An observational study on the prevalence of choledochal cyst with pancreatitis: Geographical implications and management.

The objective of this study was to analyse the prevalence, risk factors and need for intervention in a sample of Indian children with choledochal cyst (CDC) complicated by pancreatitis with a special focus on chronic pancreatitis. A retrospective review of medical records of children admitted with CDC over 11 years was done and pancreatitis identified using INSPPIRE guidelines. Children were divided into two groups-one having choledochal cyst alone and the other choledochal cyst along with pancreatitis to determine associated risk factors. 40.2% of children with CDC had pancreatitis based on elevation of enzymes or radiological imaging. Age, total bilirubin and indirect bilirubin, requirement of intervention was significantly higher in the group with pancreatitis. 47% of those with radiological features of pancreatitis had imaging features of chronic pancreatitis. Chronic pancreatitis has not been reported previously in children with CDC and maybe peculiar to the Indian subcontinent.

Estimation of exocrine pancreatic insufficiency in children with acute pancreatitis using the 13C mixed triglyceride breath test.

BACKGROUND: /Objective: The extent of exocrine pancreatic insufficiency (EPI) in the paediatric population with acute pancreatitis (AP) is unknown. The primary objective was to use a 6 h stable-isotope breath test to determine the prevalence of EPI in children with AP. The secondary objective was to determine the diagnostic ability of a 4 h abbreviated breath test in the detection of EPI. METHODS: 13C-mixed triglyceride (MTG) breath test was used to measure fat digestibility in 12 children with AP and 12 normal children. EPI was diagnosed based on a cumulative dose percentage recovery (cPDR) cut-off value < 26.8% present in literature. To reduce the test burden, the diagnostic accuracy of an abbreviated 4 h test was evaluated, using a cPDR cut-off that was the 2.5th percentile of its distribution in control children. RESULTS: The cPDR of cases was significantly lower than that of controls (27.71 ± 7.88% vs 36.37 ± 4.70%, p = 0.005). The cPDR during acute illness was not significantly different to that at 1 month follow up (24.69 ± 6.83% vs 26.98 ± 11.10%, p = 0.52). The 4 h and 6 h breath test results correlated strongly (r = 0.93, p < 0.001) with each other. The new 4 h test had 87.5% sensitivity and 93.8% specificity for detecting EPI. CONCLUSION: Two-thirds (66.7%) of this sample of children with AP had EPI during admission, which persisted at 1 month follow up. The 4 h abbreviated 13C-MTG breath test has good diagnostic ability to detect EPI in children and may improve its clinical utility in this age group.

Surgical versus nonsurgical treatment of acute Achilles ruptures in the high demand patient: Using decision analysis to help clinical decisions.

BACKGROUND: Recent literature suggests that functional treatment of acute non-insertional Achilles tendon ruptures yields outcomes (re-rupture and function) similar to those of surgery, but does not address the unique issues in treating high performance athletes or other high demand patients. METHODS: Decision analysis was used to develop an estimate of outcome utility for both types of treatment using published Costs and Quality-Adjusted Life Years (QALYs) values. The expected value for either treatment was then calculated for high, intermediate, and normal demand patients, using the specific functional needs of the patients. RESULTS: Nonoperative treatment is the preferred management for normal demand patients, while high and intermediate demand patients are more likely to experience better expected functional outcomes from surgery. CONCLUSION: The combination of a decision analysis and expected value analysis provides evidence-based support for the existing intuitive recommendations that favor surgical treatment in elite athletes and other high demand patients. LEVEL OF EVIDENCE: III.

Efficacy of titratable mandibular advancement device versus continuous positive airway pressure therapy in the treatment of obstructive sleep apnea: A clinical crossover trial.

