SARC009: Phase 2 study of dasatinib in patients with previously treated, high-grade, advanced sarcoma

BACKGROUND

Dasatinib exhibited activity in preclinical models of sarcoma. The Sarcoma Alliance for Research through Collaboration (SARC) conducted a multicenter, phase 2 trial of dasatinib in patients with advanced sarcoma.

METHODS

Patients received dasatinib twice daily. The primary objective was to estimate the clinical benefit rate (CBR) (complete response or partial response within 6 months or stable disease duration of ≥6 months) with a target of ≥25%. Patients were enrolled into 1 of 7 different cohorts and assessed by imaging every 8 weeks using Choi criteria tumor response and a Bayesian hierarchical design. For each subtype, enrollment was stopped after a minimum of 9 patients were treated if there was a <1% chance the CBR was ≥25%.

RESULTS

A total of 200 patients were enrolled. Accrual was stopped early in 5 cohorts because of low CBR. The leiomyosarcoma (LMS) and undifferentiated pleomorphic sarcoma (UPS) cohorts fully accrued and 6 of 47 and 8 of 42 evaluable patients, respectively, exhibited clinical benefit. The probability that the CBR was ≥25% in the LMS and UPS cohorts was 0.008 and 0.10, respectively. The median progression-free survival ranged from 0.9 months in patients with rhabdomyosarcoma to 2.2 months in patients with LMS. The median overall survival was 8.6 months. The most frequent adverse events were constitutional, gastrointestinal, and respiratory, and 36% of patients required dose reduction for toxicity. Serious adverse events attributed to therapy occurred in 11% of patients.

CONCLUSIONS

Dasatinib may have activity in patients with UPS but is inactive as a single agent in the other sarcoma subtypes included herein. The Bayesian design allowed for the early termination of accrual in 5 subtypes because of lack of drug activity. Cancer 2015. © 2015 American Cancer Society.

from #MedicinebyAlexandrosSfakianakis via xlomafota13 on Inoreader http://ift.tt/1MDeo5L
via IFTTT

Identification of patient subgroups with markedly disparate rates of MYCN amplification in neuroblastoma: A report from the International Neuroblastoma Risk Group project

BACKGROUND

MYCN gene amplification (MNA) is a hallmark of aggressive neuroblastoma. This study was performed to determine univariate and multivariate predictors of tumor MNA.

METHODS

Data from the International Neuroblastoma Risk Group were analyzed for a subset of 7102 patients with known MYCN status. Chi-square testing and logistic regression were used to identify univariate and multivariate predictors of MYCN status. Recursive partitioning was used to identify groups of patients with maximal differences in rates of MNA.

RESULTS

All clinical features (age ≥ 18 months, high ferritin levels, high lactate dehydrogenase [LDH] levels, International Neuroblastoma Staging System stage 4, and adrenal sites) and pathological/biological features (DNA index ≤ 1, high mitosis-karyorrhexis index [MKI], undifferentiated/poorly differentiated grade, unfavorable histology according to the International Neuroblastoma Pathology Classification, and segmental chromosomal aberrations [SCAs]) were significantly associated with MNA. LDH (odds ratio [OR], 8.4; P < .001) and chromosomal 1p loss of heterozygosity (OR, 19.8; P < .001) were the clinical and biological variables, respectively, most strongly associated with MNA. In logistic regression, all variables except chromosome 17q aberration and pooled SCAs were independently predictive of MNA. Recursive partitioning identified subgroups with disparate rates of MNA, including subgroups with 85.7% MNA (patients with high LDH levels who had poorly differentiated adrenal tumors with chromosome 1p deletion) and 0.6% MNA (localized tumors having hyperdiploidy and low MKIs and lacking chromosome 1p aberrations).

CONCLUSIONS

MNA is strongly associated with other clinical and biological variables in neuroblastoma. Recursive partitioning has identified subgroups of neuroblastoma patients with highly disparate rates of MNA. These findings can be used to inform investigations of molecular mechanisms of MNA. Cancer 2015. © 2015 American Cancer Society.

from #MedicinebyAlexandrosSfakianakis via xlomafota13 on Inoreader http://ift.tt/1YIDKvq
via IFTTT

Oncolytic reovirus in combination with chemotherapy in metastatic or recurrent non–small cell lung cancer patients with KRAS-activated tumors

BACKGROUND

The type 3 Dearing reovirus (Reolysin) is a naturally occurring virus that preferentially infects and causes oncolysis in tumor cells with a Ras-activated pathway. It induces host immunity and cell cycle arrest and acts synergistically with cytotoxic agents.

