Synthesis of 2,2-dimethyl-chroman-based stereochemically flexible and constrained anti-breast cancer agents.

Receptors are proteinous macromolecules which remain in the apo form under normal/unliganded conditions. As the ligand approaches, there are specific stereo-chemical changes in the apo form of the receptor as per the stereochemistry of a ligand. Accordingly, a series of substituted dimethyl-chroman-based stereochemically flexible and constrained Tamoxifen analogs were synthesized as anti-breast cancer agents. The synthesized compounds 19a-e, 20a-e, 21, and 22a-e, showed significant antiproliferative activity against estrogen receptor-positive (ER+, MCF-7) and negative (ER-, MDA MB-231) cells within IC50 value 8.5-25.0 µM. Amongst all, four potential molecules viz 19b, 19e, 22a, and 22c, were evaluated for their effect on the cell division cycle and apoptosis of ER+ and ER- cancer cells (MCF-7 & MDA MB-231cells), which showed that these compounds possessed antiproliferative activity through triggering apoptosis. In-silico docking experiments elucidated the possible affinity of compounds with estrogen receptors-α and -ß.

Is Hypoglycemia Secondary to Metastatic Retroperitoneal Sarcoma - A Therapeutic Challenge? Case Report and Review of Literature.

Most soft tissue sarcomas afflict the extremities; however, the retro peritoneum can also be affected rarely. Retroperitoneal sarcomas are relatively asymptomatic. Although tumor-induced hypoglycemia is rare in tumors other than insulinomas, extrapancreatic tumors are a subset that displays this phenomenon. The occurrence of hypo-insulinemic hypoglycemia with low GH and IGF-1 should prompt consideration of the secretion of a hypoglycemic substance impeding the secretion of insulin and GH, such as IGF-2 or one of its related substances. The present case report is of a 38-year-old male with retroperitoneal round cell sarcoma with liver metastasis with severe symptomatic hypoglycemia who was managed with multipronged symptomatic therapy and oncological management after which he had shown significant improvement in hypoglycemic episodes and symptom profile. A literature review revealed our case report to be the first reported case of a young male (preponderance in the older population) with hypoglycemia associated with retroperitoneal sarcoma which presented with liver metastasis and the only one treated with Gemcitabine /Docetaxel. The presence of these features might point toward a poorer prognosis in a disease with an already dismal course. All these points towards the need for further research regarding intensified oncological treatment after evidence-based prognostication of high-risk groups and modalities for the management of symptomatic hypoglycemia such as Somatostatin analogs and glucagon which aid in symptom control.

Synthesis of amide derivatives of 3-aryl-3H-benzopyrans as osteogenic agent concomitant with anticancer activity.

The present study reports a series of 3-aryl-3H-benzopyran-based amide derivatives as osteogenic agents concomitant with anticancer activity. Six target compounds viz 22e, 22f, 23i, and 24b-d showed good osteogenic activity at 1 pM and 100 pM concentrations. One of the potential molecules, 24b, effectively induced ALP activity and mRNA expression of osteogenic marker genes at 1 pM and bone mineralization at 100 pM concentrations. These molecules also presented significant growth inhibition of osteosarcoma (MG63) and estrogen-dependent and -independent (MCF-7 and MDA-MB-231) breast cancer cells. The most active compound, 24b, inhibited the growth of all the cancer cells within the IC50 10.45-12.66 µM. The mechanistic studies about 24b showed that 24b induced apoptosis via activation of the Caspase-3 enzyme and inhibited cancer cell migration. In silico molecular docking performed for 24b revealed its interaction with estrogen receptor-ß (ER-ß) preferentially.

Physical activity and liver disease affect the fat-free mass in adolescents with cystic fibrosis.

