An objective way to predict remission and relapse in Cushing disease using Bayes' theorem of probability.

OBJECTIVE: In this study on patients with Cushing disease, post-transsphenoidal surgery (TSS), we attempt to predict the probability of remaining in remission, at least for a year and relapse after that, using Bayes' theorem and the equation of conditional probability. The number of parameters, as well as the weightage of each, is incorporated in this equation. DESIGN AND METHODS: The study design was a single-centre ambispective study. Ten clinical, biochemical, radiological and histopathological parameters capable of predicting Cushing disease remission were identified. The presence or absence of each parameter was entered as binary numbers. Bayes' theorem was applied, and each patient's probability of remission and relapse was calculated. RESULTS: A total of 145 patients were included in the study. ROC plot showed a cut-off value of the probability of 0.68, with a sensitivity of 82% (range 73-89%) and a specificity of 94% (range 83-99%) to predict the probability of remission. Eighty-one patients who were in remission at 1 year were followed up for relapse and 23 patients developed relapse of the disease. The Bayes' equation was able to predict relapse in only 3 out of 23 patients. CONCLUSIONS: Using various parameters, remission of Cushing disease can be predicted by applying Bayes' theorem of conditional probability with a sensitivity and a specificity of 82% and 94%, respectively. This study provided an objective way of predicting remission after TSS and relapse in patients with Cushing disease giving a weightage advantage to every parameter.

Remission in Cushing's disease is predicted by cortisol burden and its withdrawal following pituitary surgery.

AIM: To ascertain the predictors of remission and relapse in patients of Cushing's disease (CD) undergoing pituitary transsphenoidal surgery (TSS). METHODS: Patients with CD subjected to TSS over 35 years at a tertiary care center were included. Patients were grouped into remission and persistent disease at 1 year after surgery, and were further followed up for relapse. Demographic, clinical, biochemical, histological, radiological and post-operative follow-up parameters were analyzed. RESULTS: Of the 152 patients of CD, 145 underwent TSS. Remission was achieved in 95 (65.5%) patients at 1 year. Patients in remission had shorter duration of symptoms prior to presentation (p = 0.009), more frequent presence of proximal myopathy (p = 0.038) and a tumor size of < 2.05 cm (p = 0.016) in comparison to those with persistent disease. Post-TSS, immediate post-operative 0800-h cortisol (< 159.85 nmol/L; p = 0.001), histological confirmation of tumor (p = 0.045), duration of glucocorticoid replacement (median 90 days; p = 0.001), non-visualization of tumor on MRI (p = 0.003), new-onset hypogonadism (p = 0.001), 3-month 0800-h cortisol (< 384.9 nmol/L; p = 0.001), resolution of diabetes (p = 0.001) and hypertension (p = 0.001), and recovery of hypothalamic-pituitary-adrenal axis (p = 0.018) favored remission. In logistic regression model, requirement of glucocorticoid replacement (p = 0.033), and resolution of hypertension post-TSS (p = 0.003) predicted remission. None of the parameters could predict relapse. CONCLUSION: The study could ascertain the predictors of remission in CD. Apart from the tumor characteristics, surgical aspects and low post-operative 0800-h cortisol, the results suggest that baseline clinical parameters, longer glucocorticoid replacement, and resolution of metabolic complications post-TSS predict remission in CD. Long-term follow-up is essential to look for relapse.

Primary hyperparathyroidism in pregnancy: observations from the Indian PHPT registry.

PURPOSE: To present the data on primary hyperparathyroidism (PHPT) in pregnancy from India obtained from a large database maintained over 15 years. METHODS: We retrieved data of all women with gestational PHPT from the Indian PHPT registry between July 2005 and January 2020, and compared their clinical, biochemical, and other characteristics with age-matched non-pregnant women with PHPT. RESULTS: Out of 386 women, eight had gestational PHPT (2.1%). The common presenting manifestations were acute pancreatitis (50%) and renal stone disease (50%); two were asymptomatic. Five women (62.5%) had a history of prior miscarriages. Seven patients (88%) had preeclampsia during the present gestation. Serum calcium and intact parathyroid hormone (iPTH) were not statistically different from the age-matched non-pregnant PHPT group. Six patients with mild-to-moderate hypercalcemia were medically managed with hydration with/without cinacalcet while one patient underwent percutaneous ethanol ablation of the parathyroid adenoma; none underwent surgery during pregnancy. Mean serum calcium maintained from treatment initiation till delivery was 10.5 ± 0.4 mg/dl. One patient had spontaneous preterm delivery at 36 weeks; the remaining patients had normal vaginal delivery at term. None had severe preeclampsia/eclampsia. Fetal outcomes included low birth weight in three newborns (37.5%); two of them had hypocalcemic seizures. CONCLUSION: The prevalence of gestational PHPT was 2.1% in this largest Indian PHPT cohort, which is higher than that reported from the West (< 1%). Gestational PHPT can lead to preeclampsia and miscarriage. Pregnant PHPT patients with mild-to-moderate hypercalcemia can be managed with hydration/cinacalcet; however, long-term safety data and large-scale randomized controlled trials are required.

Dysregulated mitogen-activated protein kinase pathway mediated cell cycle disruption in sporadic parathyroid tumors.