METHODS

This study evaluated Reolysin combined with paclitaxel and carboplatin in patients with metastatic/recurrent KRAS-mutated or epidermal growth factor receptor (EGFR)–mutated/amplified non–small cell lung cancer.

RESULTS

Thirty-seven patients were treated. Molecular alterations included 20 KRAS mutations, 10 EGFR amplifications, 3 EGFR mutations, and 4 BRAF-V600E mutations. In total, 242 cycles (median, 4; range, 1-47) were completed. The initial doses were area under the curve (AUC) 6 mg/mL/min for carboplatin, 200 mg/m² for paclitaxel on day 1, and 3 × 10¹⁰ 50% tissue culture infective dose for Reolysin on days 1 to 5 of each 21-day cycle. Because of diarrhea and febrile neutropenia (in the first 2 patients), subsequent doses were reduced to 175 mg/m² for paclitaxel and AUC 5 mg/mL/min for carboplatin. Toxicities included fatigue, diarrhea, nausea/vomiting, neutropenia, arthralgia/myalgia, anorexia, and electrolyte abnormalities. Response Evaluation Criteria in Solid Tumors 1.0 responses included the following: partial response for 11 patients, stable disease (SD) for 20 patients, progressive disease for 4 patients, and not evaluable for 2 patients (objective response rate, 31%; 90% 1-sided lower confidence interval, 21%). Four SD patients had >40% positron emission tomography standardized uptake value reductions. The median progression-free survival, median overall survival, and 12-month overall survival rate were 4 months, 13.1 months, and 57%, respectively. Seven patients were alive after a median follow-up of 34.2 months; they included 2 patients without disease progression at 37 and 50 months.

CONCLUSIONS

Reolysin in combination with paclitaxel and carboplatin was well tolerated. The observed response rate suggests a benefit of the reovirus for chemotherapy. A follow-up randomized study is recommended. The proportion of patients surviving longer than 2 years (30%) suggests a second/third-line treatment effect or possibly the triggering of an immune response after tumor reovirus infiltration. Cancer 2015. © 2015 American Cancer Society.

from #MedicinebyAlexandrosSfakianakis via xlomafota13 on Inoreader http://ift.tt/1YIDKeQ
via IFTTT

Disparities in the use of screening magnetic resonance imaging of the breast in community practice by race, ethnicity, and socioeconomic status

BACKGROUND

Uptake of breast magnetic resonance imaging (MRI) coupled with breast cancer risk assessment offers the opportunity to tailor the benefits and harms of screening strategies for women with differing cancer risks. Despite the potential benefits, there is also concern for worsening population-based health disparities.

METHODS

Among 316,172 women aged 35 to 69 years from 5 Breast Cancer Surveillance Consortium registries (2007-2012), the authors examined 617,723 negative screening mammograms and 1047 screening MRIs. They examined the relative risks (RRs) of MRI use by women with a <20% lifetime breast cancer risk and RR in the absence of MRI use by women with a ≥20% lifetime risk.

RESULTS

Among women with a <20% lifetime risk of breast cancer, non-Hispanic white women were found to be 62% more likely than nonwhite women to undergo an MRI (95% confidence interval, 1.32-1.98). Of these women, those with an educational level of some college or technical school were 43% more likely and those who had at least a college degree were 132% more likely to receive an MRI compared with those with a high school education or less. Among women with a ≥20% lifetime risk, there was no statistically significant difference noted with regard to the use of screening MRI by race or ethnicity, but high-risk women with a high school education or less were less likely to undergo screening MRI than women who had graduated from college (RR, 0.40; 95% confidence interval, 0.25-0.63).

CONCLUSIONS

Uptake of screening MRI of the breast into clinical practice has the potential to worsen population-based health disparities. Policies beyond health insurance coverage should ensure that the use of this screening modality reflects evidence-based guidelines. Cancer 2015. © 2015 American Cancer Society.

from #MedicinebyAlexandrosSfakianakis via xlomafota13 on Inoreader http://ift.tt/1ZxbVTS
via IFTTT

Polymorphisms of CASR gene increase the risk of primary hyperparathyroidism

Abstract

Objective

To evaluate correlations between polymorphisms of calcium-sensing receptor (CASR) gene [A986S (rs1081725), R990G (rs1042636) and Q1011E (rs1801726)] and the risk of primary hyperparathyroidism (PHPT) among human population.

