The latest medical research on Oncology

The research magnet gathers the latest research from around the web, based on your specialty area. Below you will find a sample of some of the most recent articles from reputable medical journals about oncology gathered by our medical AI research bot.

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Germline cancer predisposition variants and pediatric glioma: a population-based study in California.

Neuro-Oncology

Pediatric astrocytoma constitutes a majority of malignant pediatric brain tumors. Previous studies that investigated pediatric cancer predisposition have primarily been conducted in tertiary referral centers and focused on cancer predisposition genes. In this study, we investigated the contribution of rare germline variants to risk of malignant pediatric astrocytoma on a population level.

DNA samples were extracted from neonatal dried bloodspots from 280 pediatric astrocytoma patients (predominantly high grade) born and diagnosed in California and were subjected to whole-exome sequencing. Sequencing data were analyzed using agnostic exome-wide gene-burden testing and variant identification for putatively pathogenic variants in 175 a priori candidate cancer-predisposition genes.

We identified thirty-three putatively pathogenic germline variants among 31 patients (11.1%) which located in 24 genes largely involved in DNA repair and cell cycle control. Patients with pediatric glioblastoma were most likely to harbor putatively pathogenic germline variants (14.3%, N=9/63). Five variants were located in TP53, of which four were identified among patients with glioblastoma (6.3%, N=4/63). The next most frequently mutated gene was NF1, in which putatively pathogenic variants were identified in four astrocytoma NOS patients. Gene-burden testing also revealed that putatively pathogenic variants in TP53 were significantly associated with pediatric glioblastoma on an exome-wide level (OR:32.8, p=8.04×10-7).

A considerable fraction of pediatric glioma patients, especially those of higher grade, harbor a putatively pathogenic variant in a cancer predisposition gene. Some of these variants may be clinically actionable or may warrant genetic counseling.

Subtype switching in breast cancer brain metastases: a multicenter analysis.

Neuro-Oncology

Breast cancer brain metastases (BCBM) can have discordant hormonal (HR) or human epidermal growth factor receptor 2 (HER2) expression compared to corresponding primary tumors. This study aimed to describe incidence, predictors, and survival outcomes of discordant receptors and associated subtype switching in the brain metastasis (BM).

BCBM patients seen at four tertiary institutions who had undergone BM resection or biopsy were included. Surgical pathology reports were retrospectively assessed to determine discordance between the primary tumor and the BCBM. In discordant cases, expression in extracranial metastases was also assessed.

In brain metastases from 219 patients, prevalence of any discordance was 36.3%; receptor-specific discordance was 16.7% for estrogen (ER), 25.2% for progesterone (PR), and 10.4% for HER2. Because ER and PR were considered together for hormonal status, fifty (22.8%) patients switched subtype as a result; 20 of these switches were HER2-based. Baseline subtype predicted switching, which occurred in up to 37.5% of primary HR+ patients. Moreover, 14.8% of initially HER2-negative patients gained HER2 in the BM. Most (63.6%) discordant patients with extracranial metastases also had discordance between BM and extracranial subtype. Loss of receptor expression was generally associated with worse survival, which appeared to be driven by ER loss (hazard ratio=1.80, p=0.03). Patients gaining HER2 status (n=8) showed a nonsignificant tendency towards improved survival (hazard ratio=0.64, p=0.17).

In this multicenter study, we report incidence and predictors of subtype switching, the risk of which varies considerably by baseline subtype. Switches can have clinical implications for prognosis and treatment choice.

Optimizing eligibility criteria and clinical trial conduct to enhance clinical trial participation for primary brain tumor patients.

Neuro-Oncology

Building on an initiative to enhance clinical trial participation involving the Society for Neuro-Oncology (SNO), the Response Assessment in Neuro-...

Nerves in cancer.

Nature Reviews Cancer

The contribution of nerves to the pathogenesis of malignancies has emerged as an important component of the tumour microenvironment. Recent studies...

N-acetyltransferase 2 genotypes amongst Zulu Speaking South Africans and isoniazid/N-acetyl-isoniazid pharmacokinetics during anti-tuberculosis treatment.

Antimicrobial Agents and Chemotherapy

Distribution of N-acetyltransferase2 (NAT2) polymorphisms varies considerably among different ethnic groups. Information on NAT2 single-nucleotide polymorphisms in South African population is limited. We investigated NAT2 polymorphisms and their effect on isoniazid pharmacokinetics in Zulu black HIV-infected South Africans in Durban, South Africa.