Background: To compare efficacy of continuous positive airway pressure (CPAP) and oral appliance (OA) in management of various grades of obstructive sleep apnea (OSA). Methods: Thirty polysomnography diagnosed cases of OSA were divided into three groups based on baseline apnea hypopnea index (AHI) as follows: group 1: mild OSA (AHI = 5-14.9), group 2: moderate OSA (AHI = 15-29.9), and group 3: severe OSA (AHI >30) with 10 patients in each group. Half of the patients in each group were randomly allocated to CPAP or OA therapy, and crossover of therapy was performed after two months. AHI, Epworth's Sleepiness Scale (ESS), and mean oxygen saturation (SPO2) were measured at baseline, after each arm of treatment and after the crossover. A questionnaire survey including information regarding pretreatment sleep symptoms and improvement after therapy was performed at above time frames. At the end of therapy, the patients were surveyed regarding satisfaction and perceived effectiveness with both modalities. Results: CPAP was more efficacious in reducing AHI and SPO2 as compared with OA across the three study groups. The improvement in most sleep-related symptoms was higher with CPAP. The satisfaction and perception on effectiveness of treatment were higher with OA than CPAP across three study groups (P-value<0.05 for all). Conclusions: OA is an effective alternative to CPAP across all grades of OSA in selected cases, which is more preferred owing to higher effectiveness and satisfaction among the patients.

Influence of Serum Levels of Vitamin D on Insulin Resistance in Patients with Type II Diabetes Mellitus.

BACKGROUND: Vitamin D plays an important role in bone and modulates mineral metabolism and immune function with probable link to several chronic and infectious conditions. In vivo studies have revealed that vitamin D deficiency reduces insulin secretion capacity of the islet beta cells in pancreas. Several studies have shown a correlation between vitamin D levels and insulin resistance, nonetheless, extensive studies showing the relationship between the two are lacking especially among southern Indian population. So the present study was aimed at evaluating the relationship between vitamin D and insulin resistance by using homeostatic model assessment-insulin resistance (HOMA-IR). MATERIALS AND METHODS: In a cross-sectional study, 184 people among which 92 were diabetic and 92 were nondiabetic were recruited at RL Jalappa Hospital, Kolar in the Department of Medicine between May 2018 and April 2019. Fasting serum insulin (I0), fasting plasma glucose (G0), hemoglobin A1c (HbA1C), renal function test, liver function test (LFT), lipid profile, and vitamin D levels were estimated. IBM SPSS version 22 was used for statistical analysis. RESULTS: The prevalence of vitamin D deficiency in our study was (72) 78.2% among diabetic cases and (59) 64.1% among the nondiabetic controls, with the diabetic cases showing lower levels of vitamin D than the controls, however, it was not statistically significant. There was no significant difference in homeostatic model assessment-beta-cell function (HOMA-B) and HOMA-IR between vitamin D deficient and nondeficient groups among cases and controls. CONCLUSION: Vitamin D deficiency is prevalent in both type II diabetes mellitus (T2DM) as well as nondiabetic. Furthermore, there is no association between vitamin D deficiency and insulin resistance or beta-cell function.

Novel Management of Hypersensitive Dentin Using Propolis-based Herbal Desensitizing Agents: An In Vitro Scanning Electron Microscopic Study.

AIM: The objective of this in vitro study was to assess the efficacy of novel propolis-based varnish against the two conventional varnishes on quantitative and qualitative assessments of occlusion of dentin tubules and resistance to erosive and abrasive wears employing scanning electron microscope (SEM). METHODS: Thirty human premolars free from caries extracted due to orthodontic reasons were included in the study. Experimental group was done based on treatment received and divided into three groups. Group A: ClinProXT Varnish (n = 10), Group B: MI Varnish (n = 10), and Group C: Propolis Varnish (n = 10) were applied. Teeth were cleaned and decoronation of crown was done with dentin disks. Dentin specimens of dimension 4 × 4 × 2 mm were prepared and subjected to finishing and polishing. The sample specimens were submersed in EDTA solution for a period of five minutes to open up the dentinal tubules. This was followed by treatment with varnishes and subjection to acidic-abrasive challenge. The specimens were analyzed with an image analyzer connected to SEM for the verification of the number of opened dentin tubules. The parameter assessed in SEM includes size, topography and surface characteristics of dentinal tubule were assessed. The obliteration potential of dentinal tubules was assessed with SEM images. Additionally, the dentin surface loss and resistance to acidic and abrasive wear were also evaluated with SEM. Data were analyzed with two-way analysis of variance (ANOVA) with post hoc Tukey's test. RESULTS: MI Varnish caused higher obliteration of dentin tubules followed by ClinproXT Varnish. Propolis Varnish showed the least obliteration of dentinal tubules among tested experimental groups. After acidic-abrasive challenge, Propolis Varnish was found to be more efficient with less material loss among the experimental groups tested. There was an insignificant difference among the MI Varnish and ClinProXT Varnish groups. CONCLUSION: Simulation of hypersensitive lesions mimicking the clinical scenario was a challenging task in this in vitro study. All varnishes tested in the study had good efficacy in the management of dentin hypersensitivity (DH). Propolis-based varnish had good resistance to material loss after subjection to acidic-abrasive challenge among the tested materials. The casein phosphopeptide (CPP)-amorphous calcium phosphate (ACP)-based MI Varnish had good efficacy to obliterate the dentinal tubules among the tested materials. It was prudent to select the varnishes with good long-term efficacy to survive in the clinical scenario which still remains a challenging task for the clinicians. CLINICAL SIGNIFICANCE: The stability of the varnish plays a vital role in maintenance of its long-term efficacy. The chemical nature along with the ability of the material to interact with the substrate plays a major role in management of DH.