Methods

Relevant studies were retrieved from online databases using computer-based search strategies, which were then supplemented by manual search strategies. Case–control studies related to our topic were identified based on strict inclusion and exclusion criteria. Statistical analyses were conducted using the Comprehensive Meta-analysis 2.0 (Biostat Inc., Englewood, NJ, USA).

Results

We retrieved 202 studies from online databases and other sources initially and eventually enrolled six studies into our meta-analysis. These six studies contained a sum of 693 PHPT patients and 1252 healthy controls. Our meta-analysis results showed that single nucleotide polymorphisms (SNPs) of CASR gene A986S (rs1081725) and R990G (rs1042636), but not Q1011E (rs1801726), may increase the risk of PHPT [A986S (rs1081725): allele model: P = 0.013; dominant model: P = 0.044; R990G (rs1042636): allele model: P = 0.023; dominant model: P = 0.026)]. Subgroup analyses based on ethnicity showed that among Asians, A986S (rs1081725) increased the PHPT risk (P = 0.04) under the allele model, but not under the dominant model. Among Caucasians, there was no association between gene frequencies and PHPT under both the allele and dominant model. In Asians, no significant association was observed between R990G (rs1042636) and PHPT risk, but in Caucasians, R990G (rs1042636) significantly increased the incidence of PHPT [R990G (rs1042636): allele model: P = 0.015; dominant model: P = 0.009)].

Conclusion

Our results indicate that SNPs of CASR gene A986S (rs1081725) and R990G (rs1042636) may increase the risk of PHPT, and the polymorphisms can potentially be used as important biological markers for early diagnosis of PHPT.

from #MedicinebyAlexandrosSfakianakis via xlomafota13 on Inoreader http://ift.tt/1knILqb
via IFTTT

Efficacy and safety of growth hormone treatment in children with short stature: the Italian cohort of the GeNeSIS clinical study

Abstract

Purpose

We examined auxological changes in growth hormone (GH)-treated children in Italy using data from the Italian cohort of the multinational observational Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS) of pediatric patients requiring GH treatment.

Methods

We studied 711 children (median baseline age 9.6 years). Diagnosis associated with short stature was as determined by the investigator. Height standard deviation score (SDS) was evaluated yearly until final or near-final height (n = 78). Adverse events were assessed in all GH-treated patients.

Results

The diagnosis resulting in GH treatment was GH deficiency (GHD) in 85.5 % of patients, followed by Turner syndrome (TS 6.6 %). Median starting GH dose was higher in patients with TS (0.30 mg/kg/week) than patients with GHD (0.23 mg/kg/week). Median (interquartile range) GH treatment duration was 2.6 (0.6–3.7) years. Mean (95 % confidence interval) final height SDS gain was 2.00 (1.27–2.73) for patients with organic GHD (n = 18) and 1.19 (0.97–1.40) for patients with idiopathic GHD (n = 41), but lower for patients with TS, 0.37 (−0.03 to 0.77, n = 13). Final height SDS was >−2 for 94 % of organic GHD, 88 % of idiopathic GHD and 62 % of TS patients. Mean age at GH start was lower for organic GHD patients, and treatment duration was longer than for other groups, resulting in greater mean final height gain. GH-related adverse events occurred mainly in patients diagnosed with idiopathic GHD.

Conclusions

Data from the Italian cohort of GeNeSIS showed auxological changes and safety of GH therapy consistent with results from international surveillance databases.

from #MedicinebyAlexandrosSfakianakis via xlomafota13 on Inoreader http://ift.tt/1mKRfJO
via IFTTT

Absence of the BRAF V600E mutation in pheochromocytoma

Abstract

Purpose

Pheochromocytomas (PCCs) are rare endocrine tumors originating from the adrenal medulla. These tumors display a highly heterogeneous mutation profile, and a substantial part of the causative genetic events remains to be explained. Recent studies have reported presence of the activating BRAF V600E mutation in PCC, suggesting a role for BRAF activation in tumor development. This study sought to further investigate the occurrence of the BRAF V600E mutation in these tumors.

Methods

A cohort of 110 PCCs was screened for the BRAF V600E mutation using direct Sanger sequencing.

Results

All cases investigated displayed wild-type sequences at nucleotide 1799 in the BRAF gene.

Conclusions

Taken together with all previously screened tumors up to date, only 1 BRAF V600E mutation has been found among 361 PCCs. These findings imply that the BRAF V600E mutation is a rare event in pheochromocytoma.

from #MedicinebyAlexandrosSfakianakis via xlomafota13 on Inoreader http://ift.tt/1mKRfcZ
via IFTTT