Phase II Trial Assessing Toxicity of Personalized Response-Based Radiation Treatment in Patients with Locally Advanced Non-Small Cell Lung Cancer.

INTRODUCTION: Local failure rates after treatment for locally advanced non-small-cell lung cancer (NSCLC) remain high. Efforts to improve local control with uniform dose-escalation or dose-escalation to mid-treatment PET-avid residual disease have been limited by heightened toxicity. This trial aimed to refine response-based adaptive radiation (RT) and minimize toxicity by incorporating FDG-PET and V/Q SPECT imaging mid-treatment. METHODS: 47 patients with Stage IIA-III unresectable NSCLC were prospectively enrolled in this single-institution trial (NCT02492867). Patients received concurrent chemoradiation with personalized response-based adaptive RT over 30 fractions incorporating V/Q SPECT and FDG-PET. The first 21 fractions (46.2Gy at 2.2 Gy/fraction) were delivered to the tumor while minimizing dose to SPECT-defined functional lung. The plan was then adapted for the final 9 fractions (2.2-3.8Gy/fraction) up to a total of 80.4Gy, based on mid-treatment FDG-PET tumor response to escalate dose to residual tumor while minimizing dose to SPECT-defined functional lung. Non-progressing patients received consolidative carboplatin/paclitaxel or durvalumab. The primary endpoint of the study was ≥ grade 2 lung and esophageal toxicities. Secondary endpoints included time to local progression, tumor response, and overall survival. RESULTS: At one year post-treatment, the rates of grade 2 and grade 3 pneumonitis were 21.3% and 2.1%, respectively, with no difference in pneumonitis rates among patients who received and did not receive adjuvant durvalumab (p=0.74). While there were no grade 3 esophageal-related toxicities, 66.0% of patients experienced grade 2 esophagitis. 1- and 2-year local control rates were 94.5% (95% CI, 87.4% - 100%) and 87.5% (95% CI, 76.7% - 100%), respectively. Overall survival was 82.8% (95% CI, 72.6% -94.4%) at 1 year and 62.3% (95% CI, 49.6%-78.3%) at 2 years. CONCLUSIONS: Response-based adaptive dose-escalation accounting for tumor change and normal tissue function during treatment provided excellent local control, comparable toxicity to standard chemoradiation, and did not increase toxicity with adjuvant immunotherapy.

Pharmacogenomic studies of fertility outcomes in pediatric cancer survivors - A systematic review.

For the same age, sex, and dosage, there can be significant variation in fertility outcomes in childhood cancer survivors. Genetics may explain this variation. This study aims to: (i) review the genetic contributions to infertility, (ii) search for pharmacogenomic studies looking at interactions of cancer treatment, genetic predisposition and fertility-related outcomes. Systematic searches in MEDLINE Ovid, Embase Classic+Embase, and PubMed were conducted using the following selection criteria: (i) pediatric, adolescent, and young adult cancer survivors, below 25 years old at the time of diagnosis, (ii) fertility outcome measures after cancer therapy, (iii) genetic considerations. Studies were excluded if they were (i) conducted in animal models, (ii) were not published in English, (iii) editorial letters, (iv) theses. Articles were screened in Covidence by at least two independent reviewers, followed by data extraction and a risk of bias assessment using the Quality in Prognostic Studies tool. Eight articles were reviewed with a total of 29 genes. Outcome measures included sperm concentration, azoospermia, AMH levels, assessment of premature menopause, ever being pregnant or siring a pregnancy. Three studies included replication cohorts, which attempted replication of SNP findings for NPY2R, BRSK1, FANCI, CYP2C19, CYP3A4, and CYP2B6. Six studies were rated with a high risk of bias. Differing methods may explain a lack of replication, and small cohorts may have contributed to few significant findings. Larger, prospective longitudinal studies with an unbiased genome-wide focus will be important to replicate significant results, which can be applied clinically.

Impact of lung cancer screening on stage migration and mortality among the national Veterans Health Administration population with lung cancer.