Evaluation and quantification of airway changes in Class II division 1 patients undergoing myofunctional therapy using twin block appliance.

BACKGROUND: The purpose of the present study was to determine the airway changes in skeletal class II division 1 malocclusion patients with mandibular retrognathism, treated with Twin-Block (TB) appliance. METHODS: Airway assessment was carried for twelve patients (mean age 11.7 ± 1.1 years) who underwent myofunctional therapy using TB appliance for correction of skeletal class II division 1 malocclusion with mandibular retrognathism. Acoustic pharyngometry (AP) was used to assess and quantify the comparative changes in the upper airway, pretreatment and posttreatment. RESULTS: Data acquired was subjected to appropriate statistical analysis. The paired 't' test was used to compare pre-treatment (T0) and after the positive pterygoid response (T1). TB appliance increased mean minimum airway area by 0.28 ± 0.25 cm2 and mean airway by 0.47 ± 0.44 cm2 with 95% CI. Posttreatment minimum airway and mean area changes were found to be statistically significant (P-value<0.01). CONCLUSION: TB appliance therapy has a positive effect on upper airway and is beneficial for the treatment of sleep-related disorders associated with Class II division 1 malocclusion for achieving positive functional changes, esthetics, and healthier quality of life.

Training pediatric hematologist/oncologists for capacity building in Ethiopia.

PURPOSE: A considerable barrier to global pediatric oncology efforts has been the scarcity and even absence of trained professionals in many low- and middle-income countries, where the majority of children with cancer reside. In 2013, no dedicated pediatric hematology-oncology (PHO) programs existed in Ethiopia despite the estimated annual incidence of 6000-12000 cases. The Aslan Project initiative was established to fill this gap in order to improve pediatric cancer care in Ethiopia. A major objective was to increase subspecialty PHO-trained physicians who were committed to practicing locally and empowered to lead programmatic development. METHODS: We designed and implemented a PHO training curriculum to provide a robust educational and clinical experience within the existing resource-constrained environment in Ethiopia. Education relied on visiting PHO faculty, a training attachment abroad, and extraordinary initiative from trainees. RESULTS: Four physicians have completed comprehensive PHO subspecialty training based primarily in Ethiopia, and all have remained local. Former fellows are now leading two PHO centers in Ethiopia with a combined capacity of 64 inpatient beds and over 800 new diagnoses per year; an additional former fellow is developing a pediatric cancer program in Nairobi, Kenya. Two fellows currently are in training. Program leadership, teaching, and advocacy are being transitioned to these physicians. CONCLUSIONS: Despite myriad challenges, a subspecialty PHO training program was successfully implemented in a low-income country. PHO training in Ethiopia is approaching sustainability through human resource development, and is accelerating the growth of dedicated PHO services where none existed 7 years ago.

Standardised neonatal parenteral nutrition formulations - Australasian neonatal parenteral nutrition consensus update 2017.

