Assessment of clinico-radiological and biochemical markers of rickets: A hospital based prospective follow up study

Background: Rickets is a disorder of defective mineralization due to deficiency of calcium and vitamin D and is more prevalent amongst the developing nations. Rickets has been ranked amongst the five most prevalent diseases in children of developing countries. The diagnosis of rickets is based on clinical features, biochemical studies and radiological signs and confirmed by response to treatment. Aims and Objectives: The purpose of this study is to evaluate the clinical, radiological and biochemical markers of the rickets by measuring the markers at the time of presentation, at 6 weekly intervals and after completion of treatment with standard regimen for rickets. Materials and Methods: 101 cases of nutritional rickets in age group 6 month to 18 years were allocated to receive combination therapy of calcium and vitamin-D according to their age and weight during a study period of 24 weeks. Radiographs (wrist and knee) and biochemical parameters (serum calcium, inorganic phosphate, alkaline phosphatase [ALP], and Vitamin-D), as well as clinical features, were evaluated at presentation, 6, 12, 18, and 24 weeks and response of treatment and markers were assessed at subsequent interval. clinical, radiological, biochemical parameters were evaluated statistically with Chi-square test for qualitative and 2 or more different variables by ANOVAs respectively. A P<0.05 was considered statistically significant analysis was done using Statistical Package for Social Sciences version 21.0. Results: At presentation, the mean dietary intake of calcium was low in all cases (6.11±0.78 mg/dl). Mean vitamin-D level was (23.05±8.14 ng/ml) indicative of vitamin-D deficiency. At the end of treatment (i.e., 24 weeks) clinical, radiological, and biochemical evidence of healing was observed. Normal serum ALP and complete radiological healing at 12 weeks was observed in 75% of subjects with the improvement of all markers. Conclusion: Children with rickets having low dietary calcium intake and low serum Vitamin-D levels have maximum number of markers at presentation. After intervention of combination regimen of calcium and Vitamin-D, remarkable improvement in clinical, radiological, and biochemical markers was found.

ATARI trial: ATR inhibitor in combination with olaparib in gynecological cancers with ARID1A loss or no loss (ENGOT/GYN1/NCRI)

BackgroundARID1A (AT-rich interactive domain containing protein 1A) loss-of-function mutations have been reported in gynecological cancers, including rarer subtypes such as clear cell carcinoma. Preclinical studies indicate that ARID1A mutant cancers display sensitivity to ATR inhibition while tumors without ARID1A mutations may be sensitive to Ataxia telangiectasia and Rad3 related (ATR) inhibitors in combination with poly-ADP ribose polymerase (PARP) inhibitors.Primary ObjectiveTo determine whether the ATR inhibitor, ceralasertib, has clinical activity as a single agent and in combination with the PARP inhibitor, olaparib, in patients with ARID1A ‘loss’ and ‘no loss’ clear cell carcinomas and other relapsed gynecological cancers.Study HypothesisARID1A deficient clear cell carcinoma of the ovary or endometrium is sensitive to ATR inhibition, while the combination of ATR and PARP inhibition has activity in other gynecological tumors, irrespective of ARID1A status.Trial DesignATARI (ENGOT/GYN1/NCRI) is a multicenter, international, proof-of-concept, phase II, parallel cohort trial assessing ceralasertib activity as a single agent and in combination with olaparib in ARID1A stratified gynecological cancers. Patients with relapsed ovarian/endometrial clear cell carcinoma with ARID1A loss will receive ceralasertib monotherapy (cohort 1A). Relapsed ovarian/endometrial clear cell carcinoma patients with no ARID1A loss (cohort 2) or patients with other histological subtypes (endometrioid, carcinosarcoma, cervical) (cohort 3) will receive combination therapy (olaparib/ceralasertib). Treatment will continue until disease progression.Major Inclusion/Exclusion CriteriaPatients with histologically confirmed recurrent clear cell (ovarian, endometrial, or endometriosis related), endometrioid (ovarian, endometrial, or endometriosis related), cervical (adenocarcinomas or squamous), or carcinosarcomas (ovarian or endometrial) are eligible. Patients progressing after ≥1 prior platinum with evidence of measurable (RECIST v1.1) radiological disease progression since last systemic anticancer therapy and prior to trial entry are eligible. Previous ATR or PARP inhibitor treatment is not permissible.Primary EndpointBest overall objective response rate (RECIST v1.1).Sample SizeA minimum of 40 and a maximum of 116.Estimated Dates for Completing Accrual and Presenting ResultsAccrual is anticipated to be complete by the second quarter of 2022, with reporting of results by the fourth quarter of 2022. Overall accrual targets and reporting timelines are dependent on individual cohort progression to stage 2.Trial Registration NumberNCT0405269.

Real-world outcomes in older adults treated with immunotherapy: A United Kingdom multicenter series of 2,049 patients.