OBJECTIVES: The study was designed to evaluate expression profiling of mitogen-activated protein kinase (MAPK) signalling pathway genes in sporadic parathyroid adenoma. METHODS: Expression of MAPK signalling pathway genes including activated transcription factors and cell cycle regulatory genes was analysed by real-time PCR- based array in parathyroid adenoma (N = 20) and normal parathyroid tissue (N = 4). RESULTS: MAPK signalling pathway as studied by PCR array revealed that a total of 22 genes were differentially expressed (≥ twofold change, p ≤ 0.05) in parathyroid adenoma. Up-regulated genes were ARAF, MAPK12, CREBBP, MYC, HSPB1, HRAS, CDK4, CCND1, and E2F1, and down-regulated genes were MAP4K1, DLK1, MAP3K4, MAPK10, MAPK8, ATF2, SMAD4, MEF2C, LAMTOR3, FOS, CDKN2A CDKN2B, and RB1. The present study revealed that ERK1/2 signalling pathway with up-regulation of HRAS, ARAF, and MEK1 genes and up-regulation of positive regulators of cell cycle (CCND1, CDK4, and E2F1) and down-regulation negative regulators of cell cycle (CDKN2A, CDKN2B, and RB1) made highly dysregulated MAPK signalling pathway in parathyroid adenoma. Expression of CDK4 was positively associated with plasma PTH level (r = 0.60, p = 0.04) and tumor weight (r = 0.80, p = 0.02) of the adenoma patients, respectively. Expression of CDKN2A was correlated negatively with PTH level (r = - 0.52, p = 0.04) of the adenoma patients. CONCLUSION: The current study revealed that ERK pathway and associated cell cycle regulator genes are dysregulated in sporadic parathyroid adenoma.

Contact sensitization to hair colours in acquired dermal macular hyperpigmentation: results from a patch and photo-patch test study of 108 patients.

BACKGROUND: Acquired dermal macular hyperpigmentation (ADMH) is an umbrella term including lichen planus pigmentosus, erythema dyschromicum perstans and pigmented contact/cosmetic dermatitis. OBJECTIVE: To establish contact sensitization to hair colours as an aetiological factor for ADMH. METHODS: Detailed clinical examination, skin biopsies, and patch and photo-patch testing with Indian standard series and patient's own cosmetic products were performed. RESULTS: Thirty-nine (36.1%) patients were found to demonstrate a positive patch/photo-patch test with 35/39 reacting to their own products (all were hair colours) and 16/39 reacting to antigens from commercial series (commonly paraphenylenediamine). Fourteen patients developed delayed hyperpigmentation on positive patch-test sites at 1 month. Higher mean age, symptomatic pigmentation (pruritus, burning and photosensitivity), hair margins involvement (outer surface, helix and lobule of ear; temples and preauricular area), ill-defined lesions, epidermal atrophy and epidermal melanization extending >3 layers were significantly common in patch-test-positive patients. Well-defined lesions, perioral involvement and associated lichen planus were clinical pointers towards patch-test negativity. CONCLUSION: Index study exemplifies that patch-test results have distinct clinical and histopathological correlates in ADMH. Hair dye contact sensitization appears to be an important aetiological factor in about one-third patients presenting with ADMH.

Quantitative proteomics analysis of sporadic parathyroid adenoma tissue samples.

OBJECTIVE: Molecular pathogenesis of parathyroid tumors is incompletely understood. Identification of novel molecules and understanding their role in parathyroid tumorigenesis by proteomics approach would be informative with potential clinical implications. METHOD: Adenomatous (n = 5) and normal (n = 2) parathyroid tissue lysates were analyzed for protein profile by LC-MS/MS method and the proteins were classified using bioinformatics tools such as PANTHER and toppfun functional enrichment tool. Identified proteins were further validated by western blotting and qRT-PCR (n = 20). RESULT: Comparative proteomics analysis revealed that a total of 206 proteins (74 upregulated and 132 downregulated) were differentially expressed (≥ twofold change) in adenomas. Bioinformatics analysis revealed that 48 proteins were associated with plasma membrane, 49 with macromolecular complex, 39 were cytoplasm, 38 were organelle related, 21 were cell junction and 10 were extracellular proteins. These proteins belonged to a diverse protein family such as enzymes, transcription factors, cell signalling, cell adhesion, cytoskeleton proteins, receptors, and calcium-binding proteins. The major biological processes predicted for the proteins were a cellular, metabolic and developmental process, cellular localization, and biological regulation. The differentially expressed proteins were found to be associated with MAPK, phospholipase C (PLC) and phosphatidylinositol (PI) signalling pathways, and with chromatin organization. Western blot and qRT-PCR analysis of three proteins (DNAJC2, ACO2, and PRDX2) validated the LC-MS/MS findings. CONCLUSION: This exploratory study demonstrates the feasibility of proteomics approach in finding the dysregulated proteins in benign parathyroid adenomas, and our preliminary results suggest that MAPK, PLC and PI signalling pathways and chromatin organization are involved in parathyroid tumorigenesis.

A prospective observational study to compare efficacy of topical triamcinolone acetonide 0.1% oral paste, oral methotrexate, and a combination of topical triamcinolone acetonide 0.1% and oral methotrexate in moderate to severe oral lichen planus.

Topical corticosteroids are considered to be the most effective treatment for oral lichen planus (OLP). Methotrexate has been found to be effective in extensive cutaneous lichen planus. The objectives of the study were to evaluate the clinical efficacy and safety of topical triamcinolone 0.1% oral paste, oral methotrexate and a combination of these in symptomatic moderate-to- severe OLP. Forty-five patients were recruited and were allocated to three treatment arms with 15 patients in each treatment arm. They were treated for a period of 16 weeks or until complete clinical remission, whichever was earlier. The parameters assessed were clinical severity score, visual analogue score, and quality of life impairment questionnaire score. Forty-three patients completed the study. All three treatment modalities were effective. The patients in the combination group had significantly better reduction in the outcome parameters assessed compared to the other two groups. Nine patients achieved complete clinical remission, 6 in the combination group and 3 in the topical triamcinolone group. Systemic methotrexate, alone or in combination with topical triamcinolone, is effective in management of moderate to severe OLP.