BACKGROUND: The first consensus standardised neonatal parenteral nutrition formulations were implemented in many neonatal units in Australia in 2012. The current update involving 49 units from Australia, New Zealand, Singapore, Malaysia and India was conducted between September 2015 and December 2017 with the aim to review and update the 2012 formulations and guidelines. METHODS: A systematic review of available evidence for each parenteral nutrient was undertaken and new standardised formulations and guidelines were developed. RESULTS: Five existing preterm Amino acid-Dextrose formulations have been modified and two new concentrated Amino acid-Dextrose formulations added to optimise amino acid and nutrient intake according to gestation. Organic phosphate has replaced inorganic phosphate allowing for an increase in calcium and phosphate content, and acetate reduced. Lipid emulsions are unchanged, with both SMOFlipid (Fresenius Kabi, Australia) and ClinOleic (Baxter Healthcare, Australia) preparations included. The physicochemical compatibility and stability of all formulations have been tested and confirmed. Guidelines to standardise the parenteral nutrition clinical practice across facilities have also been developed. CONCLUSIONS: The 2017 PN formulations and guidelines developed by the 2017 Neonatal Parenteral Nutrition Consensus Group offer concise and practical instructions to clinicians on how to implement current and up-to-date evidence based PN to the NICU population.

Caught Off Guard with COVID-19 Bowel Gangrene: A Case Report.

BACKGROUND: Isolated and predominant gastrointestinal presentation in coronavirus disease 2019 (COVID-19) is reported less often. With evolving evidence that gastrointestinal tract can be a portal of entry, multiplication, primary site of affliction and symptomatic manifestation, and source of infectivity through prolonged fecal shedding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), it is essential that isolated gastrointestinal symptoms can also be a mode of presentation of this novel virus and illness. CASE DESCRIPTION: The index case is a 10-year-old female child who presented with acute onset abdominal pain. Emergency surgery showed extensive gangrenous small bowel. The small bowel had herniated into a transmesenteric defect near the mid-ileum and was obstructed. Reverse-transcription polymerase chain reaction for SARS-CoV2 sent as preoperative work-up turned positive. The histopathology showed platelet aggregate thrombus in the venules with patent adjacent arterioles. CONCLUSION: This is probably the first reported case of COVID-19-related bowel gangrene. HOW TO CITE THIS ARTICLE: Kenchappa Y, Hegde S, Kumar P, Lalitha AV, Bukelo M. Caught Off Guard with COVID-19 Bowel Gangrene: A Case Report. Indian J Crit Care Med 2020;24(12):1269-1271.

It's About Time: Advances in Understanding the Circadian Regulation of DNA Damage and Repair in Carcinogenesis and Cancer Treatment Outcomes.

The circadian rhythm is established by a coordinated network of peripheral clocks interlocked and regulated by a central pacemaker. This network is maintained by the rhythmic expression of core clock genes, which in turn generate oscillatory expression patterns of different sets of target proteins in a tissue-specific manner. Precise regulation of biological processes driven by the body's circadian network in response to periodic changes in the environment determines healthy life. The delicate balance in the cycling of enzymes, metabolites, cofactors, and immune regulators is essential to achieve cellular homeostasis. Disruption of this circadian homeostasis has been linked with the development and progression of various diseases including cancer. Over the years, circadian regulation of drug metabolism and processing has been employed in the treatment of diabetes, hypertension, peptic ulcers, and allergic rhinitis. Although time dictated drug administration was demonstrated many decades ago, its application in cancer treatment is limited due to insufficient mechanistic data supporting experimental results and inconsistency between clinical trials. However, timed administration of anti-cancer drugs is rapidly gaining attention as studies with animal and human models unveil molecular intricacies involved in the circadian control of biological pathways. In this regard, striking a balance between maximizing tumor responsiveness and minimizing side effects is crucial to achieve positive patient outcomes. This review focuses on regulation of the circadian clock in carcinogenesis outcomes through DNA damage and repair mechanisms and its application in therapy with specific emphasis on skin and breast cancers.

Impact of race on dose selection of molecular-targeted agents in early-phase oncology trials.