Cystic fibrosis (CF) is predominantly a lung disease but is also characterised by impaired skeletal muscularity and a reduction in fat-free mass. We aimed to test the hypothesis that clinical and anthropometric parameters would determine fat-free mass impairment in adolescents with CF. We measured the fat-free mass index (FFMI) using bioelectrical impedance, the lung function using spirometry, the number of shuttles as a measure of exercise tolerance and the reported physical activity in children and young people with CF in a tertiary centre at King's College Hospital, London, UK. CF-related liver disease was diagnosed by abnormal liver enzymes and/or ultrasonography. We studied 28 children and young people (11 male) with a median (interquartile range (IQR)) age of 15 (13-17) years. They had a median (IQR) FFMI of 13.5 (11.6-15.1) kg/m2. The FFMI significantly correlated with age (rho = 0.568, p = 0.002), number of shuttles (rho = 0.691, p < 0.001) and reported hours of activity per day (rho = 0.426, p = 0.024). The median (IQR) FFMI was significantly higher in male [15.1 (13.1-18.6) kg/m2] compared to female participants [12.7 (11.6-14.1) kg/m2, p = 0.008]. The median (IQR) FFMI was significantly lower in the 10 (36%) participants with liver disease [11.9 (11.5-13.4) kg/m2] compared to the FFMI in the remaining 18 participants without liver disease [14.4 (12.5-15.9) kg/m2, p = 0.027]. CONCLUSION: Fat-free mass increases with increasing age and growth in adolescents with CF. Physical activity exerts a beneficial effect on fat-free mass, and CF-related liver disease negatively affects fat-free mass in adolescents with CF. WHAT IS KNOWN: • Health behaviours in adolescence influence lifelong health in cystic fibrosis (CF). • A normal body mass index in CF might fail to reveal a low fat-free mass (FFM), and quality of life in CF is strongly associated with a reduced FFM. WHAT IS NEW: • FFM increases with increasing age and growth in adolescents with CF. • Physical activity exerts a beneficial effect, and liver disease negatively affects FFM in adolescents with CF.

Application of Hydrogel Spacer SpaceOAR Vue for Prostate Radiotherapy.

Damage in the surrounding structures, including the rectum, due to unintended exposure to radiation is a large burden to bear for patients who undergo radiation therapy for prostate cancer. The use of injectable rectal spacers to distance the anterior rectum from the prostate is a potential strategy to reduce the dose of unintended radiation to the rectum. Hydrogel spacers are gaining increasing popularity in the treatment regimen for prostate cancer. After FDA approval of SpaceOAR, specialists are receiving an increasing number of referrals for hydrogel placements. In this paper, we review hydrogel spacers, the supporting clinical data, the best practices for hydrogel placement, and the risk of adverse events.

Promoting smoking cessation in the paediatric respiratory clinic.

Exposure to tobacco smoke is harmful to children and young people (CYP). There is, to our knowledge, no published evidence quantifying the success of smoking cessation interventions targeted at both CYP and their parents or guardians in paediatric respiratory clinics. We offered 102 participants smoking cessation advice, using motivational interviewing and exhaled carbon monoxide measurements to help them quit smoking. In total, 16 of 102 participants quit smoking, with 4 lost to follow-up. A further 40 participants cut down on how much they smoked. CONCLUSION: Formal screening questions on smoking and the provision of smoking cessation advice should form a regular part of all respiratory clinics where CYP and their parents are seen. Simple smoking cessation interventions can lead to reduced smoking in this population. WHAT IS KNOWN: • Tobacco smoking is strongly associated with significant morbidity and mortality. • Adolescents with chronic respiratory diseases may themselves smoke, or may have parents who do so. WHAT IS NEW: • Smoking cessation interventions are well received in paediatric respiratory clinic by patients and their families. • Simple smoking cessation interventions can help young people and their parents to stop smoking or cut down on smoking.

Lissencephaly-pachygyria spectrum in a North Indian boy with Wolcott-Rallison syndrome due to homozygous deletion of exon 1 in the EIF2AK3 gene.

