Background
We previously reported excellent three‐year overall survival (OS) for patients with newly diagnosed intermediate‐risk neuroblastoma treated with a biology‐ and response‐based algorithm on ...the Children's Oncology Group study ANBL0531. We now present the long‐term follow‐up results.
Methods
All patients who met the age, stage, and tumor biology criteria for intermediate‐risk neuroblastoma were eligible. Treatment was based on prognostic biomarkers and overall response. Event‐free survival (EFS) and OS were estimated by the Kaplan‐Meier method.
Results
The 10‐year EFS and OS for the entire study cohort (n = 404) were 82.0% (95% confidence interval (CI), 77.2%‐86.9%) and 94.7% (95% CI, 91.8%‐97.5%), respectively. International Neuroblastoma Staging System stage 4 patients (n = 133) had inferior OS compared with non–stage 4 patients (n = 271; 10‐year OS: 90.8% 95% CI, 84.5%‐97.0% vs 96.6% 95% CI, 93.9%‐99.4%, p = .02). Infants with stage 4 tumors with ≥1 unfavorable biological feature (n = 47) had inferior EFS compared with those with favorable biology (n = 61; 10‐year EFS: 66.8% 95% CI, 50.4%‐83.3% vs 86.9% 95% CI, 76.0%‐97.8%, p = .02); OS did not differ (10‐year OS: 84.4% 95% CI, 71.8%‐97.0% vs 95.0% 95% CI, 87.7%‐100.0%, p = .08). Inferior EFS but not OS was observed among patients with tumors with (n = 26) versus without (n = 314) 11q loss of heterozygosity (10‐year EFS: 68.4% 95% CI, 44.5%‐92.2% vs 83.9% 95% CI, 78.7%‐89.2%, p = .03; 10‐year OS: 88.0% 95% CI, 72.0%‐100.0% vs 95.7% 95% CI, 92.8%‐98.6%, p = .09).
Conclusions
The ANBL0531 trial treatment algorithm resulted in excellent long‐term survival. More effective treatments are needed for subsets of patients with unfavorable biology tumors.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
To determine adherence to nutritional guidelines by pregnant women in New Zealand and maternal characteristics associated with adherence.
A cohort of the pregnant women enrolled into New Zealand's ...new birth cohort study, Growing Up in New Zealand.
Women residing within a North Island region of New Zealand, where one-third of the national population lives.
Pregnant women (n 5664) were interviewed during 2009-2010. An FFQ was administered during the face-to-face interview.
The recommended daily number of servings of vegetables and fruit (≥6) were met by 25 % of the women; of breads and cereals (≥6) by 26 %; of milk and milk products (≥3) by 58 %; and of lean meat, meat alternatives and eggs (≥2) by 21 %. One in four women did not meet the recommendations for any food group. Only 3 % met all four food group recommendations. Although adherence to recommendation for the vegetables/fruit group did not vary by ethnicity (P=0·38), it did vary for the breads/cereals, milk/milk products and meat/eggs groups (all P<0·001). Adherence to recommendations for the vegetables/fruit group was higher among older women (P=0·001); for the breads/cereals group was higher for women with previous children (P<0·001) and from lower-income households (P<0·001); and for the meat/eggs group was higher for women with previous children (P=0·003) and from lower-income households (P=0·004).
Most pregnant women in New Zealand do not adhere to nutritional guidelines in pregnancy, with only 3 % meeting the recommendations for all four food groups. Adherence varies more so with ethnicity than with other sociodemographic characteristics.
Background: Clonidine, gabapentin, and promethazine are commonly used by people who use opioids, including heroin, raising concern for increased morbidity and mortality in a vulnerable population. We ...aimed to characterize how and why individuals use opioids in combination with these three psychoactive medications (PAMs). Methods: Participants (n = 103) were a convenience sample of adults attending a syringe service program who reported using a PAM in addition to opioids or opioid agonist therapies (buprenorphine or methadone). Face-to-face structured interviews consisted of closed and open-ended questions. Results: Patterns of PAM use varied. Risky use, including use of high doses and with other sedating medications, was common. Most individuals reported multiple medical reasons for use, even while reporting the PAM had mind-altering effects. Use of high doses of PAMs was associated with a history of overdose. Among those with a history of overdose, 32% reported that a PAM was involved. Conclusion: The use of clonidine, gabapentin and promethazine among individuals who use opioids is complex. Providers should take individualized approaches to PAM prescribing, recognizing both the risks of PAMs and the potential unintended consequences of supply-side interventions in the era of the overdose crisis. Harm reduction interventions are needed to prevent PAM-involved overdoses.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The aim of this study was to identify and independently validate a novel gene signature predicting locoregional tumor control (LRC) for treatment individualization of patients with locally advanced ...HPV-negative head and neck squamous cell carcinomas (HNSCC) who are treated with postoperative radio(chemo)therapy (PORT-C).