BACKGROUND: Despite randomized trials demonstrating a mortality benefit to low-dose computed tomography screening to detect lung cancer, uptake of lung cancer screening (LCS) has been slow, and the benefits of screening remain unclear in clinical practice. METHODS: This study aimed to assess the impact of screening among patients in the Veterans Health Administration (VA) health care system diagnosed with lung cancer between 2011 and 2018. Lung cancer stage at diagnosis, lung cancer-specific survival, and overall survival between patients with cancer who did and did not receive screening before diagnosis were evaluated. We used Cox regression modeling and inverse propensity weighting analyses with lead time bias adjustment to correlate LCS exposure with patient outcomes. RESULTS: Of 57,919 individuals diagnosed with lung cancer in the VA system between 2011 and 2018, 2167 (3.9%) underwent screening before diagnosis. Patients with screening had higher rates of stage I diagnoses (52% vs. 27%; p ≤ .0001) compared to those who had no screening. Screened patients had improved 5-year overall survival rates (50.2% vs. 27.9%) and 5-year lung cancer-specific survival (59.0% vs. 29.7%) compared to unscreened patients. Among screening-eligible patients who underwent National Comprehensive Cancer Network guideline-concordant treatment, screening resulted in substantial reductions in all-cause mortality (adjusted hazard ratio [aHR], 0.79; 95% confidence interval [CI], 0.67-0.92; p = .003) and lung-specific mortality (aHR, 0.61; 95% CI, 0.50-0.74; p < .001). CONCLUSIONS: While LCS uptake remains limited, screening was associated with earlier stage diagnoses and improved survival. This large national study corroborates the value of LCS in clinical practice; efforts to widely adopt this vital intervention are needed.

Minimising Adverse Drug Reactions and Verifying Economic Legitimacy-Pharmacogenomics Implementation in Children (MARVEL- PIC): protocol for a national randomised controlled trial of pharmacogenomics implementation.

INTRODUCTION: DNA-informed prescribing (termed pharmacogenomics, PGx) is the epitome of personalised medicine. Despite international guidelines existing, its implementation in paediatric oncology remains sparse. METHODS AND ANALYSIS: Minimising Adverse Drug Reactions and Verifying Economic Legitimacy-Pharmacogenomics Implementation in Children is a national prospective, multicentre, randomised controlled trial assessing the impact of pre-emptive PGx testing for actionable PGx variants on adverse drug reaction (ADR) incidence in patients with a new cancer diagnosis or proceeding to haematopoetic stem cell transplant. All ADRs will be prospectively collected by surveys completed by parents/patients using the National Cancer Institute Pediatric Patient Reported [Ped-PRO]-Common Terminology Criteria for Adverse Events (CTCAE) (weeks 1, 6 and 12). Pharmacist will assess for causality and severity in semistructured interviews using the CTCAE and Liverpool Causality Assessment Tool. The primary outcome is a reduction in ADRs among patients with actionable PGx variants, where an ADR will be considered as any CTCAE grade 2 and above for non-haematological toxicities and any CTCAE grade 3 and above for haematological toxicities Cost-effectiveness of pre-emptive PGx (secondary outcome) will be compared with standard of care using hospital inpatient and outpatient data along with the validated Childhood Health Utility 9D Instrument. Power and statistics considerations: A sample size of 440 patients (220 per arm) will provide 80% power to detect a 24% relative risk reduction in the primary endpoint of ADRs (two-sided α=5%, 80% vs 61%), allowing for 10% drop-out. ETHICS AND DISSEMINATION: The ethics approval of the trial has been obtained from the Royal Children's Hospital Ethics Committee (HREC/89083/RCHM-2022). The ethics committee of each participating centres nationally has undertaken an assessment of the protocol and governance submission. TRIAL REGISTRATION NUMBER: NCT05667766.

Pneumonitis After Chemoradiotherapy and Adjuvant Durvalumab in Stage III Non-Small Cell Lung Cancer.

