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The evolution of drug-resistant cell subpopulations causes cancer treatment failure. Current preclinical evidence shows that it is possible to model herding of clonal evolution and collateral sensitivity where an initial treatment could favourably influence the response to a subsequent one. Novel therapy strategies exploiting this understanding are being considered, and clinical trial designs for steering cancer evolution are needed. Furthermore, preclinical evidence suggests that different subsets of drug-sensitive and resistant clones could compete between themselves for nutrients/blood supply, and clones that populate a tumour do so at the expense of other clones. Treatment paradigms based on this clinical application of exploiting cell-cell competition include intermittent dosing regimens or cycling different treatments before progression. This will require clinical trial designs different from the conventional practice of evaluating responses to individual therapy regimens. Next-generation sequencing to assess clonal dynamics longitudinally will improve current radiological assessment of clinical response/resistance and be incorporated into trials exploiting evolution. Furthermore, if understood, clonal evolution can be used to therapeutic advantage, improving patient outcomes based on a new generation of clinical trials., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Limited evidence exists regarding the cost and health-related quality of life (HRQoL) effects of non-muscle-invasive bladder cancer (NMIBC) recurrence and progression to muscle-invasive bladder cancer (MIBC). We examined these effects using evidence from a recent randomized control trial., Material and Methods: The costs and HRQoL associated with bladder cancer were assessed using data from the BOXIT trial (bladder COX-2 inhibition trial; n = 472). The cost and HRQoL effects from clinical events were estimated using generalized estimating equations. The costs were derived from the recorded resource usage and UK unit costs. HRQoL was assessed using the EQ-5D-3L and reported UK preference tariffs. The events were categorized using the TMN classification., Results: Cases of grade 3 recurrence and progression were associated with statistically significant HRQoL decrements (-0.08; 95% confidence interval [CI], -0.13 to -0.03; and -0.10; 95% CI, -0.17 to -0.03, respectively). The 3-year average cost per NMIBC patient was estimated at £8735 (95% CI, 8325-9145). Cases of grade 1, 2, and 3 recurrence were associated with annual cost effects of £1218 (95% CI, 403-2033), £1677 (95% CI, 920-2433), and £3957 (95% CI, 2332-5583), respectively. Progression to MIBC was associated with an average increase in costs of £5407 (95% CI, 2663-8152)., Conclusion: Evidence from the BOXIT trial suggests that patients with NMIBC will both experience decrements in HRQoL and incur significant costs, especially in the event of a grade 3 recurrence or a progression to MIBC., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Activation of the PI3K/AKT/mTOR pathway through loss of phosphatase and tensin homolog (PTEN) occurs in approximately 50% of patients with metastatic castration-resistant prostate cancer (mCRPC). Recent evidence suggests that combined inhibition of the androgen receptor (AR) and AKT may be beneficial in mCRPC with PTEN loss., Patients and Methods: mCRPC patients who previously failed abiraterone and/or enzalutamide, received escalating doses of AZD5363 (capivasertib) starting at 320 mg twice daily (b.i.d.) given 4 days on and 3 days off, in combination with enzalutamide 160 mg daily. The co-primary endpoints were safety/tolerability and determining the maximum tolerated dose and recommended phase II dose; pharmacokinetics, antitumour activity, and exploratory biomarker analysis were also evaluated., Results: Sixteen patients were enrolled, 15 received study treatment and 13 were assessable for dose-limiting toxicities (DLTs). Patients were treated at 320, 400, and 480 mg b.i.d. dose levels of capivasertib. The recommended phase II dose identified for capivasertib was 400 mg b.i.d. with 1/6 patients experiencing a DLT (maculopapular rash) at this level. The most common grade ≥3 adverse events were hyperglycemia (26.7%) and rash (20%). Concomitant administration of enzalutamide significantly decreased plasma exposure of capivasertib, though this did not appear to impact pharmacodynamics. Three patients met the criteria for response (defined as prostate-specific antigen decline ≥50%, circulating tumour cell conversion, and/or radiological response). Responses were seen in patients with PTEN loss or activating mutations in AKT, low or absent AR-V7 expression, as well as those with an increase in phosphorylated extracellular signal-regulated kinase (pERK) in post-exposure samples., Conclusions: The combination of capivasertib and enzalutamide is tolerable and has antitumour activity, with all responding patients harbouring aberrations in the PI3K/AKT/mTOR pathway., Clinical Trial Number: NCT02525068., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Appropriate post-natal growth remains a mainstay of therapeutic goals for infants with