HIV-infected participants with culture-confirmed pulmonary tuberculosis (TB) were enrolled from two unrelated studies. Culture-confirmed participants were genotyped for NAT2 polymorphisms 282C>T, 341T>C, 481C>T, 857G>A, 590G>A and 803A>G using Life Technologies pre-validated Taqman assays (Life Technologies, Paisley, UK). Participants underwent sampling for determination of plasma isoniazid and N-acetylisoniazid concentrations.

Amongst the 120 patients, 63/120 (52.5%) were slow metabolisers (NAT2*5/*5), 43/120 (35.8%) had intermediate (NAT2*5/12), and 12/120 (11.7%) had rapid genotype (NAT2*4/*11, NAT2*11/12 and NAT2*12/12). NAT2 alleles in this study were *4, *5C, *5D, *5E, *5J, *5K, *5KA, *5T, *11A, *12A/12C and *12M. NAT2*5 was the most frequent allele (70.4%) followed by NAT2*12 (27.9%). 34/40 had both PK results and NAT2 genotyping results. The median area under the concentration-time-curve to infinity (AUC0-∞) interquartile range (IQR) was 7.81 (5.87 - 16.83) μg/ml/hr and maximum concentration (Cmax) 3.14 μg/ml (2.42 - 4.36) μg/mL. Individual polymorphisms were not equally distributed, with some represented in small numbers. Genotype did not correlate with phenotype, rapid genotype showing higher AUC0-∞ than slow but not significant, p=0.43.

There was high prevalence of slow followed by intermediate then rapid acetylator genotypes. The poor concordance between genotype and phenotype suggests that other factors or genetic loci influence INH metabolism, and warrants further investigation in this population.

Are standard dosing regimens of Amikacin suitable in Critically Ill Patients with Open Abdomen and Negative Pressure Wound Therapy? A population pharmacokinetic study.

Antimicrobial Agents and Chemotherapy

To assess the appropriateness of recommended regimens for empirical MIC coverage in critically ill patients with open abdomen and negative pressure therapy (OA/NPT).

Over a 5-year period, every critically ill patient who received amikacin and who underwent therapeutic drug monitoring (TDM) while treated by OA/NPT was retrospectively included. A population PK modelling was performed considering the effect of ten covariates (age, sex, TBW, ABW, BSA, modified SOFA score, vasopressor use, CLCr, fluid balance and amount of fluids collected by the NPT over the sampling day) in patients who underwent or not continuous renal replacement therapy (CRRT). Monte Carlo simulations were employed to determine the fractional target attainment (FTA) for the PK/PD targets (Cmax/MIC ratio ≥ 8 and AUC0-24h/MIC ≥ 75).

Seventy critically ill patients treated by OA/NPT (contributing for 179 concentration values) were included. Amikacin PK concentrations were best described by a two-compartment model with linear elimination and proportional residual error, with CLCR and ABW as significant covariates for Vd and CLCR for CL. The reported volume of distribution (Vd) in non-CRRT and CRRT patients was 35.8 and 40.2 L respectively. In Monte Carlo simulations, ABW-adjusted doses between 25 and 35 mg/kg were needed to reach an FTA > 85% for various renal functions.

Despite an increased Vd and a wide inter-individual variability, desirable PK/PD targets may be achieved using an ABW-pondered loading dose of 25 - 30 mg/kg. When targeting less susceptible pathogens, higher dosing regimens are probably needed in ARC patients. Further studies are needed to assess the effect of OA/NPT in PK parameters of antimicrobial agents.

6'-β-Fluoro-homoaristeromycin and 6'-fluoro-homoneplanocin A are potent inhibitors of chikungunya virus replication through their direct effect on the viral non-structural protein 1.

Antimicrobial Agents and Chemotherapy

Alphaviruses are arthropod-borne, positive-stranded RNA viruses capable of causing severe disease with high morbidity. Chikungunya virus (CHIKV) is...

Use of Radiomics for the Prediction of Local Control of Brain Metastases After Stereotactic Radiosurgery.

Neuro-Oncology

Local response prediction for brain metastases (BM) after stereotactic radiosurgery (SRS) is challenging, particularly for smaller BM, as existing criteria are based solely on unidimensional measurements. This investigation sought to determine whether radiomic features provide additional value to routinely available clinical and dosimetric variables to predict local recurrence following SRS.

