Adrenocortical Carcinoma: a Therapeutic Challenge - 44 Cases from a Single Tertiary Care Center in India.

This study was conducted among patients with adrenocortical carcinoma (ACC) to analyze their clinico-pathological profile, management outcomes, and risk factors for local recurrence, systemic metastasis, and survival. The data of patients with ACC who were managed at a single institution between January 2004 and December 2016 was retrospectively collected and analyzed using STATA 13.1. Forty-four patients with a diagnosis of ACC were included in the study. The mean age at presentation was 38.5 ± 14.6 (9-74) with a male preponderance. Functioning tumors represented 59.1% (n = 26), cortisol being the most common hormone secreted. Forty patients (90.9%) underwent surgery, 14 (35%) of whom required an en bloc resection of adjacent organs. Fifteen (37.5%) received radiation (RT) to the postoperative bed while chemotherapy and mitotane were administered in 12 (27.3%) and 9 (20.5%) respectively. The mean follow-up was 34.3 ± 32.7 months. Twelve (30%) patients developed local recurrence, 21 (55.3%) had systemic metastasis, and 15 (34.1%) expired. The mean 1-year and 5-year overall survival rates were 77% and 65.7% respectively. On multivariate analysis, patients with ENSAT stage III/IV were significantly associated with local recurrence (p = 0.011) and metastasis (p = 0.037). Age > 50 (p = 0.003) and ENSAT III/IV (p = 0.017) were significantly associated with mortality on univariate analysis but not on multivariate analysis. In our study population, patients presented at a younger age with a male preponderance. Ninety percent underwent surgery, a subset (35%) requiring resection of adjacent organs to ensure R0 resection. Patients presenting at ENSAT stage I/II have better outcomes.

USP8, USP48, and BRAF mutations differ in their genotype-phenotype correlation in Asian Indian patients with Cushing's disease.

PURPOSE: To estimate the prevalence of USP8, USP48, and BRAF mutations in patients with Cushing's disease (CD) from the Indian subcontinent, and determine their genotype-phenotype correlation. METHODS: We prospectively recruited 46 patients with CD who underwent surgery between September 2015 and July 2019 at our institute. Fresh frozen tumour tissue was obtained in all patients. Using Sanger sequencing, the presence of somatic USP8 mutations was documented and the frequency of USP48 and BRAF mutations in USP8 wild-type corticotroph adenomas was determined. Clinical, hormonal, and surgical data were then compared between USP8-, USP48- and BRAF-variant carriers and patients with wild-type tumours. RESULTS: Signature USP8 mutations were detected in 17 (37%) patients. Of the 29 USP8 wild-type adenomas, 4 (13.8%) harboured USP48 mutations, one of them being a splice-site mutation that has previously not been described. BRAF mutations were not found in any of the 29 patients. Corticotroph adenomas with USP8 mutations had a higher incidence of Crooke's hyaline change than wild-type tumours (70.6 vs. 37.9%, p = 0.032). Adenomas with USP48 mutations had a higher rate of cavernous sinus invasion than their wild-type counterparts (50 vs. 4%, p = 0.042). No other significant phenotypic difference could be established between mutant and wild-type tumours. CONCLUSIONS: The prevalence of USP8 mutations in our series of patients with CD was 37%. The prevalence of USP48 mutations in USP8 wild-type adenomas was 13.8%, including a novel splice-site mutation. BRAF mutations were not found in any USP8 wild-type tumour. USP8-mutants showed significantly more Crooke's hyaline change and USP48-mutants were more likely to demonstrate cavernous sinus invasion.

Impact of Experience on Outcomes After Endoscopic Transsphenoidal Surgery for Acromegaly.