12026 Background: Immune checkpoint inhibitor (ICI) therapy is now commonly used in a range of tumours and settings. Most data relating to outcomes and rates of immune-related adverse events (irAE) is derived from clinical trial or registry populations and small case series. Limited data exist for patients aged > 75 years. Here we present a multi-centre, real-world analysis of the outcomes and incidence of irAEs in older adults managed within a single comprehensive public health service. We also compare these outcomes to younger patients in the same cohort. Methods: A retrospective analysis of 2049 patients treated with ICIs was undertaken across 12 centres. All patients were managed within the UK National Health Service outside of a trial setting between June 2016 and September 2018. Patients received either ICI monotherapy (MT) or duel combination ICI therapy (CT) for malignant melanoma (MM), non-small cell lung cancer (NSCLC) or renal cell cancer (RCC). Data were collected using a standardised, collection tool. IrAEs ≥ grade 2 or all-grade endocrinopathies were recorded as per the Common Terminology Criteria for Adverse Events (V5) (CTCAE). Statistical analyses were performed using T-tests, Mann-Whitney and Chi-squared. Kaplan-Meier analysis and log-rank test were used for overall survival (OS) analysis. Results: 409 (20%) of patients were aged > 75 years(a), 1413 (69%) aged 50-75(b) and 227 (11.1%) aged < 50(c). There was no difference in sex, ethnicity or PD-L1 status (in the NSCLC cohort) between groups. Older patients were less likely to receive combination therapy (3%(a) v 13%(b) v 34%(c), p < 0.001). There was no difference in median OS across age groups in the cohort as a whole (p = 0.822) or for the individual tumour groups when treated with single agent ICI. Across the total cohort patients aged > 75 had no increased risk of any irAE (35%(a) v 33%(b) v 41%(c),p = 0.074). However there was an increase in irAEs in older patients treated with MT (36%(a) v 26(b) v 25%(c), p = 0.011) However there was no difference in the > 75s with regard to severe (G3/4) toxicity, toxicity type, admission or discontinuation due to toxicity in the aPD-1 group. In the overall cohort younger patients were more likely to develop irAEs and be admitted. Conclusions: Patients aged > 75 years treated with anti-PD1 therapy in the standard of care setting derive similar survival benefit to younger patients. There was no increase in ≥G3 toxicity. Our data support the safety of single agent aPD-1 ICI therapy in older adults and provide reassurance relating to the impact of toxicity.[Table: see text]

A phase 2 basket trial of combination therapy with trastuzumab and pertuzumab in patients with solid cancers harboring HER2 amplification (JUPITER trial).

TPS3141 Background: The human epidermal growth factor receptor 2 (HER2) gene amplification and mutations have emerged as oncogenic drivers and therapeutic targets not limited to breast and gastric cancers, but also in a variety of cancers. However, even if an actionable gene alteration is found, the incidence of HER2 amplification in these cancers is less than 5%. Despite its considerable therapeutic potential, the evidence is not yet mature enough for use as treatment in clinical practice. To address this unmet clinical need, we have designed an organ-agnostic basket trial, which covers a variety of solid cancers harboring HER2 amplification. Methods: JUPITER trial is a Japanese multicenter, single-arm, phase 2 basket study of combination therapy with trastuzumab and pertuzumab. Patients with solid cancers harboring HER2 amplification, who have progressed with standard treatment, or rare cancers for which there is no standard treatment, are eligible. Types of cancer include bile duct, urothelial, uterine, ovarian, and other solid cancers that HER2 amplification is detected by comprehensive genomic profiling using next-generation sequencing technology. Target sample size is 38. All enrolled patients receive combination therapy with trastuzumab and pertuzumab every 3 weeks until disease progression, unacceptable toxicity, death, or withdrawal of informed consent. Response assessment using RECIST version 1.1 is performed at weeks 9 and 17, followed by every 12 weeks. The primary endpoint is the objective response rate, and secondary endpoints are progression-free survival, overall survival, duration of response, and safety. In total, 40 patients were enrolled by June 2020. Data fix is scheduled in September 2021. Trial registration: jRCT2031180150 Clinical trial information: jRCT2031180150.