408 BM in 87 patients treated with SRS were analyzed. A total of 440 radiomic features were extracted from the tumor core, and the peritumoral regions, using the baseline pre-treatment volumetric post-contrast T1 (T1c) and volumetric T2 fluid-attenuated inversion recovery (FLAIR) MRI sequences. Local tumor progression was determined based on RANO-BM criteria, with a maximum axial diameter growth of >20% on the follow-up T1c indicating local failure. The top radiomic features were determined based on resampled Random Forest (RF) feature importance. An RF classifier was trained using each set of features and evaluated using the area under the receiver operating characteristic curve (AUC).

The addition of any one of the top ten radiomic features to the set of clinical features resulted in a statistically significant (p<0.001) increase in the AUC. An optimized combination of radiomic and clinical features resulted in a 19% higher resampled AUC (mean = 0.793, 95% C.I. = 0.792-0.795) than clinical features alone (0.669, 0.668-0.671).

The increase in AUC of the RF classifier, after incorporating radiomic features, suggests that quantitative characterization of tumor appearance on pretreatment T1c and FLAIR adds value to known clinical and dosimetric variables for predicting local failure.

Neurologic and oncologic features of Erdheim-Chester disease: a 30-patient series.

Neuro-Oncology

Erdheim-Chester disease (ECD) is a rare histiocytic neoplasm characterized by recurrent alterations in the mitogen-activating protein kinase (MAPK) pathway. The existing literature about the neuro-oncological spectrum of ECD is limited.

We present retrospective clinical, radiographic, pathologic, molecular, and treatment data from 30 patients with ECD neurohistiocytic involvement treated at a tertiary center.

Median age was 52 (range: 7-77) years and 20 (67%) patients were male. Presenting symptoms included ataxia in 19 (63%), dysarthria in 14 (47%), diabetes insipidus in 12 (40%), cognitive impairment in 10 (33%), and bulbar affect in 9 (30%) patients. Neurosurgical biopsy specimens in 8 patients demonstrated varied morphologic findings often uncharacteristic of typical ECD lesions. Molecular analysis revealed mutations in BRAF (18 patients), MAP2K1 (5), RAS isoforms (2), and two fusions involving BRAF and ALK. Conventional therapies (corticosteroids, immunosuppresants, interferon-alpha [IFN-α], cytotoxic chemotherapy) led to partial radiographic response in 8/40 (20%) by MRI with no complete responses, partial metabolic response in 4/16 (25%) and complete metabolic response in 1/16 (6%) by FDG-PET scan. In comparison, targeted (kinase inhibitor) therapies yielded partial radiographic response in 10/27 (37%) and complete radiographic response in 14/27 (52%) by MRI, and partial metabolic response in 6/25 (24%) and complete metabolic response in 17/25 (68%) by FDG-PET scan.

These data highlight underrecognized symptomatology, heterogenous neuropathology, and robust responses to targeted therapies across the mutational spectrum in ECD patients with neurological involvement, particularly when conventional therapies have failed.

FYN tyrosine kinase, a downstream target of receptor tyrosine kinases, modulates anti-glioma immune responses.

Neuro-Oncology

High grade gliomas are aggressive and immunosuppressive brain tumors. Molecular mechanisms that regulate the inhibitory immune tumor microenvironment (TME) and glioma progression remain poorly understood. FYN tyrosine kinase is a downstream target of the oncogenic receptor tyrosine kinases pathway and is overexpressed in human gliomas. FYN's role in vivo in glioma growth remains unknown. We investigated whether FYN regulates glioma initiation, growth and invasion.

We evaluated the role of FYN using genetically engineered mouse glioma models (GEMM). We also generated FYN knockdown stem cells to induce gliomas in immune-competent and immune-deficient mice (NSG, CD8-/-, CD4-/-). We analyzed molecular mechanism by RNA-Seq and bioinformatics analysis. Flow cytometry was used to characterize immune cellular infiltrates in the FYN knockdown glioma TME.