OBJECTIVE: Acromegaly is a syndrome of metabolic alterations secondary to increased growth hormone levels from a somatotroph pituitary adenoma. A multidisciplinary approach beginning with surgery, followed by adjuvant radiation or medical therapy for residual disease, is considered standard of care. Several factors affect the likelihood of remission after surgery, but the impact of surgical experience on remission rates has not been adequately assessed. METHODS: Retrospective review of 203 patients, divided into 2 eras (era 1, 102 patients; era 2, 101 patients) of patients who underwent transsphenoidal surgery for acromegaly by a single surgeon over 11 years, was performed, determining the effect of surgical experience on rates of remission and various complications. Remission was defined according to the 2014 Endocrine Society Clinical Practice Guideline. RESULTS: The rate of surgical remission was 40.6% (62.9% among noninvasive adenomas). Rates of surgical remission significantly improved in the latter half of this cohort (31.2% in the first half vs. 50% in the second half), despite other factors being comparable. On multivariate analysis, surgeon experience, cavernous sinus invasion, and preoperative growth hormone levels affected the rates of surgical remission. Rates of cerebrospinal fluid leak and hypopituitarism were lower in the second half, whereas resolution of acromegaly-associated comorbidities was increased. CONCLUSIONS: We report, in this large single-surgeon review of endoscopically operated acromegaly cases, increased rates of surgical remission and reduced complications with increasing surgeon experience. The overall experience of the treating team in dealing with perioperative and intraoperative factors also contributes to improved outcomes.

Selective perioperative steroid supplementation protocol in patients undergoing endoscopic transsphenoidal surgery for pituitary adenomas.

BACKGROUND: There is no consensus regarding the use of perioperative steroids for transsphenoidal pituitary surgery. We audited the effectiveness and safety of our selective perioperative steroid supplementation protocol in patients with pituitary adenomas. METHODS: Two hundred ninety-seven patients underwent 306 endoscopic transsphenoidal surgeries for removal of their pituitary tumors. Steroids were given to those with an impaired hypothalamic-pituitary-adrenal (HPA) axis, age ≥ 60 years, clinical apoplexy, hyponatremia, or if the pituitary gland was not preserved at surgery. We excluded 111 patients in whom the integrity of the HPA axis could not be determined. We compared the incidence of early postoperative adrenal insufficiency and complications in 135 patients with intact HPA axes who underwent surgery without steroids (group A) with 60 patients who had compromised preoperative HPA axes and received perioperative steroids (group B). In addition, we audited the total number of protocol violations during this period. RESULTS: Five patients (3.7%) in group A developed postoperative hypocortisolemia. There was no significant difference in the incidence of cerebrospinal fluid leak, diabetes insipidus, or hyponatremia between both groups. There were protocol deviations in 47 (15.4%) patients. Twenty one of these patients did not receive perioperative steroids in violation of the protocol, of whom 4 (19%) developed postoperative hypocortisolemia. CONCLUSIONS: Our steroid sparing protocol was both safe and effective. The 15% incidence of protocol deviations is a reminder that the rigorous usage of checklists is mandatory for successful clinical practice.

Bone Health after Fifth Decade in Rural Ambulatory South Indian Postmenopausal Women.

BACKGROUND: The incidence of postmenopausal osteoporosis continues to rise, as population ages. The morbidity and mortality associated with osteoporotic fractures have a significant negative impact on the economy and quality of life of the affected individual and the community, at large. OBJECTIVES: We aimed to study the prevalence of osteoporosis in ambulant rural postmenopausal women, and to look at their dietary calcium intake (DCI) and Vitamin D status. SUBJECTS AND METHODS: This was a cross-sectional study conducted in 1565 ambulant South Indian rural postmenopausal women. Bone mineral density was estimated by a dual-energy X-ray absorptiometry scan at the femoral neck (FN) and lumbar spine (LS). DCI was calculated by recall for the previous week, and the blood bone biochemical profile was measured. RESULTS: The mean standard deviation (SD) age and body mass index of this population were 60.7 (7.2) years and 26.2 (4.8) kg/m2, respectively. The prevalence of osteoporosis was 22% at the FN and 39% at the LS. An increase in the prevalence of osteoporosis was noted at both sites, in successive age categories. Mean (SD) DCI was 420 (282) mg/24 h. Fifty-four percent had Vitamin D deficiency (VDD) (<20 ng/ml) and 6% had severe VDD (<10 ng/ml). CONCLUSION: A significant proportion of this large cohort of south Indian healthy rural postmenopausal women had osteoporosis at either site with advancing age. Most of them had a suboptimal DCI, and over half of them had VDD.