PURPOSE: Adjuvant durvalumab after definitive chemoradiotherapy (CRT) for unresectable stage III non-small cell lung cancer (NSCLC) is well-tolerated in clinical trials. However, pneumonitis rates outside of clinical trials remain poorly defined with CRT followed by durvalumab. We aimed to describe the influence of durvalumab on pneumonitis rates among a large cohort of patients with stage III NSCLC. METHODS AND MATERIALS: We studied patients with stage III NSCLC in the national Veterans Health Administration from 2015 to 2021 who received concurrent CRT alone or with adjuvant durvalumab. We defined pneumonitis as worsening respiratory symptoms with radiographic changes within 2 years of CRT and graded events according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. We used Cox regression to analyze risk factors for pneumonitis and the effect of postbaseline pneumonitis on overall survival. RESULTS: Among 1994 patients (989 CRT alone, 1005 CRT followed by adjuvant durvalumab), the 2-year incidence of grade 2 or higher pneumonitis was 13.9% for CRT alone versus 22.1% for CRT plus durvalumab (unadjusted P < .001). On multivariable analysis, durvalumab was associated with higher risk of grade 2 pneumonitis (hazard ratio, 1.45; 95% CI, 1.09-1.93; P = .012) but not grade 3 to 5 pneumonitis (P = .2). Grade 3 pneumonitis conferred worse overall survival (hazard ratio, 2.51; 95% CI, 2.06-3.05; P < .001) but grade 2 pneumonitis did not (P = .4). CONCLUSIONS: Adjuvant durvalumab use was associated with increased risk of low-grade but not higher-grade pneumonitis. Reassuringly, low-grade pneumonitis did not increase mortality risk. We observed increased rates of high-grade pneumonitis relative to clinical trials; the reasons for this require further study.

National Long-term Survival Estimates After Radical Prostatectomy for Prostate Cancer.

OBJECTIVE: To examine survival and disease control outcomes, including metastasis-related survival outcomes, in a large contemporary cohort of patients undergoing radical prostatectomy for localized prostate cancer. METHODS: We conducted a retrospective study of men with localized prostate cancer treated with radical prostatectomy from 2005 to 2015 with follow-up through 2019 in the Veterans Health Administration. We defined biochemical recurrence (BCR) as a prostate-specific antigen ≥0.2 ng/mL. We used a validated natural language processing encoded dataset to identify incident metastatic prostate cancer. We estimated overall survival from time of surgery, time of BCR, and time of first metastasis using the Kaplan-Meier method. We then estimated time from surgery to BCR, BCR to metastatic disease, and prostate-cancer-specific survival from various time points using cumulative incidence considering competing risk of death. RESULTS: Of 21,992 men undergoing radical prostatectomy, we identified 5951 (27%) who developed BCR. Of men with BCR, 677 (11%) developed metastases. We estimated the 10-year cumulative incidence of BCR and metastases after BCR were 28% and 20%, respectively. Median overall survival after BCR was 14years, with 10-year survival of 70%. From the time of metastasis, median overall survival approached 7years, with 10-year overall survival of 34%. Prostate cancer-specific survival for the entire cohort at 10years was 94%. CONCLUSION: In this large contemporary national cohort, survival for men with biochemically recurrent prostate cancer is longer than historical cohorts. When counseling patients and designing clinical studies, these updated estimates may serve as more reliable reflections of current outcomes.

Lessons learnt in the first year of an Australian pediatric cardio oncology clinic.

BACKGROUND: Modern oncological therapies together with chemotherapy and radiotherapy have broadened the agents that can cause cardiac sequelae, which can manifest for pediatric oncology patients while on active treatment. Recommendations for high-risk patients who should be monitored in a pediatric cardio-oncology clinic have previously been developed by expert Delphi consensus by our group. In 2022 we opened our first multidisciplinary pediatric cardio-oncology clinic adhering to these recommendations in surveillance and management. OBJECTIVES: Our pediatric cardio-oncology clinic aimed to: (i) Document cardiovascular toxicities observed within a pediatric cardio-oncology clinic and. (ii) Evaluate the applicability of the Australian and New Zealand Pediatric Cardio-Oncology recommendations. METHODS: Monthly multidisciplinary cardio-oncology clinics were conducted in an Australian tertiary pediatric hospital. Structured standardised approaches to assessment were built into the electronic medical record (EMR). All patients underwent baseline echocardiogram and electrocardiogram assessment together with vital signs in conjunction with standard history and examination. RESULTS: Nineteen (54%) individuals had a documented cardiovascular toxicity or pre-existing risk factor prior to referral. The two most common cardiovascular toxicities documented during clinic review included Left Ventricular Dysfunction (LVD) and hypertension. Of note 3 (8.1%) patients had CTCAE grade III LVD. An additional 10 (27%) patients reviewed in clinic had CTCAE grade I hypertension. None of these patients had hypertension noted within their referral. Cascade testing for cardiac history was warranted in 2 (5.4%) of patients. CONCLUSIONS: Pediatric cardio-oncology clinics are likely beneficial to documenting previously unrecognised cardiotoxicity and relevant cardiac family histories, whilst providing an opportunity to address lifestyle risk factors.