We demonstrate that FYN knockdown in diverse immune-competent GEMMs of glioma reduced tumor progression and significantly increased survival. Gene ontologies (GOs) analysis of differentially expressed genes in wild type vs. FYN knockdown gliomas showed enrichment of GOs related to immune reactivity. However, in NSG, CD8-/- and CD4-/- immune-deficient mice, FYN knockdown gliomas failed to show differences in survival. These data suggest that the expression of FYN in glioma cells reduces anti-glioma immune activation. Examination of glioma immune infiltrates by flow-cytometry displayed reduction in the amount and activity of immune suppressive myeloid derived cells (MDSCs) in the FYN glioma TME.

Gliomas employ FYN mediated mechanisms to enhance immune-suppression and promote tumor progression. We propose that FYN inhibition within glioma cells could improve the efficacy of anti-glioma immunotherapies.

Stereotactic body radiation therapy for medically inoperable early-stage lung cancer: Tata Memorial Hospital perspective and practice recommendations.

Indian Journal of Cancer

Stereotactic body radiotherapy (SBRT) is now considered the standard treatment for medically inoperable early-stage non-small lung cell cancer (ES-NSCLC).

There is a paucity of data related to outcomes with SBRT in ES-NSCLC from the developing countries. We report the early outcomes of ES-NSCLC patients treated with SBRT at our institute.

Between 2007 and 2015, 40 consecutive patients with histologically proven ES-NSCLC were treated with SBRT. Median age was 71 years (range: 46-88 years) and median Charlson comorbidity index (CCI) was 3. The majority had stage I (70%) and 45% of the tumors were centrally located. The median tumor diameter was 3.8 cm (range: 2-7.6 cm). The mean gross tumor volume was 41 cc (range: 4-139 cc) and the mean planning target volume (PTV) was 141 cc (range: 27-251 cc). Varying dose and fraction (fr) sizes were used depending on tumor location, tumor size, and treatment period. The median biologically effective dose (BED) was 77 Gy10 (range: 77-105 Gy10) for the initial cohort (2007-2012) and 105 Gy10 (range: 77-132 Gy10) for the subsequent cohort (2013-2015).

After a median follow-up of 16 months (range: 3-99 months), the 2-year local control (LC), overall survival, and cancer-specific survival (CSS) rates were 94%, 41%, and 62%, respectively. The univariate and multivariate analysis determined CCI >3 and PTV >80.6 cc as significant predictors of worse OS and CSS (P < 0.01). The clinical stage, tumor location, BED, and treatment period (2007-2012 vs. 2013-2015) did not significantly predict any of the outcomes. The most common acute toxicities were skin erythema (10%), grade 1 esophagitis (8%), and exacerbation of previous chronic obstructive pulmonary disease (10%). Grade ≥2 late radiation pneumonitis was seen in 17.5%. One patient developed a rib fracture. No neurological or vascular complications were seen.

SBRT results in excellent local control (LC) and acceptable survival in medically inoperable ES-NSCLC with minimal adverse effects. Charlson comorbidity index and target volume are important prognostic factors and may aid in patient selection.

Diagnostic value of a power Doppler ultrasound-based malignancy index for differentiating malignant and benign solid breast lesions.

Indian Journal of Cancer

Power Doppler ultrasound (PDUS) can provide useful information regarding the vascularity of breast lesions. The aim of this study was to investigate the diagnostic performance of a new PDUS-driven malignancy index in differentiating between malignant and benign causes of solid breast lesions.

Patients with solid breast lesions were enrolled consecutively and evaluated first by PDUS and subsequently by histopathologic assessment after undergoing surgical biopsy. A custom-made software was used to extract data from images for calculating malignancy index formula.

A total of 87 patients with solid breast lesions were enrolled. Histopathologic evaluation identified 49 patients as benign and 38 patients as malignant. Malignancy index was significantly higher in the malignant group as compared to benign tumors (6.31 vs 0.30, P < 0.001). Area under the receiver operating characteristics (ROC) curve (AUC) was 0.98 (95% confidence interval (CI) 0.95-1.00). According to the ROC curve analysis, the cut-off point of 1.23 for malignancy index had a sensitivity and specificity of 94.7% (95% CI 82.2-99.3) and 94.0% (95% CI 83.1-98.7), respectively.

Comparing with the histopathologic evaluation as the gold standard for diagnosing breast lesions, PDUS-driven malignancy index was shown to have a high discriminative performance in identifying malignant lesions with high sensitivity, specificity, and diagnostic accuracy. The noninvasive nature of PDUS is an important advantage that could prevent unnecessary biopsies.