BACKGROUND: We examined the impact of race on the maximum tolerated doses (MTD) and final approved doses (FAD) of single-agent molecular-targeted agents (MTA) in North America/Europe (NA/EU) and Asia. METHODS: We searched PubMed and regulatory databases to identify targeted drugs approved globally and compared their FAD and MTD in corresponding phase I/II studies conducted separately in NA/EU and Asia. To evaluate this further, we conducted parallel, prospective, first-in-human studies of DS-7423, a dual PI3K/mTOR inhibitor, in patients with advanced solid tumours in the US and Japan. We pooled and compared the pharmacokinetics (PK), pharmacodynamics (PD), toxicity, and efficacy between these populations. RESULTS: 17 MTA were approved in NA/EU and Asia from 2001 to 2015. Recommended phase 2 doses (RP2D) were identical across races in 14 of 17 (80%) studies and differences were not clinically meaningful. FAD were identical across all regions. 42 and 27 patients from US and Japan, respectively, were enrolled in the phase I studies of DS-7423. Despite differences in race, body weight, and body mass index, the RP2D were 240 mg/day with no differences in toxicities, PK, PD, or efficacy. CONCLUSIONS: Conducting separate clinical trials of single-agent MTA in Caucasian and Asian populations may be redundant.

Natural History, Predictors and Management of Ureteroenteric Strictures after Robot Assisted Radical Cystectomy.

PURPOSE: Ureteroenteric strictures represent the most common complication requiring reoperation after radical cystectomy. We investigated the prevalence, outcomes, predictors and management of ureteroenteric strictures. MATERIALS AND METHODS: We retrospectively reviewed our quality assurance, robot assisted radical cystectomy database to identify patients in whom ureteroenteric strictures developed. Data were reviewed for demographics, perioperative outcomes and ureteroenteric stricture characteristics. The Kaplan-Meier method was used to calculate time to ureteroenteric stricture and multivariable stepwise regression was done to evaluate predictors of ureteroenteric strictures. RESULTS: Ureteroenteric strictures developed in 12%, 16% and 19% of 51 patients (13%) at 1, 3 and 5 years after robot assisted radical cystectomy, respectively. All patients were initially treated endoscopically or percutaneously, including 57% treated only endoscopically or percutaneously and 43% who required surgery, which was open repair in 6 and robot assisted repair in 16. At a median followup of 23 months 33 patients (65%) were free of disease, including 13 after endoscopic or percutaneous treatment, 15 after robot assisted repair and 5 after open revision. Open and robot assisted revisions showed comparable perioperative outcomes. On multivariable analysis the predictors of ureteroenteric anastomotic strictures were body mass index (OR 1.07, 95% CI 1.01-1.13, p = 0.02), intracorporeal urinary diversion (OR 3.28, 95% CI 1.41-7.61, p = 0.006), length of the right resected ureter (OR 0.66, 95% CI 0.50-0.88, p = 0.004), estimated glomerular filtration rate 30 days after assisted radical cystectomy (OR 0.85, 95% CI 0.74-0.98, p = 0.03), urinary tract infection (OR 2.68, 95% CI 1.31-5.49, p = 0.007) and leakage (OR 3.85, 95% CI 1.05-14.1, p = 0.04). Male gender (OR 0.19, 95% CI 0.04-0.96, p = 0.04) and higher body mass index (OR 0.85, 95% CI 0.72-0.996, p = 0.05) were associated with lower odds of successful endoscopic management. CONCLUSIONS: Multiple modifiable factors were associated with ureteroenteric anastomotic strictures following robot assisted radical cystectomy. Surgical revision can provide a definitive management with comparable outcomes for open and robotic repairs.

First-in-human study of the antibody DR5 agonist DS-8273a in patients with advanced solid tumors.