Osteoporosis knowledge and beliefs among postmenopausal women: A cross-sectional study from a teaching hospital in southern India.

OBJECTIVES: Osteoporosis continues to be underrecognized in many parts of India. This study was undertaken to assess the level of knowledge of osteoporosis among postmenopausal women referred for a dual-energy X-ray absorptiometry (DXA) scan in a teaching hospital in southern India. METHODOLOGY: This cross-sectional study assessed the state of awareness in consecutive postmenopausal women referred for a DXA scan using a validated questionnaire - Osteoporosis Knowledge Assessment Tool. The proportion of correct responses was expressed as percentages. The mean scores obtained were also compared between different educational groups. RESULTS: A total of 302 consecutive postmenopausal women who were referred for DXA participated in this study. The mean (standard deviation) age of the postmenopausal women included in this study was 58.8 (6) years. Although most subjects were aware of the consequences of osteoporosis, there was generalized lack of awareness with regard to risk factors and available treatment options. Overall about 60% had poor awareness about osteoporosis. CONCLUSION: This study showed a gross deficit in awareness of osteoporosis in Indian postmenopausal women. There is a need to prioritize on designing appropriate awareness campaigns in subjects at risk, according to their level of literacy.

Influence of Different Reference Databases on Categorization of Bone Mineral Density: A Study on Rural Postmenopausal Women from Southern India.

BACKGROUND AND OBJECTIVES: Currently available DXA (Dual energy X-ray Absorptiometry) scanners utilise bone mineral density (BMD) of Caucasian population to calculate T scores and categorise BMD. We studied the influence of various databases on classification of BMD in south-Indian postmenopausal women aged above 50 years. METHODOLOGY: This was a cross-sectional study. Hologic DXA scanner was used to estimate BMD at lumbar spine (LS) and femoral neck (FN). T scores of ≤-2.5, -2.4 to -1, -0.9 to +1 were diagnostic of osteoporosis, osteopenia and normal respectively. Three reference databases(Italian, Korean and north Indian) were used to recalculate T scores. The agreement (K=kappa) between manufacturer provided database and the other databases was studied. The impact of different databases in diagnosing osteoporosis in subjects with FN fracture was assessed. RESULTS: A total of 1956 postmenopausal women with mean (SD) age of 62 (4.3) years and 211 femoral neck(FN) fracture subjects with mean(SD) age of 68 (7.2) years were recruited. In subjects with fracture, osteoporosis at FN was found in 72% with Caucasian, 88% with North Indian, 56% with Italian, and 45% with Korean database. On comparing manufacturer provided database with the other population-specific reference, there was perfect agreement with north Indian (κ = 0.81 [FN], κ = 0.82 [LS]) and good agreement with the Italian database (κ = 0.78 [FN], κ = 0.74 [LS]). CONCLUSION: North-Indian database identified most of the participants with FN fracture as having osteoporosis and had perfect agreement with the manufacturer's database. Follow up studies will further validate the impact of utilizing this database in clinical practice.

Paget's Disease of Bone: An Entity Still Exists in India.

BACKGROUND: Paget's disease of bone (PDB) is uncommonly reported from India. We attempted to study the clinical and imaging features and management of participants who presented with PDB. MATERIALS AND METHODS: In this retrospective study, clinical and imaging profile, biochemistry, and treatment outcomes of participants with PDB (n = 48) were obtained. RESULTS: The mean age was 60 ± 11.3 years and 35% were women. Twenty percent were asymptomatic. Many (87%) had polyostotic involvement. Sixty percent (n = 29) underwent treatment with zoledronic acid and rest with oral bisphosphonates, and all achieved remission. CONCLUSION: Most of the pagetic participants had polyostotic disease and one-fifth were asymptomatic. All participants had disease remission following treatment.

An uncommon cause of osteoporosis.

Osteoporosis in the younger age group is an important cause of morbidity. Prolactinoma is an uncommon but reversible cause of osteoporosis. The main mechanisms of osteoporosis in prolactinoma are reduced osteoblast activity and hypogonadism. A high index of suspicion is the key in diagnosis and management of this treatable entity.