Black and White Patients With Inflammatory Bowel Disease Show Similar Biologic Use Patterns With Medicaid Insurance

Background Prior studies have identified racial disparities in the treatment and outcomes of inflammatory bowel disease (IBD). These disparities could be secondary to differences in biology, care delivery, or access to appropriate therapy. The primary aim of this study was to compare medication use among Medicaid-insured black and white patients with IBD, given uniform access to gastroenterologists and therapies. Methods We analyzed Medicaid Analytic eXtract data from 4 states (California, Georgia, North Carolina, and Texas) between 2006 and 2011. We compared the use of IBD-specific therapies, including analyses of postoperative therapy among patients with Crohn disease (CD). We performed bivariate analyses and multivariable logistic regression, adjusting for potential confounders. Results We identified 14,735 patients with IBD (4672 black [32%], 8277 with CD [58%]). In multivariable analysis, there was no significant difference in the odds of anti-tumor necrosis factor use by race for CD (adjusted odds ratio [aOR] = 1.13; 95% confidence interval [CI], 0.99-1.28] or ulcerative colitis (aOR = 1.12; 95% CI, 0.96-1.32). Black patients with CD were more likely than white patients to receive combination therapy (aOR = 1.50; 95% CI, 1.15-1.96), and black patients were more likely than white patients to receive immunomodulator monotherapy after surgery for CD (31% vs 18%; P = 0.004). Conclusions In patients with Medicaid insurance, where access to IBD-specific therapy should be similar for all individuals, there was no significant disparity by race in the utilization of IBD-specific therapies. Disparities in IBD treatment discussed in prior literature seem to be driven by socioeconomic or other issues affecting access to care.

PROFIL KADAR GULA DARAH PASIEN DIABATES MELITUS TIPE 2 RAWAT JALAN YANG MENDAPAT TERAPI KOMBINASI GLIKLAZID-METFORMIN DI RS. DR. SARDJITO YOGYAKARTA

The purpose of this research is to find out how the fluctuation of outpatients’ blood-glucose concentrations of type 2 diabetic patients who receive combination therapy of the oral antihiperglicemic drugs (gliclazide-metformin) in DR. Sardjito Hospital. The research was conducted using an analysis-descriptive design employing a number of medical-records of patients with diabetes mellitus to collect the glucose content data. Data derived from the medical records is the data of each patient’s blood-glucose content during six months, beginning from March to August 2002. The results give that profile of the glucose concentrations in fasting condition and 2 hours postprandial condition who recieve combination therapy of the oral antidiabetic (gliclazide-metformin) can reach out for normal concentration.

2253. Comparison of Outcomes Between Patients with and without Cystic Fibrosis Treated with Ceftolozane–Tazobactam for Pseudomonas aeruginosa Infections

Background Ceftolozane–tazobactam (C/T) was designed to have enhanced activity against P. aeruginosa and has been shown to retain activity against many isolates that are resistant to other antipseudomonal β-lactams. However, there are no data comparing outcomes in patients with and without cystic fibrosis (CF). Methods Retrospective, multicenter cohort study conducted at 5 hospitals that included all patients with P. aeruginosa infections who received C/T as definitive therapy between November 2016 and December 2018. The primary outcome at 90 days was a composite of mortality, recurrence, readmission, and inappropriate response at end of therapy (EOT). The secondary outcome was to describe baseline C/T susceptibility and emergence of resistance. All outcomes were adjudicated by 2 infectious diseases specialists. Results Thirty-five, 27 non-CF and 8 CF, patients were included. CF patients were younger, had greater baseline C/T resistance (50.0% vs. 8.3%, P = 0.02) and were more likely to receive combination therapy. The most common site of infection was pulmonary (71.4%) followed by intra-abdominal (14.3%) and osteomyelitis (5.7%). Overall, 54.3% of patients had an unsuccessful outcome with no difference between CF and non-CF patients (62.5% vs. 51.9%, P = 0.70). There was also no difference between each component of the primary outcome. All 4 CF patients with a baseline-resistant isolate had an appropriate response at EOT, while neither of the 2 non-CF patients did. The C/T MIC distribution in CF and non-CF patients was ≤ 2 μg/mL (0.0%, 64.2%), 4 μg/mL (50.0%, 25%) ≥ 8 μg/mL (50.0%, 8.4%). The median duration of C/T in CF and non-CF patients was 18.5 days (interquartile range [IQR], 14–37.5 days) and 15 days (IQR, 10–25 days). Ten, 7 non-CF and 3 CF, patients had a P. aeruginosa isolate cultured and tested for C/T susceptibility within 90 days of index culture with 80% having an MIC increase. Non-CF patients treated for > 14 days were more likely to have an MIC increase (P = 0.047). All CF patients had an MIC increase. Conclusion We did not observe a difference in the rate of unsuccessful outcome between CF and non-CF patients; however, our sample size was small. CF patients were more likely to be resistant to C/T at baseline. Resistance emerged frequently in both groups following exposure to C/T. Disclosures All authors: No reported disclosures.