Background DR5 is a transmembrane receptor that transduces extracellular ligand-binding to activate apoptosis signaling cascades. This phase 1 study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of a new monoclonal antibody potent DR5 agonist, DS-8273a, in subjects with advanced solid tumors. Methods The study comprised dose escalation and dose expansion cohorts. The dose escalation cohorts intended to determine the safety and to identify the maximum tolerated dose (MTD) or maximum administered dose (MAD) and to characterize the pharmacokinetics and pharmacodynamics by a conventional 3 + 3 design (starting at 2 mg/kg and escalating through 8, 16 and 24 mg/kg once every 3 weeks). In the dose expansion cohort, additional subjects were treated at the MAD for further evaluation of PK and safety. Results Thirty two subjects were enrolled and treated, 16 in the dose escalation cohorts and 16 in the dose expansion cohort. No subjects experienced a dose limiting toxicity (DLT). Treatment emergent adverse events were observed in 29 (91%) subjects, 14 (44%) of which were attributed to study-drug; all drug-related events were grade 1 and 2 in severity, and were mainly fatigue, nausea, vomiting and diarrhea. Measures of plasma exposure increased dose-proportionally and the mean terminal elimination half-life was 11 days. Blood samples available from a subset of patients treated at 24 mg/kg revealed declines in myeloid derived suppressor cells (MDSC) at 2 weeks. No objective responses were observed in any subjects. Conclusions DS-8273a was well tolerated and demonstrated linear pharmacokinetics. Decreases in MDSC were temporally associated with DS-8273a exposure. This agent could be studied further in combination with other agents, pending further proof-of-target-engagement.

Primary Pulmonary Rhabdomyosarcoma in a Child.

A 9-year-old female presented with fever, cough, and hemoptysis for a week. The chest skiagram and contrast-enhanced computerized tomography delineated a well-defined solid lesion localized to the superior segment of the right lower lobe with features of a congenital pulmonary airway malformation. The lesion was surgically managed with a segmentectomy and histopathology confirmed a contained pulmonary rhabdomyosarcoma (RMS). No other primary site of origin was evident, and a final diagnosis of "primary" pulmonary RMS was made. She received adjuvant chemotherapy and was disease free after 6 years of surveillance. The unique clinicoradiological features of the case are discussed and the sparse literature is reviewed.

Rate of intrusion of maxillary incisors in Class II Div 1 malocclusion using skeletal anchorage device and Connecticut intrusion arch.

BACKGROUND: Nonsurgical correction of deep bite involves either extrusion of posterior teeth, intrusion of incisors, or combination of both. The introduction of skeletal anchorage device with microimplant provides near absolute anchorage without producing any untoward effects on anchor unit. Connecticut Intrusion Arch (CIA) provided an efficient system of intruding anterior segment without producing much adverse affects on anchor teeth. METHODS: The study comprised of 30 patients of Class II Div 1 malocclusion with overbite of >6 mm and required therapeutic extractions of all first premolars, randomly distributed into two groups. Group 1 was treated using orthodontic microimplants, while Group 2 treated with CIA. Lateral cephalograms were taken pre-intrusion (T1) and post-intrusion at the end of six months (T2). RESULTS: The rate of intrusion was 0.51 and 0.34 mm/month for Group 1 and Group 2 respectively. The average amount of change in centroid point to PP distance and U1-SN angle was significantly higher in Group 1 compared to Group 2 (P < 0.001). The average amount of change in U6 to PP distance did not differ significantly between two study groups (P > 0.05). CONCLUSION: The amount of intrusion is significantly higher in SAD group. Although vertical molar positional change was higher in CIA group than the SAD group, it was not changed significantly in both treatment modalities. SAD group overall had better results and was easier in handling during intrusion.

Lobular neoplasia detected in MRI-guided core biopsy carries a high risk for upgrade: a study of 63 cases from four different institutions.

There are certain criteria to recommend surgical excision for lobular neoplasia diagnosed in mammographically detected core biopsy. The aims of this study are to explore the rate of upgrade of lobular neoplasia detected in magnetic resonance imaging (MRI)-guided biopsy and to investigate the clinicopathological and radiological features that could predict upgrade. We reviewed 1655 MRI-guided core biopsies yielding 63 (4%) cases of lobular neoplasia. Key clinical features were recorded. MRI findings including mass vs non-mass enhancement and the reason for biopsy were also recorded. An upgrade was defined as the presence of invasive carcinoma or ductal carcinoma in situ in subsequent surgical excision. The overall rate of lobular neoplasia in MRI-guided core biopsy ranged from 2 to 7%, with an average of 4%. A total of 15 (24%) cases had an upgrade, including 5 cases of invasive carcinoma and 10 cases of ductal carcinoma in situ. Pure lobular neoplasia was identified in 34 cases, 11 (32%) of which had upgrade. In this group, an ipsilateral concurrent or past history of breast cancer was found to be associated with a higher risk of upgrade (6/11, 55%) than contralateral breast cancer (1 of 12, 8%; P=0.03). To our knowledge, this is the largest series of lobular neoplasia diagnosed in MRI-guided core biopsy. The incidence of lobular neoplasia is relatively low. Lobular neoplasia detected in MRI-guided biopsy carries a high risk for upgrade warranting surgical excision. However, more cases from different types of institutions are needed to verify our results.