A systematic review of knowledge, attitude and practice of pharmacogenomics in pediatric oncology patients.

Pharmacogenomics remains underutilized in clinical practice, despite the existence of internationally recognized, evidence-based guidelines. This systematic review aims to understand enablers and barriers to pharmacogenomics implementation in pediatric oncology by assessing the knowledge, attitudes, and practice of healthcare professionals and consumers. Medline, Embase, Emcare, and PsycINFO database searches identified 146 relevant studies of which only three met the inclusion criteria. These studies reveal that consumers were concerned with pharmacogenomic test costs, insurance discrimination, data sharing, and privacy. Healthcare professionals possessed mostly positive attitudes toward pharmacogenomic testing yet identified lack of experience and training as barriers to implementation. Education emerged as the key enabler, reported in all three studies and both healthcare professionals and consumer groups. However, despite the need for education, no studies utilizing a pediatric oncology consumer or healthcare professional group have reported on the implementation or analysis of a pharmacogenomic education program in pediatric oncology. Increased access to guidelines, expert collaborations and additional guidance interpreting results were further enablers established by healthcare professionals. The themes identified mirror those reported in broader pediatric genetic testing literature. As only a small number of studies met inclusion criteria for this review, further research is warranted to elicit implementation determinants and advance pediatric pharmacogenomics.

GLA-modified RNA treatment lowers GB3 levels in iPSC-derived cardiomyocytes from Fabry-affected individuals.

Recent studies in non-human model systems have shown therapeutic potential of nucleoside-modified messenger RNA (modRNA) treatments for lysosomal storage diseases. Here, we assessed the efficacy of a modRNA treatment to restore the expression of the galactosidase alpha (GLA), which codes for α-Galactosidase A (α-GAL) enzyme, in a human cardiac model generated from induced pluripotent stem cells (iPSCs) derived from two individuals with Fabry disease. Consistent with the clinical phenotype, cardiomyocytes from iPSCs derived from Fabry-affected individuals showed accumulation of the glycosphingolipid Globotriaosylceramide (GB3), which is an α-galactosidase substrate. Furthermore, the Fabry cardiomyocytes displayed significant upregulation of lysosomal-associated proteins. Upon GLA modRNA treatment, a subset of lysosomal proteins were partially restored to wild-type levels, implying the rescue of the molecular phenotype associated with the Fabry genotype. Importantly, a significant reduction of GB3 levels was observed in GLA modRNA-treated cardiomyocytes, demonstrating that α-GAL enzymatic activity was restored. Together, our results validate the utility of iPSC-derived cardiomyocytes from affected individuals as a model to study disease processes in Fabry disease and the therapeutic potential of GLA modRNA treatment to reduce GB3 accumulation in the heart.

Outcomes after definitive radiation therapy for localized prostate cancer in a national health care delivery system.

PURPOSE: Accurate information regarding real-world outcomes after contemporary radiation therapy for localized prostate cancer is important for shared decision-making. Clinically relevant end points at 10 years among men treated within a national health care delivery system were examined. METHODS: National administrative, cancer registry, and electronic health record data were used for patients undergoing definitive radiation therapy with or without concurrent androgen deprivation therapy within the Veterans Health Administration from 2005 to 2015. National Death Index data were used through 2019 for overall and prostate cancer-specific survival and identified date of incident metastatic prostate cancer using a validated natural language processing algorithm. Metastasis-free, prostate cancer-specific, and overall survival using Kaplan-Meier methods were estimated. RESULTS: Among 41,735 men treated with definitive radiation therapy, the median age at diagnosis was 65 years and median follow-up was 8.7 years. Most had intermediate (42%) and high-risk (33%) disease, with 40% receiving androgen deprivation therapy as part of initial therapy. Unadjusted 10-year metastasis-free survival was 96%, 92%, and 80% for low-, intermediate-, and high-risk disease. Similarly, unadjusted 10-year prostate cancer-specific survival was 98%, 97%, and 90% for low-, intermediate-, and high-risk disease. The unadjusted overall survival was lower across increasing disease risk categories at 77%, 71%, and 62% for low-, intermediate-, and high-risk disease (p < .001). CONCLUSIONS: These data provide population-based 10-year benchmarks for clinically relevant end points, including metastasis-free survival, among patients with localized prostate cancer undergoing radiation therapy using contemporary techniques. The survival rates for high-risk disease in particular suggest that outcomes have recently improved.