BACKGROUND: Wolcott-Rallison syndrome (WRS) is a rare autosomal recessive disorder characterized by neonatal diabetes mellitus (NDM), epiphyseal dysplasia, and hepatic and renal dysfunction. Although neuro-psychological features are common in patients with WRS, malformations of cortical development (MCDs) are rarely reported. CASE PRESENTATION: A 3-month-old boy, born to non-consanguineous parents, presented with right focal seizures since two months of age and recently detected diabetes mellitus. He also had a small head and lissencephaly-pachygyria spectrum on brain imaging. Genetic testing confirmed the diagnosis of WRS by identifying a biallelic homozygous deletion of exon 1 in the EIF2AK3 gene. The child achieved reasonable glycemic control on the basal-bolus insulin regimen. CONCLUSIONS: Presentation of WRS may occur with neurological manifestations such as lissencephaly-pachygyria spectrum. Early confirmation of the genetic diagnosis of WRS by screening for pathogenic variants in the EIF2AK3 gene is important in children with NDM and associated syndromic features. Establishing the diagnosis of WRS helps in predicting the development of subsequent clinical features, guides management, and may improve patient outcomes.

Study of montelukast in children with sickle cell disease (SMILES): a study protocol for a randomised controlled trial.

BACKGROUND: Young children with sickle cell anaemia (SCA) often have slowed processing speed associated with reduced brain white matter integrity, low oxygen saturation, and sleep-disordered breathing (SDB), related in part to enlarged adenoids and tonsils. Common treatments for SDB include adenotonsillectomy and nocturnal continuous positive airway pressure (CPAP), but adenotonsillectomy is an invasive surgical procedure, and CPAP is rarely well-tolerated. Further, there is no current consensus on the ability of these treatments to improve cognitive function. Several double-blind, randomised controlled trials (RCTs) have demonstrated the efficacy of montelukast, a safe, well-tolerated anti-inflammatory agent, as a treatment for airway obstruction and reducing adenoid size for children who do not have SCA. However, we do not yet know whether montelukast reduces adenoid size and improves cognition function in young children with SCA. METHODS: The Study of Montelukast In Children with Sickle Cell Disease (SMILES) is a 12-week multicentre, double-blind, RCT. SMILES aims to recruit 200 paediatric patients with SCA and SDB aged 3-7.99 years to assess the extent to which montelukast can improve cognitive function (i.e. processing speed) and sleep and reduce adenoidal size and white matter damage compared to placebo. Patients will be randomised to either montelukast or placebo for 12 weeks. The primary objective of the SMILES trial is to assess the effect of montelukast on processing speed in young children with SCA. At baseline and post-treatment, we will administer a cognitive evaluation; caregivers will complete questionnaires (e.g. sleep, pain) and measures of demographics. Laboratory values will be obtained from medical records collected as part of standard care. If a family agrees, patients will undergo brain MRIs for adenoid size and other structural and haemodynamic quantitative measures at baseline and post-treatment, and we will obtain overnight oximetry. DISCUSSION: Findings from this study will increase our understanding of whether montelukast is an effective treatment for young children with SCA. Using cognitive testing and MRI, the SMILES trial hopes to gain critical knowledge to help develop targeted interventions to improve the outcomes of young children with SCA. TRIAL REGISTRATION: ClinicalTrials.gov NCT04351698 . Registered on April 17, 2020. European Clinical Trials Database (EudraCT No. 2017-004539-36). Registered on May 19, 2020.

Synthesis and biological evaluation of substituted amide derivatives of C4-ageratochromene dimer analog.

Substituted amide derivatives of C4-ageratochromene dimer analog (19) were synthesized through structural modification of precocene-I (4a), isolated from the essential oil of Ageratum conyzoides L. The target compounds (18-20, 23I-VI, 24I-VI, and 25I-VI) were evaluated for their bone-forming effect using osteoblast differentiation assay. Seven compounds (23I, 23II, 23IV, 23VI, 24III, 24VI, and 25VI) presented good activity within 1 pM-1 nM concentration. At 1 pM concentration, the most active compound i.e. 23II showed effective mineralization of osteoblast cells along with expression of osteogenic marker genes viz RUNX 2, BMP-2, and type 1 collagen (Type-1 col) without any toxicity towards osteoblast cells. Single crystal X-ray analysis of 18 and 20 revealed that the core nucleus of these molecules bear phenyl rings in a Trans-stilbenoid system and had a good structural correlation with 17ß-estradiol (1) and diethylstilbestrol (DES, 3). In-silico study about 23II showed its structural complementarities with the LBD of estrogen receptor (ER) which indicated possible ER-mediated activity of compounds.