Spectrum of phenotype and genotype of congenital isolated hypogonadotropic hypogonadism in Asian Indians.

BACKGROUND: Congenital isolated hypogonadotropic hypogonadism (IHH) is caused due to defect in GnRH neuronal development, migration and action. Although genetic aetiology of IHH is increasingly being studied, Asian Indian data on phenotypic spectrum and genetic basis are scarce. OBJECTIVE: To investigate the phenotypic and genotypic spectrum of IHH in Asian Indian subjects. DESIGN, SETTING AND SUBJECTS: A cohort of 135 IHH probands were characterized phenotypically for reproductive and nonreproductive features and screened for rare sequence variations (RSVs) in five genes KAL1, FGFR1, FGF8, GNRHR and KISS1R. RESULT: Of 135 probands [56 normosmic IHH (nIHH) and 79 Kallmann syndrome (KS)], 20 were familial cases. KS group had more male dominance (M:F ratio of 8:1) as compared to nIHH group (M:F ratio of 1·5:1). Complete absence of puberty was more prevalent in KS probands (81% in KS vs 46% in nIHH). The prevalence of MRI abnormalities was more in anosmic group (92·8%) as compared to hyposmic (37·5%) and normosmic groups (15·4%). No particular nonreproductive phenotypic predominance was seen in any group. Genotyping revealed rare sequence variation (RSV) detection rate of 15·5% in five genes studied: (KAL1 - 4·4%, FGFR1 - 4·4%, GNRHR - 6·7%, oligogenicity - 1·5%). Prevalence of RSV was more common in familial cases (35%) as compared to sporadic (12·2%). GNRHR RSV p.C279Y (not reported in patients of ethnicities other than south Asians) was recurring in four unrelated patients. CONCLUSION: In our cohort, 60% were KS with majority of males and a severe reproductive phenotype as against nIHH. Contribution of the genetic burden for the five genes studied was 15·5%. RSV p.C279Y in GNRHR may have a founder effect originating from south Asia. This study provides a model for molecular and phenotypic representation of Asian Indian subjects with IHH.

The risk of upgrade for atypical ductal hyperplasia detected on magnetic resonance imaging-guided biopsy: a study of 100 cases from four academic institutions.

AIMS: To identify variables that can predict upgrade for magnetic resonance imaging (MRI)-detected atypical ductal hyperplasia (ADH). METHODS AND RESULTS: We reviewed 1655 MRI-guided core biopsies between 2005 and 2013, yielding 100 (6%) cases with ADH. The pathological features of ADH and MRI findings were recorded. An upgrade was considered when the subsequent surgical excision yielded invasive carcinoma (IC) or ductal carcinoma in situ (DCIS). The rate of ADH between institutions was 3.3-7.1%, with an average of 6%. A total of 15 (15%) cases had upgrade, 12 DCIS and three IC. When all cases were included, only increased number of involved cores was statistically significant (P = 0.02). When cases with concurrent lobular neoplasia (LN) were excluded (n = 14), increased number of ADH foci and increased number of involved cores were statistically significant (P = 0.002, P = 0.009). We analysed the data separately from a single institution (n = 61). Increased number of foci, increased number of total cores and involved cores and larger ADH size predicted upgrade with statistical significance. CONCLUSIONS: The incidence of ADH in MRI-guided core biopsy is rare. The rate of upgrade is comparable to mammographically detected ADH, warranting surgical excision. Similar to mammographically detected lesions, the volume of the ADH predicts the upgrade.