Initial Feasibility and Acute Toxicity Outcomes From a Phase 2 Trial of 18F-Fluorodeoxyglucose Positron Emission Tomography Response-Based De-escalated Definitive Chemoradiotherapy for p16+ Oropharynx Cancer: A Planned Interim Analysis.

PURPOSE: 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) parameters are prognostic of oncologic outcomes in human papillomavirus-associated oropharyngeal squamous cell carcinoma (OPSCC). We used FDG-PET imaging biomarkers to select patients for de-escalated chemoradiotherapy (CRT), hypothesizing that acute toxicity will be improved with de-escalation. METHODS AND MATERIALS: This is a planned interim initial feasibility and acute toxicity report from a phase 2, prospective, nonrandomized study, which enrolled patients with stage I-II p16+ OPSCC. All patients started definitive CRT to 70 Gy in 35 fractions, and those who met de-escalation criteria on midtreatment FDG-PET at fraction 10 completed treatment at 54 Gy in 27 fractions. We report the acute toxicity and patient-reported outcomes for 59 patients with a minimum follow-up of 3 months. RESULTS: There were no statistically significant differences between baseline patient characteristics in the standard and de-escalated cohorts. There were 28 of 59 (47.5%) patients who met FDG-PET de-escalation criteria and collectively received 20% to 30% less dose to critical organs at risk known to affect toxicity. At 3 months posttreatment, patients who received de-escalated CRT lost significantly less weight (median, 5.8% vs 13.0%; P < .001), had significantly less change from baseline in penetration-aspiration scale score (median, 0 vs 1; P = .018), and had significantly fewer aspiration events on repeat swallow study (8.0% vs 33.3%, P = .037) compared with patients receiving standard CRT. CONCLUSIONS: Approximately half of patients with early-stage p16+ OPSCC are selected for de-escalation of definitive CRT using midtreatment FDG-PET biomarkers, which resulted in significantly improved rates of observed acute toxicity. Further follow-up is ongoing and will be required to determine whether this de-escalation approach preserves the favorable oncologic outcomes for patients with p16+ OPSCC before adoption.

Successful retrograde regeneration using a sensory branch for motor nerve transfer.

OBJECTIVE: The objective of this study was to test whether regenerating motor axons from a donor nerve can travel in a retrograde fashion using sensory branches to successfully reinnervate a motor nerve end organ. METHODS: This study has two parts. In part I, rats (n = 30) were assigned to one of five groups for obturator nerve (ON)-to-femoral nerve transfer: group 1, ON-to-saphenous nerve (SN) distal stump; group 2, ON-to-SN proximal stump without femoral nerve proper (FNP) injury; group 3, ON-to-SN proximal stump with FNP crush injury; group 4, ON-to-SN proximal stump with FNP transection injury; and group 5, gold standard transfer, ON-to-motor femoral nerve (MFN) branch. At 8 weeks, retrograde labeling was done from the distal MFN, and the spinal cords were examined to assess the degree of obturator motor axon regeneration across the five groups. In part II, only group 4 was examined (n = 8). Through use of immunostaining and optical tissue clearing methods, the nerve transfer networks were cleared and imaged using light-sheet fluorescence microscopy to visualize the regeneration pathways in 2D and 3D models at 2- and 8-week time points. RESULTS: Proximal FNP transection (group 4) enabled a significantly higher number of retrogradely regenerated motor axons compared with control groups 1-3. Moreover, group 4 had modest, but nonsignificant, superiority of motor neuron counts compared with the positive control group, group 5. Optical tissue clearing demonstrated that the axons traveled in a retrograde fashion from the recipient sensory branch to the FNP mixed stump, then through complex turns, down to distal branches. Immunostaining confirmed the tissue clearing findings and suggested perineurium disruption as a means by which axons could traverse across fascicular boundaries. CONCLUSIONS: Sensory branches can transmit regenerating axons from donor nerves back to main mixed recipient nerves, then distally toward target organs. The extent of retrograde regeneration is markedly influenced by the type and severity of injury sustained by the recipient nerve. Using a sensory branch as a bridge for retrogradely regenerating axons can open new potential horizons in nerve repair surgery for severely injured mixed nerves.

Cardio-Oncology Recommendations for Pediatric Oncology Patients: An Australian and New Zealand Delphi Consensus.