Gene expression analyses were performed using NanoString technology on a multicenter training cohort of 130 patients and an independent validation cohort of 121 patients. The analyzed gene set was composed of genes with a previously reported association with radio(chemo)sensitivity or resistance to radio(chemo)therapy. Gene selection and model building were performed comparing several machine-learning algorithms.
We identified a 7-gene signature consisting of the three individual genes
, and one metagene combining the highly correlated genes
, and
The 7-gene signature was used, in combination with clinical parameters, to fit a multivariable Cox model to the training data (concordance index, ci = 0.82), which was successfully validated (ci = 0.71). The signature showed improved performance compared with clinical parameters alone (ci = 0.66) and with a previously published model including hypoxia-associated genes and cancer stem cell markers (ci = 0.65). It was used to stratify patients into groups with low and high risk of recurrence, leading to significant differences in LRC in training and validation (
< 0.001).
We have identified and validated the first hypothesis-based gene signature for HPV-negative HNSCC treated by PORT-C including genes related to several radiobiological aspects. A prospective validation is planned in an ongoing prospective clinical trial before potential application in clinical trials for patient stratification.
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Adiposity traits have been associated with risk of many cancers in observational studies, but whether these associations are causal is unclear. Mendelian randomization (MR) uses genetic predictors of ...risk factors as instrumental variables to eliminate reverse causation and reduce confounding bias. We performed MR analyses to assess the possible causal relationship of birthweight, childhood and adult body mass index (BMI), and waist-hip ratio (WHR) on the risks of breast, ovarian, prostate, colorectal and lung cancers.
We tested the association between genetic risk scores and each trait using summary statistics from published genome-wide association studies (GWAS) and from 51 537 cancer cases and 61 600 controls in the Genetic Associations and Mechanisms in Oncology (GAME-ON) Consortium.
We found an inverse association between the genetic score for childhood BMI and risk of breast cancer odds ratio (OR) = 0.71 per standard deviation (s.d.) increase in childhood BMI; 95% confidence interval (CI): 0.60, 0.80; P = 6.5 × 10(-5)). We also found the genetic score for adult BMI to be inversely associated with breast cancer risk (OR = 0.66 per s.d. increase in BMI; 95% CI: 0.57, 0.77; P = 2.5 × 10(-7)), and positively associated with ovarian cancer (OR = 1.35; 95% CI: 1.05, 1.72; P = 0.017), lung cancer (OR = 1.27; 95% CI: 1.09, 1.49; P = 2.9 × 10(-3)) and colorectal cancer (OR = 1.39; 95% CI: 1.06, 1.82, P = 0.016). The inverse association between genetically predicted adult BMI and breast cancer risk remained even after adjusting for directional pleiotropy via MR-Egger regression.
Findings from this study provide additional understandings of the complex relationship between adiposity and cancer risks. Our results for breast and lung cancer are particularly interesting, given previous reports of effect heterogeneity by menopausal status and smoking status.
Metabolically active cells require robust mechanisms to combat oxidative stress. The cytoplasmic thioredoxin reductase/thioredoxin (Txnrd1/Txn1) system maintains reduced protein dithiols and provides ...electrons to some cellular reductases, including peroxiredoxins.
Here we generated mice in which the txnrd1 gene, encoding Txnrd1, was specifically disrupted in all parenchymal hepatocytes. Txnrd1-deficient livers exhibited a transcriptome response in which 56 mRNAs were induced and 12 were repressed. Based on the global hybridization profile, this represented only 0.3% of the liver transcriptome. Since most liver mRNAs were unaffected, compensatory responses were evidently effective. Nuclear pre-mRNA levels indicated the response was transcriptional. Twenty-one of the induced genes contained known antioxidant response elements (AREs), which are binding sites for the oxidative and chemical stress-induced transcription factor Nrf2. Txnrd1-deficient livers showed increased accumulation of nuclear Nrf2 protein and chromatin immunoprecipitation on the endogenous nqo1 and aox1 promoters in fibroblasts indicated that Txnrd1 ablation triggered in vivo assembly of Nrf2 on each.