Hypovitaminosis D and Other Risk Factors of Femoral Neck Fracture in South Indian Postmenopausal Women: A Pilot Study.

BACKGROUND: Non-communicable diseases like hip fractures are a significant problem in a developing country like India. The risk factors for hip fractures vary according to local practices and the availability of preventive health care delivery systems. There is paucity of data on risk factors for hip fracture in the south Indian population. AIM: This study was undertaken to assess risk factors associated with femoral neck (FN) fracture in South Indian postmenopausal women along with subsequent one year mortality. MATERIALS AND METHODS: One hundred four postmenopausal women with FN fracture and 104 age and BMI matched controls were included. Sedative use, visual impairment and other relevant risk factors were assessed. Bone biochemistry and Bone Mineral Density (BMD) were evaluated. A telephonic interview was done at the end of one year to ascertain the well-being. RESULTS: Sedative use, visual impairment, low FN BMD and vitamin-D deficiency (<20 ng/ml) were seen more in fracture subjects compared to controls (p≤0.05). At the end of one year, 20% of the fracture subjects and 5% of the controls had died (p=0.001). CONCLUSION: Risk factors identified in our study are potentially correctable, and needs special attention in an Indian context to prevent hip fractures.

Maturity onset diabetes of the young in India - a distinctive mutation pattern identified through targeted next-generation sequencing.

OBJECTIVE: To establish and utilize a Next-Generation Sequencing (NGS)-based strategy to screen for maturity onset diabetes of the young (MODY) gene mutations in subjects with early-onset diabetes. PATIENTS AND METHODS: Maturity onset diabetes of the young (MODY) genetic testing was carried out in 80 subjects of Asian Indian origin with young onset diabetes to identify mutations in a comprehensive panel of ten MODY genes. A novel multiplex polymerase chain reaction (PCR)-based target enrichment was established, followed by NGS on the Ion Torrent Personal Genome Machine (PGM). All the mutations and rare variants were confirmed by Sanger sequencing. RESULTS: We identified mutations in 11 (19%) of the 56 clinically diagnosed MODY subjects and seven of these mutations were novel. The identified mutations include p.H241Q, p.E59Q, c.-162G>A 5' UTR in NEUROD1, p.V169I cosegregating with c.493-4G>A and c.493-20C>T, p.E271K in HNF4A, p.A501S in HNF1A, p.E440X in GCK, p.V177M in PDX1, p.L92F in HNF1B and p.R31L in PAX4 genes. Interestingly, two patients with NEUROD1 mutation were also positive for the p.E224K mutation in PDX1 gene. These patients with coexisting NEUROD1-PDX1 mutations showed a marked reduction in glucose-induced insulin secretion. All 24 subjects who had not met the clinical criteria of MODY were negative for the mutations. To the best of our knowledge, this is the first report of PDX1, HNF1B, NEUROD1 and PAX4 mutations from India. CONCLUSIONS: Multiplex PCR coupled with NGS provides a rapid, cost-effective and accurate method for comprehensive parallelized genetic testing of MODY. When compared to earlier reports, we have identified a higher frequency and a novel digenic mutation pattern involving NEUROD1 and PDX1 genes.

Osteoporosis in healthy South Indian males and the influence of life style factors and vitamin d status on bone mineral density.

Objective. To study the prevalence of osteoporosis and vitamin D deficiency in healthy men and to explore the influence of various life style factors on bone mineral density (BMD) and also to look at number of subjects warranting treatment. Methods. Ambulatory south Indian men aged above 50 were recruited by cluster random sampling. The physical activity, risk factors in the FRAX tool, BMD, vitamin D, and PTH were assessed. The number of people needing treatment was calculated, which included subjects with osteoporosis and osteopenia with 10-year probability of major osteoporotic fracture >20 percent and hip fracture >3 percent in FRAX India. Results. A total of 252 men with a mean age of 58 years were studied. The prevalence of osteoporosis and osteopenia at any one site was 20% (50/252) and 58%, respectively. Vitamin D deficiency (<20 ng/dL) was seen in 53%. On multiple logistic regression, BMI (OR 0.3; P value = 0.04) and physical activity (OR 0.4; P value < 0.001) had protective effect on BMD. Twenty-five percent warranted treatment. Conclusions. A significantly large proportion of south Indian men had osteoporosis and vitamin D deficiency. Further interventional studies are needed to look at reduction in end points like fractures in these subjects.