Cardio-oncology is a new multidisciplinary area of expertise that seeks to pre-emptively and proactively address cardiac complications that emerge during and following cancer therapy. Modern therapies including molecular targeted therapy and immunotherapy have broadened the agents that can cause cardiac sequelae, often with complications arising within days to weeks of therapy. Several international guidelines have been developed for the acute monitoring of cardio-oncology side effects. However, none are specific to pediatrics. We have addressed this gap in the literature by undertaking a rigorous Delphi consensus approach across 11 domains of cardio-oncology care using an Australian and New Zealand expert group. The expert group consisted of pediatric and adult cardiologists and pediatric oncologists. This Delphi consensus provides an approach to perform risk and baseline assessment, screening, and follow-up, specific to the cancer therapeutic. This review is a useful tool for clinicians involved in the cardio-oncology care of pediatric oncology patients.

The Australia and New Zealand Cardio-Oncology Registry: evaluation of chemotherapy-related cardiotoxicity in a national cohort of paediatric cancer patients.

Cancer therapy related cardiac dysfunction (CTRCD) is an area of increasing focus, particularly during the survivorship period, for paediatric, adolescent and adult cancer survivors. With the advent of immunotherapy and targeted therapy, there is a new set of mechanisms from which paediatric and young adult patients with cancer may suffer cardiovascular injury. Furthermore, cardiovascular disease is the leading cause of morbidity and mortality in the survivorship period. The recently established Australian Cardio-Oncology Registry is the largest and only population-based cardiotoxicity database of paediatric and adolescent and young adult oncology patients in the world, and the first paediatric registry that will document cardiotoxicity caused by chemotherapy and novel targeted therapies using a prospective approach. The database is designed for comprehensive data collection and evaluation of the Australian practice in terms of diagnosis and management of CTRCD. Using the Australian Cardio-Oncology Registry critical clinical information will be collected regarding predisposing factors for the development of CTRCD, the rate of subclinical left ventricular dysfunction and transition to overt heart failure, further research into protectant molecules against cardiac dysfunction and aid in the discovery of which genetic variants predispose to CTRCD. A health economic arm of the study will assess the cost/benefit of both the registry and cardio-oncology clinical implementation. Finally, an imaging arm will establish if exercise cardiac magnetic resonance imaging and VO2 max testing is a more sensitive predictor of cardiac reserve in paediatric and adolescent and young adult oncology patients exposed to cardiac toxic therapies.

Exercise cardiovascular magnetic resonance reveals reduced cardiac reserve in pediatric cancer survivors with impaired cardiopulmonary fitness.

BACKGROUND: Pediatric cancer survivors are at increased risk of cardiac dysfunction and heart failure. Reduced peak oxygen consumption (peak VO2) is associated with impaired cardiac reserve (defined as the increase in cardiac function from rest to peak exercise) and heart failure risk, but it is unclear whether this relationship exists in pediatric cancer survivors. This study sought to investigate the presence of reduced peak VO2 in pediatric cancer survivors with increased risk of heart failure, and to assess its relationship with resting cardiac function and cardiac haemodynamics and systolic function during exercise. METHODS: Twenty pediatric cancer survivors (8-24 years; 10 male) treated with anthracycline chemotherapy ± radiation underwent cardiopulmonary exercise testing to quantify peak VO2, with a value < 85% of predicted defined as impaired peak VO2. Resting cardiac function was assessed using 2- and 3-dimensional echocardiography, with cardiac reserve quantified from resting and peak exercise heart rate, stroke volume index (SVI) and cardiac index (CI) using exercise cardiovascular magnetic resonance (CMR). RESULTS: Twelve of 20 survivors (60%) had reduced peak VO2 (70 ± 16% vs. 97 ± 14% of age and gender predicted). There were no differences in echocardiographic or CMR measurements of resting cardiac function between survivors with normal or impaired peak VO2. However, those with reduced peak VO2 had diminished cardiac reserve, with a lesser increase in CI and SVI during exercise (Interaction P < 0.01 for both), whilst the heart rate response was similar (P = 0.71). CONCLUSIONS: Whilst exercise intolerance is common among pediatric cancer survivors, it is poorly explained by resting measures of cardiac function. In contrast, impaired exercise capacity is associated with impaired haemodynamics and systolic functional reserve measured during exercise. Consequently, measures of cardiopulmonary fitness and cardiac reserve may aid in early identification of survivors with heightened risk of long-term heart failure.