CDH, with the hypothesis that optimizing linear growth will improve survival through functional improvements in pulmonary hypoplasia. However, descriptions of growth and the effect on survival are limited in affected infants., Objective: Describe in-hospital weight gain related to survival among infants with CDH., Design/methods: Children's Hospitals Neonatal Database (CHND) identified infants with CDH born ≥34weeks' gestation (2010-14). Exclusion criteria were: admission age>7days, death/discharge age<14days, or surgical CDH repair prior to admission. Weight gain velocity (WGV: g/kg/day) was calculated using an established exponential approximation and the cohort stratified by Q1: <25%ile, Q2-3: 25-75%ile, and Q4: >75%ile. Descriptive measures and unadjusted Kaplan-Meier analyses describe the implications of WGV on mortality/discharge., Results: In 630 eligible infants, median WGV was 4.6g/kg/day. After stratification by WGV [Q1: (n=156; <3.1g/kg/day); Q2-3 (n=316; 3.1-5.9g/kg/day), and Q4 (n=158, >5.9g/kg/day)] infants in Q1 had shortest median length of stay, less time on TPN and intervention for gastro-esophageal reflux relative to the other WGV strata (p<0.01 for all). Unadjusted survival estimates revealed that Q1 [hazard ratio (HR)=9.5, 95% CI: 5.7, 15.8] and Q4 [HR=2.9, 95% CI: 1.7, 5.1, p<0.001 for both] WGV were strongly associated with NICU mortality relative to Q2-3 WGV., Conclusion: Variable WGV is evident in infants with CDH. Highest and lowest WGV appear to be related to adverse outcomes. Efforts are needed to develop nutritional strategies targeting optimal growth., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Cancer is one of the main causes of death in Western countries, and a major issue for human health. Prolonged exposure to a number of chemicals was observed to be one of the primary causes of cancer in occupationally exposed persons. Thus, the development of tools for identifying hazardous chemicals and the increase of mechanistic understanding of their toxicity is a major goal for scientific research. We constructed a new knowledge-based expert system accounting the effect of different substituents for the prediction of mutagenicity (Ames test) of aromatic amines, a class of compounds of major concern because of their widespread application in industry. The herein presented model implements a series of user-defined structural rules extracted from a database of 616 primary aromatic amines, with their Ames test outcomes, aimed at identifying mutagenic and non-mutagenic chemicals. The chemical rationale behind such rules is discussed. Besides assessing the model's ability to correctly classify aromatic amines, its predictivity was further evaluated on a second database of 354 azo dyes, another class of chemicals of major concern, whose toxicity has been predicted on the basis of the toxicity of aromatic amines potentially generated from the metabolic reduction of the azo bond. Good performance in classification on both the amine (MCC, Matthews Correlation Coefficient=0.743) and the azo dye (MCC=0.584) datasets confirmed the predictive power of the model, and its suitability for use on a wide range of chemicals. Finally, the model was compared with a series of well-known mutagenicity predicting software. The good performance of our model compared with other mutagenicity models, especially in predicting azo dyes, confirmed the usefulness of this expert system as a reliable support to in vitro mutagenicity assays for screening and prioritization purposes. The model has been fully implemented as a KNIME workflow and is freely available for downstream users., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease of infancy, and BPD-associated pulmonary hypertension (PH) is a serious complication that can negatively impact later childhood health. There is growing evidence that lung injury leading to BPD and PH is due to chronic fetal hypoxia-ischemia. The purpose of this study was to investigate whether placental pathologic changes of maternal vascular underperfusion (MVU) are associated with BPD, and further increased with PH., Methods: We conducted a 5-year retrospective cohort study of premature infants born ≤28 weeks. BPD was defined as persistent oxygen requirement at 36 weeks corrected gestational age. PH was identified using a standardized algorithm of echocardiogram review. Archived placental slides underwent standardized masked histopathologic review. Logistic regression modeling was performed, taking into account important maternal and infant covariates., Results: Among 283 births, 121 had MVU, of which 67 (55%) developed BPD, and 24 (20%) had PH. Among the common neonatal complications of extreme prematurity, BPD was the only outcome that was increased with MVU (P < 0.001). After adjustment for birth weight, fetal growth restriction, preeclampsia and other factors, infants with MVU were more likely to develop BPD (adjusted odds ratio = 2.6; 95% confidence interval = 1.4, 4.8). Certain MVU sublesions (fibrinoid necrosis/acute atherosis and distal villous hypoplasia/small terminal villi) were increased with PH (P < 0.001)., Discussion: Placental MVU may identify BPD infants who were exposed to intrauterine