Human immunodeficiency virus-associated lipodystrophy: an objective definition based on dual-energy x-ray absorptiometry-derived regional fat ratios in a South Asian population.

OBJECTIVE: To develop an objective definition of human immunodeficiency virus (HIV)-associated lipodystrophy by using regional fat mass ratios and to assess the utility of anthropometric and skinfold measurements in the initial screening for lipodystrophy. METHODS: Male patients between 25 and 50 years old with proven HIV infection (highly active antiretroviral therapy [HAART]-naïve subjects and those receiving successful HAART) were studied and compared with body mass index (BMI)-matched HIV-negative control subjects. Anthropometric variables, body composition, dual-energy x-ray absorptiometry findings, and metabolic variables were compared among the 3 study groups and between those patients with and those without lipodystrophy. RESULTS: Trunk fat/lower limb fat mass ratio >2.28 identified 54.3% of patients with HIV receiving HAART as having lipodystrophy and had the highest odds ratio for predicting metabolic syndrome. The "clinical diagnosis of lipodystrophy" and the "clinical scoring system" had too many false-positive and false-negative results. Triceps skinfold thickness (SFT)/BMI ratio ≤0.49 and abdominal SFT/triceps SFT ratio >1.385 have good sensitivity but poor specificity in identifying lipodystrophy. In comparison with HAART-naïve patients with HIV, those receiving HAART had significantly higher insulin resistance, and a significantly greater proportion had impaired glucose tolerance and dyslipidemia. Among patients receiving HAART, those with lipodystrophy had a greater degree of insulin resistance, higher triglyceride levels, and lower levels of high-density lipoprotein cholesterol. CONCLUSION: The trunk fat/lower limb fat mass ratio in BMI-matched normal subjects can be used to derive cutoff values to define lipodystrophy objectively in HIV-infected patients. Defining lipodystrophy in this way is better than other methods of identifying those patients with increased cardiovascular risk. Triceps SFT/BMI and abdominal SFT/triceps SFT ratios may be useful as screening tools in resource-poor settings.

Hypovitaminosis D and bone mineral density in human immunodeficiency virus-infected men from India, with or without antiretroviral therapy.

OBJECTIVE: To study the vitamin D status and bone mineral density (BMD) in men infected with human immunodeficiency virus (HIV) in a tertiary care center from southern India. METHODS: We conducted a cross-sectional study of 35 HIV-infected men (between 20 and 50 years old) receiving highly active antiretroviral therapy (HAART) (group 1) in comparison with 35 age- and body mass index-matched HIV-positive antiretroviral therapy-naïve men (group 2) and 35 HIV-negative healthy control subjects (group 3). RESULTS: A significantly greater proportion (P = .002) of patients (74%) in the HAART group had vitamin D deficiency (<20 ng/mL) in comparison with the other 2 groups (37% in each group). The mean intact parathyroid hormone level was higher (P<.001) and the mean duration of exposure to sunlight was lower (P = .001) in the HAART group than in the other 2 groups. By logistic regression analysis, HAART was found to be significantly associated with vitamin D deficiency. The BMD in the femoral neck was significantly lower in men with HIV infection who were receiving HAART in comparison with the other 2 groups (P = .006). On multivariate logistic regression, older age, low body mass index, and high parathyroid hormone levels emerged as factors significantly associated with decreased BMD at the femoral neck. CONCLUSION: A significant proportion of patients receiving HAART had vitamin D deficiency. The secondary hyperparathyroidism probably due to vitamin D deficiency is an important contributing factor for the observed changes in BMD. Vitamin D deficiency noted in this group is probably multifactorial, and further research is needed to determine whether the effect of HAART on vitamin D metabolism is an additional causative factor and what benefit vitamin D supplementation might confer in these patients.