The burden of sleep disordered breathing in children with sickle cell disease.

Children with sickle cell disease (SCD) have an increased risk of sleep disordered breathing (SDB) compared with the general pediatric population. There has been a growing research interest on this field in recent years, yet many questions regarding risk factors and clinical implications of SDB remain unclear. The aim of this review is to provide a concise narrative and systematic synthesis of the available evidence on the epidemiology, clinical presentation, complications, and management, of SDB in children with SCD. An electronic search was conducted on studies published from the 1st of January 2000 to the 31st of December 2020 in PubMed/Medline, Scopus, and Cochrane databases. All studies focusing on SDB in children with SCD aged from 0 to 20 years were included. Studies were eligible for inclusion if available in the English language. A quantitative synthesis of the included studies was performed. Only studies focusing on specific treatment outcomes were included in a meta-analytic process. A total of 190 papers were initially identified. After screening the title and abstract, 112 articles were evaluated for eligibility. At the end of the selection process, 62 studies were included in the analysis. Sleep disordered breathing is associated with worse neurological, neurocognitive, and cardiological outcomes, whereas the association with frequency or severity of vaso-occlusive pain events and acute chest syndrome was not clarified. Therapeutic interventions like adenotonsillectomy or oxygen supplementation may result in a significant increase in mean nocturnal oxygen saturation but effective clinical implications remain still unclear.

Cytological diagnosis of angiomatoid fibrous histiocytoma: Report of a case and review of literature.

Angiomatoid fibrous histiocytoma (AFH) is an unusual superficially located tumor primarily affecting children and young adults. It grows slowly and most often occurs on the extremities. There is a paucity of literature on the cytological findings of AFH owing to the rarity of the lesion and its superficial location which makes it easier to perform the biopsy. Here, we present a case of AFH in a 7-year-old girl who presented with a left upper arm swelling. The cytology of this tumor along with histopathologic correlation and review of literature is discussed.

A Predictive Model for Pediatric Postoperative Respiratory Failure: A National Inpatient Sample Study.

STUDY OBJECTIVE: To identify risk factors for pediatric postoperative respiratory failure and develop a predictive model. DESIGN: This retrospective case-control study utilized the US National Inpatient Sample (NIS) from 2012 to 2014. Significant predictors were selected, and the predicted probability of pediatric postoperative respiratory failure was calculated. Sensitivity, specificity, and accuracy were then calculated, and receiver-operator curves were drawn. SETTING: National Inpatient Sample data sets from years 2012, 2013, and 2014 were used. PATIENTS: Patients aged 17 and younger in the 2012, 2013, and 2014 NIS data sets. INTERVENTIONS: Candidate predictors included demographic variables, type of surgical procedure, a modified pediatric comorbidity score, presence of substance abuse diagnosis, and presence/absence of kyphoscoliosis. MEASUREMENTS: The primary outcome measure was the pediatric quality indicator (PDI 09), which is defined by the Agency for Healthcare Research Quality, and identifies pediatric patients with postoperative respiratory failure. MAIN RESULTS: The incidence of pediatric postoperative respiratory failure in each year's data set varied from 1.31% in 2012 to 1.41% in 2014. Significant risk factors for the development of postoperative respiratory failure included abdominal surgery ([OR] = 1.92 in 2012 data set, 1.79 in 2013 data set), spine surgery (OR = 7.10 in 2012 data set, 6.41 in 2013 data set), and an elevated pediatric comorbidity score (score of 3 or greater: OR = 32.58 in 2012 data set, 22.74 in 2013 data set). A predictive model utilizing these risk factors achieved a C statistic of 0.82. CONCLUSIONS: Risk factors associated with postoperative respiratory failure in pediatric patients undergoing noncardiac surgery include type of surgery (abdominal and spine) and higher pediatric comorbidity scores. A prediction model based on the identified factors had good predictive ability.

Ten-year use of recombinant parathyroid hormone for the treatment of hypoparathyroidism in a boy with partial Jacobsen syndrome.