Chronic deletion of Txnrd1 results in induction of the Nrf2 pathway, which contributes to an effective compensatory response.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
10003 Background: A subset of children with INRGSS Stage MS neuroblastoma (NBL) may be observed without treatment, while others have rapidly evolving symptoms that can be life-threatening. ANBL1232 ...adapted a previously developed semi-quantitative objective scoring system (OSS) to assign a numeric value to symptoms and laboratory abnormalities. The goal was to standardize monitoring, therapy initiation, and treatment duration in this cohort. Methods: Patients with newly diagnosed Stage MS NBL were eligible for this prospective trial. An OSS score (OSSS) was assigned at enrollment; the total number was based on scoring in 5 systems: gastrointestinal (GI), respiratory, circulatory, renal, and hepatic. Within the 5 systems, individual clinical and laboratory parameters were scored as not present = 0, mild/moderate = 1 Grade 2 CTCAEv4.0 adverse event (AE) or severe = 2 (Grade ≥3 AE). The OSSS was the sum of highest score within each organ system (maximum score: 2 per system, 10 total). Asymptomatic MS patients with an OSSS < 2 who were either < 3 months (mo) of age without hepatomegaly or 3-18 mo of age with favorable biology tumors were eligible for observation without initial treatment. Observed patients underwent monthly physical examinations and laboratory assessments for the first 6 mo following diagnosis. Tumor imaging was performed every 3 mo for 1 year, then every 6-12 mo through 36 mo. An OSSS ≥2 or a protocol-defined increase in primary tumor size prompted initiation of therapy. Results: From July 2014 to February 2021, 89 eligible and evaluable patients with newly diagnosed stage MS NBL enrolled. Among these, 18 (20.2%; 5 male and 13 female) were eligible for observation. Observed patients were older at diagnosis (median age: 2.87 vs. 1.81 mo, p = 0.23) and more likely to have primary tumors without image-defined risk factors (62.5% vs. 30.0%, p = 0.0166) than those assigned to therapy up front. Nearly all observed patients (17/18) had abdominal/adrenal primaries. The initial OSSS was 0 in all observed patients. Median reported observation time was 36 mo (range: 1-36 mo); 13 patients completed all required monthly assessments for the first 6 mo. No patients in the observation cohort required initiation of therapy for an increase in OSSS. One patient with OSSS = 1 at mo 3 had complete GI symptom resolution by mo 5. Conclusions: An OSSS of 0 at diagnosis can aid in identifying a favorable group of patients with stage MS NBL who can be safely observed. No patients in the observation cohort developed evidence of organ dysfunction or OSSS > 1 despite frequent physical examination and comprehensive laboratory testing, suggesting that follow up may be safely liberalized in this population over time. Clinical and laboratory criteria implemented at diagnosis could be used to identify patients requiring prompt treatment. Clinical trial information: NCT02176967 .
In 2008, a consortium led by the Agricultural Research Service (ARS) and the National Institute for Food and Agriculture (NIFA) published the "Blueprint for USDA Efforts in Agricultural Animal ...Genomics 2008-2017," which served as a guiding document for research and funding in animal genomics. In the decade that followed, many of the goals set forth in the blueprint were accomplished. However, several other goals require further research. In addition, new topics not covered in the original blueprint, which are the result of emerging technologies, require exploration. To develop a new, updated blueprint, ARS and NIFA, along with scientists in the animal genomics field, convened a workshop titled "Genome to Phenome: A USDA Blueprint for Improving Animal Production" in November 2017, and these discussions were used to develop new goals for the next decade. Like the previous blueprint, these goals are grouped into the broad categories "Science to Practice," "Discovery Science," and "Infrastructure." New goals for characterizing the microbiome, enhancing the use of gene editing and other biotechnologies, and preserving genetic diversity are included in the new blueprint, along with updated goals within many genome research topics described in the previous blueprint. The updated blueprint that follows describes the vision, current state of the art, the research needed to advance the field, expected deliverables, and partnerships needed for each animal genomics research topic. Accomplishment of the goals described in the blueprint will significantly increase the ability to meet the demands for animal products by an increasing world population within the next decade.
Co-observation of a gene variant with a pathogenic variant in another gene that explains the disease presentation has been designated as evidence against pathogenicity for commonly used variant ...classification guidelines. Multiple variant curation expert panels have specified, from consensus opinion, that this evidence type is not applicable for the classification of breast cancer predisposition gene variants. Statistical analysis of sequence data for 55,815 individuals diagnosed with breast cancer from the BRIDGES sequencing project was undertaken to formally assess the utility of co-observation data for germline variant classification. Our analysis included expected loss-of-function variants in 11 breast cancer predisposition genes and pathogenic missense variants in BRCA1, BRCA2, and TP53. We assessed whether co-observation of pathogenic variants in two different genes occurred more or less often than expected under the assumption of independence. Co-observation of pathogenic variants in each of BRCA1, BRCA2, and PALB2 with the remaining genes was less frequent than expected. This evidence for depletion remained after adjustment for age at diagnosis, study design (familial versus population-based), and country. Co-observation of a variant of uncertain significance in BRCA1, BRCA2, or PALB2 with a pathogenic variant in another breast cancer gene equated to supporting evidence against pathogenicity following criterion strength assignment based on the likelihood ratio and showed utility in reclassification of missense BRCA1 and BRCA2 variants identified in BRIDGES. Our approach has applicability for assessing the value of co-observation as a predictor of variant pathogenicity in other clinical contexts, including for gene-specific guidelines developed by ClinGen Variant Curation Expert Panels.
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This study demonstrates that, when appropriately calibrated, the BP5 co-observation classification criterion can be used as supporting evidence against pathogenicity for a germline variant in selected breast cancer predisposition genes. Our approach has the potential to justify use, or non-applicability, of co-observation data for other gene-specific criteria.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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