hypoxia-ischemia, which increases their risk for development of PH disease., Conclusions: Our findings have important implications for providing earlier and more effective therapies for BPD., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Kidney allograft interstitial fibrosis and tubular atrophy (IF/TA) is associated with a poorer renal function and outcome. In the current clinical practice, an early diagnosis can only be provided by invasive tests. We aimed to investigate the association of sterile leukocyturia with Banff criteria histological findings in kidney allograft protocol biopsies. We studied 348 allograft biopsies from two different European countries performed at 8.5 + 3.5 months after transplantation. In these cases, the presence of sterile leukocyturia (Leuc+, n = 70) or no leukocyturia (Leuc-, n = 278) was analyzed and related to Banff elementary lesions. Only IF/TA was significantly different between Leuc+ and Leuc- groups. IF/TA was present in 85.7% of Leuc+ and 27.7% of Leuc- patients (p < 0.001). IF/TA patients had higher serum creatinine and presence of proteinuria (p < 0.05). Independent predictors of IF/TA were donor age, donor male sex, serum creatinine and Leuc+ (hazard ratio 18.2; 95% confidence interval, 8.1-40.7). The positive predictive value of leukocyturia for predicting IF/TA was 85.7% whereas the negative predictive value was 72.3%. These studies suggest that leukocyturia is a noninvasive and low-cost test to identify IF/TA. An early diagnosis may allow timely interventional measures directed to minimize its impact and improve graft outcome., (© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.)

In our old-for-old program, we discard or allocate older extended criteria donor kidneys to single (SKT) or dual kidney transplantation (DKT) depending on histological Remuzzi's score in recipients older than 60 years. Here, we analyze the long-term results of this program and try to identify independent predictors of patient and graft survival. Between December 1996 and January 2008, we performed 115 SKT and 88 DKT. Discard rate was 15%. Acute rejection incidence was higher in SKT than in DKT (22.6% vs. 11.4%, p = 0.04). Renal function was better in DKT than in SKT up to 5 years after transplantation. Surgical complications were frequent in DKT. Ten-year cumulative graft survival was significantly lower in the SKT group (31% vs. 53%, p = 0.03). In SKT, histological score 4 provided similar graft survival than 3 or less, whereas in DKT score 4, 5 or 6 displayed similar outcome. Finally, independent predictors of graft survival were history of major adverse cardiac event and 1-year serum creatinine, rather than SKT or DKT. In conclusion, this biopsy-guided old-for-old strategy resulted in acceptable long-term graft survival. Our results suggest that DKT should be considered for scores of 5 or 6 only., (© Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.)

The ketogenic diet (KD) and the modified Atkins diet are effective therapies for intractable epilepsy. We compared retrospectively the KD and modified Atkins diet in 27 children and also assessed serum long chain fatty acid profiles. After 3 months, using an intent-to-treat analysis, the KD was more successful, with >50% seizure reduction in 11/17 (65%) vs. 2/10 (20%) with the modified Atkins diet, p=0.03. After 6 months, however, the difference was no longer significant: 7/17 (41%) vs. 2/10 (20%) (p=0.24). We observed a preventive effect of both diets on the occurrence of status epilepticus. After 1 and 3 months of either diet, responders experienced a significant decrease in serum arachidonic acid concentration compared to non-responders. The KD and modified Atkins diet led to seizure reduction in this small pilot series, with slightly better results after 3 months with the KD, but not after 6 months. The decrease of serum arachidonic acid levels might be involved in the anticonvulsive effects of KD or modified Atkins diet.

Objective: To quantify the degree of disagreement between the two most popular methods for dealing with missing data: intention to treat (ITT) and per protocol (PP)., Study Design and Setting: We performed a systematic review of randomized two-armed clinical trials (CTs) published between 2001 and 2003, abstracted in PubMed and reporting both the ITT and PP analyses on a primary binary endpoint, out of which 74 papers were finally selected. The treatment effect of each CT was measured by the odds ratio, and the disagreement between them was quantified by the Bland-Altman method., Results: On average, the PP estimator provides greater values Log(e)ORPP=1 x 25.Log(e)ORITT, (95% CI: 1.15, 1.35) than the corresponding ITT estimator, although the limits of concordance showed that the ratio between the two estimators varies greatly from 0.39 up to 2.53., Conclusion: These results confirm that missing values may cause both systematic and unpredictable bias in CTs. Further efforts should be made to minimize protocol deviations and to use better statistical methods to highlight the drawbacks of missing information. In the presence of protocol deviations, the conclusion of a CT cannot rest on the single reporting of either the ITT or the PP approach alone.