Pediatric hypoparathyroidism (HPT) is caused by inherited or acquired defects involving the synthesis or secretion of PTH, resistance to PTH action, or inappropriate regulation of PTH. Several syndromes such as DiGeorge syndrome, HDR (hypoparathyroidism, sensorineural deafness and renal dysplasia) syndrome, HRD (hypoparathyroidism, retardation, and dysmorphism) syndrome, Kenny-Caffey syndrome etc. may have associated HPT. In the present communication, we describe, the hitherto unreported, occurrence of HPT in a child with partial Jacobsen syndrome. Chromosomal Microarray analysis showed a heterozygous deletion of 4.7 Mb at cytoband 11q24.3q25 encompassing approximately 20 genes including JAM3 and NTM genes. The child was treated with recombinant human parathyroid hormone (rhPTH1-34) for 10 years. Throughout follow up, he required several adjustments in dosages of rhPTH1-34 and oral calcium to maintain serum calcium concentrations in low normal ranges. The bone turnover markers remained normal and oral calcium supplements were completely taken off after 8 years. In conclusion, our single-case experience indicates that long-term therapy of chronic HPT with rhPTH1-34 is safe and reduces the need for additional therapies.

Beneficial effects of adenotonsillectomy in children with sickle cell disease.

Tonsillectomy and adenoidectomy (T&A) is frequently performed in children with sickle cell disease (SCD). Our aim was to evaluate the impact of this surgery on overnight oxygenation and rates of complications in these patients. Children with SCD who underwent T&A between 2008 and 2014 in two tertiary hospitals were retrospectively evaluated. Overnight oximetry and admission rates due to vaso-occlusive pain episodes (VOEs) and acute chest syndrome (ACS) in the year preceding and following the surgery were compared. 19 patients (10 males, 53%) with a median age of 6 years (range 3.5-8) were included. A significant increase of mean overnight arterial oxygen saturation measured by pulse oximetry (S pO2 ) (from 93±3.6% to 95.3±2.8%, p=0.001), nadir S pO2 (from 83.0±7.1% to 88±4.1%, p=0.004) and a reduction of 3% oxygen desaturation index (from a median value of 5.7 to 1.8, p=0.003) were shown. The mean annual rate of ACS decreased from 0.6±1.22 to 0.1±0.2 events per patient-year (p=0.003), while the mean cumulative rate of hospitalisations for all causes and the incidence of VOEs were not affected. T&A improved nocturnal oxygenation and was also associated with a reduction in the incidence of ACS at 1-year follow-up after surgery.

Association Between a National Insurer's Pay-for-Performance Program for Oncology and Changes in Prescribing of Evidence-Based Cancer Drugs and Spending.

PURPOSE: Cancer drug prescribing by medical oncologists accounts for the greatest variation in practice and the largest portion of spending on cancer care. We evaluated the association between a national commercial insurer's ongoing pay-for-performance (P4P) program for oncology and changes in the prescribing of evidence-based cancer drugs and spending. METHODS: We conducted an observational difference-in-differences study using administrative claims data covering 6.7% of US adults. We leveraged the geographically staggered, time-varying rollout of the P4P program to simulate a stepped-wedge study design. We included patients age 18 years or older with breast, colon, or lung cancer who were prescribed cancer drug regimens by 1,867 participating oncologists between 2013 and 2017. The exposure was a time-varying dichotomous variable equal to 1 for patients who were prescribed a cancer drug regimen after the P4P program was offered. The primary outcome was whether a patient's drug regimen was a program-endorsed, evidence-based regimen. We also evaluated spending over a 6-month episode period. RESULTS: The P4P program was associated with an increase in evidence-based regimen prescribing from 57.1% of patients in the preintervention period to 62.2% in the intervention period, for a difference of +5.1 percentage point (95% CI, 3.0 percentage points to 7.2 percentage points; P < .001). The P4P program was also associated with a differential $3,339 (95% CI, $1,121 to $5,557; P = .003) increase in cancer drug spending and a differential $253 (95% CI, $100 to $406; P = .001) increase in patient out-of-pocket spending, but no significant changes in total health care spending ($2,772; 95% CI, -$181 to $5,725; P = .07) over the 6-month episode period. CONCLUSION: P4P programs may be effective in increasing evidence-based cancer drug prescribing, but may not yield cost savings.