Combination therapy improves vascular volume in female rats with pulmonary hypertension

Pulmonary arterial hypertension (PAH) is a female predominant disease in which progressive vascular remodeling and vasoconstriction result in right ventricular (RV) failure and death. Most PAH patients utilize multiple therapies. In contrast, the majority of preclinical therapeutic studies are performed in male rats with a single novel drug often markedly reversing disease in the model. We sought to differentiate single drug therapy from combination therapy in female rats with severe disease. One week after left pneumonectomy, we induced PH in young female Sprague-Dawley rats with an injection of monocrotaline (45 mg/kg). Female rats were then randomized to receive combination therapy (ambrisentan plus tadalafil), ambrisentan monotherapy, tadalafil monotherapy, or vehicle. We measured RV size and function on two serial echocardiograms during the development of disease. We measured RV systolic pressure (RVSP) invasively at day 28 after monocrotaline before analyzing the vascular volume with microcomputed tomography (microCT) of the right middle lobe. RVSP was significantly lower in female rats treated with combination therapy, and combination therapy resulted in increased small vessel volume density measured by microCT compared with untreated rats. Combination-treated rats had the smallest RV end-diastolic diameter on echocardiogram as compared with the other groups. In summary, we report a female model of pulmonary hypertension that can distinguish between one and two drug therapies; this model may facilitate better preclinical drug testing for novel compounds.

1136. Antifungal Prescribing Patterns among Hospitalized Children in the United States: Are There Opportunities for Antifungal Stewardship?

Background Antifungal stewardship may help reduce the toxicity, cost, and emergence of resistance related to inappropriate antifungal use. A better understanding of antifungal prescribing patterns, particularly in high-risk, high-utilization populations, is needed to guide appropriate stewardship interventions. We analyzed antifungal prescribing characteristics, including the indications for use and differences between oncology/bone marrow transplant (Onc/BMT) and non-Onc/BMT patients, using a multi-center national cohort of hospitalized children. Methods We analyzed antifungal prescribing data from 32 hospitals that participated in the SHARPS Antibiotic Resistance, Prescribing, and Efficacy among Children (SHARPEC) study, a point prevalence survey conducted quarterly between June 2016 and December 2017. We included inpatients <18 years of age with an active order for a systemic antifungal agent and evaluated the patient and antifungal characteristics. In the Onc/BMT group, we classified antifungal prescribing by indication and compared the proportion of antifungal prescriptions in each category based on antifungal class, route of administration, and use of combination therapy. Results Six percent (2,095/34,927) of patients received a total of 2,207 antifungal prescriptions. Fifty-eight percent (1,291/2,207) of antifungal prescriptions were for Onc/BMT patients. Among patients prescribed an antifungal, those with an Onc/BMT diagnosis were older, received broader-spectrum agents, and were more likely to receive combination therapy (Table 1). The majority of antifungal use in the Onc/BMT group was for prophylaxis, with significant variation in the rate and choice of prophylactic antifungal prescribing across hospitals (Figure 1). Combination antifungal use was common among Onc/BMT patients receiving targeted therapy (Table 2). Conclusion The majority of antifungal use among hospitalized children is for patients with an Onc/BMT diagnosis and the patterns of antifungal utilization in this population appear to differ significantly from non-Onc/BMT patients. Based on the variation observed in this nationwide cohort, potential stewardship targets include the rate and type of antifungal prophylaxis and the use of combination therapy in Onc/BMT patients. Disclosures All authors: No reported disclosures.

Oral idasanutlin in patients with polycythemia vera

A limited number of drugs are available to treat patients with polycythemia vera (PV) and essential thrombocythemia (ET). We attempted to identify alternative agents that may target abnormalities within malignant hematopoietic stem (HSCs) and progenitor cells (HPCs). Previously, MDM2 protein levels were shown to be upregulated in PV/ET CD34+ cells, and exposure to a nutlin, an MDM2 antagonist, induced activation of the TP53 pathway and selective depletion of PV HPCs/HSCs. This anticlonal activity was mediated by upregulation of p53 and potentiated by the addition of interferon-α2a (IFN-α2a). Therefore, we performed an investigator-initiated phase 1 trial of the oral MDM2 antagonist idasanutlin (RG7388; Roche) in patients with high-risk PV/ET for whom at least 1 prior therapy had failed. Patients not attaining at least a partial response by European LeukemiaNet criteria after 6 cycles were then allowed to receive combination therapy with low-dose pegylated IFN-α2a. Thirteen patients with JAK2 V617F+ PV/ET were enrolled, and 12 (PV, n = 11; ET, n = 1) were treated with idasanutlin at 100 and 150 mg daily, respectively, for 5 consecutive days of a 28-day cycle. Idasanutlin was well tolerated; no dose-limiting toxicity was observed, but low-grade gastrointestinal toxicity was common. Overall response rate after 6 cycles was 58% (7 of 12) with idasanutlin monotherapy and 50% (2 of 4) with combination therapy. Median duration of response was 16.8 months (range, 3.5-26.7). Hematologic, symptomatic, pathologic, and molecular responses were observed. These data indicate that idasanutlin is a promising novel agent for PV; it is currently being evaluated in a global phase 2 trial. This trial was registered at www.clinicaltrials.gov as #NCT02407080.