Evaluating anthracycline cardiotoxicity associated single nucleotide polymorphisms in a paediatric cohort with early onset cardiomyopathy.

BACKGROUND: Anthracyclines are a mainstay of chemotherapy. However, a relatively frequent adverse outcome of anthracycline treatment is cardiomyopathy. Multiple genetic studies have begun to dissect the complex genetics underlying cardiac sensitivity to the anthracycline drug class. A number of single nucleotide polymorphisms (SNPs) have been identified to be in linkage disequilibrium with anthracycline induced cardiotoxicity in paediatric populations. METHODS: Here we screened for the presence of SNPs resulting in a missense coding change in a cohort of children with early onset chemotherapy related cardiomyopathy. The SNP identity was evaluated by Sanger sequencing of PCR amplicons from genomic DNA of patients with anthracycline related cardiac dysfunction. RESULTS: All of the published SNPs were observed within our patient group. There was no correlation between the number of missense variants an individual carried with severity of disease. Furthermore, the time to cardiac disease onset post-treatment was not greater in those individuals carrying a high load of SNPs resulting from missense variants. CONCLUSIONS: We conclude that previously identified missense SNPs are present within a paediatric cohort with early onset heart damage induced by anthracyclines. However, these SNPs require further replication cohorts and functional validation before being deployed to assess anthracycline cardiotoxicity risk in the clinic.

Stem cell topography splits growth and homeostatic functions in the fish gill.

While lower vertebrates contain adult stem cells (aSCs) that maintain homeostasis and drive un-exhaustive organismal growth, mammalian aSCs display mainly the homeostatic function. Here, we use lineage analysis in the medaka fish gill to address aSCs and report separate stem cell populations for homeostasis and growth. These aSCs are fate-restricted during the entire post-embryonic life and even during re-generation paradigms. We use chimeric animals to demonstrate that p53 mediates growth coordination among fate-restricted aSCs, suggesting a hierarchical organisation among lineages in composite organs like the fish gill. Homeostatic and growth aSCs are clonal but differ in their topology; modifications in tissue architecture can convert the homeostatic zone into a growth zone, indicating a leading role for the physical niche defining stem cell output. We hypothesise that physical niches are main players to restrict aSCs to a homeostatic function in animals with fixed adult size.

Pediatric Anthracycline-Induced Cardiotoxicity: Mechanisms, Pharmacogenomics, and Pluripotent Stem-Cell Modeling.

Anthracycline-induced cardiotoxicity (ACT) is a severe adverse drug reaction for a subset of children treated with anthracyclines as part of chemotherapy protocols. The identification of genetic markers associated with increased ACT susceptibility has clinical significance toward improving patient care and our understanding of the molecular mechanisms involved in ACT. Human-induced pluripotent stem cell-derived cardiomyocytes represent a novel approach to determine the pharmacogenomics of ACT and guide the development of genetic screening tests.

Underutilization of the CROSS Regimen Among US Radiation Oncologists: A National Survey of Practice Patterns.

AIM: To examine patterns of clinical practice in locally advanced esophageal cancer among US radiation oncologists after publication of the CROSS trial. MATERIALS AND METHODS: US radiation oncologists were surveyed on 13 questions pertaining to the management of esophageal cancer. Respondents' demographics and their clinical rationale were analyzed for statistical association with their treatment recommendations. RESULTS: Few respondents (15%) offered the CROSS regimen to patients considered suitable surgical candidates, while a near-equivalent number (16%) prescribed between 41.4 and 50.4 Gy contingent upon radiation planning parameters. Among respondents who prescribed 50.4 Gy, 50% and 17% reported concurrent administration of carboplatin/paclitaxel and cisplatin/5-FU, respectively. Higher radiation doses, over 50.4 Gy, were utilized by 15% and 38% of respondents for borderline surgical candidates and candidates unfit for surgery, respectively. The majority of respondents believed that higher complete pathological response and R0 resection would be achieved, as well as higher toxicity conferred using 50.4 Gy instead of 41.4 Gy. A clinical trial comparing 41.4 Gy to 50.4 Gy with concurrent carboplatin/paclitaxel was supported by 76% of respondents. CONCLUSION: Despite results from the CROSS trial, the majority of responding US radiation oncologists do not offer 41.4 Gy with concurrent chemotherapy for surgically-fit patients with locally advanced esophageal cancer, believing that a higher dose will translate to improved response.