranged from 6.0% to 16.3%. This is perhaps the biggest study in the world shows that the triad of COVID-19, diabetes and steroid usage is a major contributing factor towards mucormycosis. Proper steps should be taken to prevent CAM.