Oncology phase I trial design and conduct: time for a change - MDICT Guidelines 2022.

In 2021, the Food and Drug Administration Oncology Center of Excellence announced Project Optimus focusing on dose optimization for oncology drugs. The Methodology for the Development of Innovative Cancer Therapies (MDICT) Taskforce met to review and discuss the optimization of dosage for oncology trials and to develop a practical guide for oncology phase I trials. Defining a single recommended phase II dose based on toxicity may define doses that are neither the most effective nor the best tolerated. MDICT recommendations address the need for robust non-clinical data which are needed to inform trial design, as well as an expert team including statisticians and pharmacologists. The protocol must be flexible and adaptive, with clear definition of all endpoints. Health authorities should be consulted early and regularly. Strategies such as randomization, intrapatient dose escalation, and real-world eligibility criteria are encouraged whereas serial tumor sampling is discouraged in the absence of a strong rationale and appropriately validated assay. Endpoints should include consideration of all longitudinal toxicity. The phase I dose escalation trial should define the recommended dose range for later testing in randomized phase II trials, rather than a single recommended phase II dose, and consider scenarios where different populations may require different dosages. The adoption of these recommendations will improve dosage selection in early clinical trials of new anticancer treatments and ultimately, outcomes for patients.

Association between morbidity among term newborns and low-risk caesarean delivery rates.

OBJECTIVE: To examine the association between county-level caesarean delivery (CD) rates among women at low risk and morbidity among term newborns. DESIGN: Cross-sectional study. SETTING: Population-based study of US county-level birth data from 2015 to 2017. POPULATION: Nulliparous women with term, singleton, vertex-presenting infants (NTSV) at low risk for morbidity. METHODS: The primary exposure was county-level CD rates. MAIN OUTCOME MEASURES: The outcome was morbidity among the low-risk NTSV cohort, categorised as severe (5-minute Apgar score of ≤3, assisted ventilation for ≥6 hours, severe neurologic injury or seizure, transfer or death) or moderate (5-minute Apgar score of <7 but >3, administration of antibiotics or assisted ventilation at delivery). We used linear regression models to determine the association between county NTSV CD and neonatal morbidity rates with cluster robust standard errors. RESULTS: The analysis included data from 2 753 522 births in 952 counties from all 48 states. The mean NTSV CD rate was 23.6% (standard deviation 4.8%). The median severe and moderate neonatal morbidity rates were 15.2 (interquartile range, IQR 9.4-23.6) and 52.5 (IQR 33.4-75.7) per 1000 births, respectively. In the unadjusted analysis using the risk-adjusted exposure and outcome, every percentage point increase in the CD rate of a county was associated with 0.6 (95% CI -0.9, -0.3) and 2.3 fewer (95% CI -3.4, -1.1) cases of severe and moderate neonatal morbidity per 1000 live births. After adjustment for other county factors, the relationships remained significant. These findings were tested in multiple sensitivity analyses. CONCLUSIONS: Lower county-level NTSV CD rates were associated with a small increase in morbidity among term newborns in the USA. TWEETABLE ABSTRACT: Lower county-level caesarean delivery rates were associated with an increase in morbidity among term newborns in the USA.

The impact of different hair-removal behaviours on the biophysical and biochemical characteristics of female axillary skin.

OBJECTIVE: The impact of hair removal on the biophysical and biochemical characteristics of human axillary skin is not fully understood. This study investigated the effect of different hair-removal techniques on biophysical parameters and the concentrations of key inflammatory biomarkers in the axillae of female Thai subjects. Axillary hair was removed by shaving, plucking or waxing. METHODS: Following a 2-week washout phase without hair removal, subjects underwent visual assessment for erythema and skin dryness in one (randomized) axilla, then, hair was removed from the axilla by shaving, plucking or waxing according to each subject's established habit. Erythema and dryness were assessed again 30 min after hair removal, and buffer scrubs collected from depilated and non-depilated axillae and analysed for inflammatory cytokines; after a further 48 h, erythema, dryness and post-inflammatory hyperpigmentation (PIHP) were assessed in the depilated axilla. Biophysical assessments (skin hydration, barrier integrity, elasticity and roughness) were made in depilated and non-depilated axillae. RESULTS: All three hair-removal techniques induced an increase in axillary erythema and skin dryness. Shaving was associated with significantly less erythema (P < 0.01), but significantly greater skin dryness (P < 0.05) versus the other techniques 30 min after hair removal. There were no between-technique differences in PIHP or biophysical parameters. Interleukins IL-1α and IL-1RA concentrations increased, and IL-8 concentration decreased following hair removal by each technique. CONCLUSION: This is the first study to identify the principal cytokines associated with the inflammatory process triggered by axillary hair removal. A single hair-removal treatment did not appear to induce PIHP or further biophysical changes to the skin.

OBJECTIF: L'impact de l'épilation sur les caractéristiques biophysiques et biochimiques de la peau axillaire humaine n'est pas entièrement compris. Cette étude a examiné l'effet de différentes techniques d'épilation sur les paramètres biophysiques et les concentrations de biomarqueurs inflammatoires clés dans les aisselles de sujets thaïlandais de sexe féminin. Les aisselles ont été épilées par rasage, à la pince ou à la cire. MÉTHODES: Après une phase de sevrage de 2 semaines sans épilation, les sujets ont subi une évaluation visuelle de l'érythème et de la sécheresse cutanée dans une aisselle (randomisé), puis l'aisselle a été épilée par rasage, à la pince ou à la cire selon l'habitude établie de chaque sujet. L'érythème et la sécheresse ont été évalués à nouveau 30 minutes après l'épilation, et des frottis tampons ont été prélevés dans les aisselles épilées et non épilées et analysés pour détecter les cytokines inflammatoires; puis, après 48 heures, l'érythème, la sécheresse et l'hyperpigmentation post-inflammatoire (PIHP) ont été évalués dans les aisselles épilées. Des évaluations biophysiques (hydratation cutanée, intégrité de la barrière cutanée, élasticité et rugosité de la peau) ont été réalisées sur les aisselles épilées et non épilées. RÉSULTATS: Les trois techniques d'épilation ont entraîné une accentuation de l'érythème axillaire et de la sécheresse de la peau. Le rasage a été associé à un érythème nettement moins important (P < 0,01), mais à une sécheresse cutanée nettement plus importante (P < 0,05) par rapport aux autres techniques 30 min après l'épilation. Aucune différence entre les techniques n'a été observée en ce qui concerne le PIHP ou les paramètres biophysiques. Les concentrations en interleukines IL-1α IL-1RA ont augmenté, et la concentration en IL-8 a diminué après l'épilation par chaque technique. CONCLUSION: Cette étude est la première à identifier les cytokines principales associées au processus inflammatoire déclenché par l'épilation des aisselles. Une seule épilation n'a pas semblé entraîner de PIHP ou d'autres modifications biophysiques de la peau.

Usp9X Regulates Cell Death in Malignant Peripheral Nerve Sheath Tumors.

Malignant peripheral nerve sheath tumors (MPNSTs) are the leading cause of death in neurofibromatosis type 1 (NF1) patients. Current treatment modalities have been largely unsuccessful in improving MPNST patient survival, making the identification of new therapeutic targets urgent. In this study, we found that interference with Usp9X, a deubiquitinating enzyme which is overexpressed in nervous system tumors, or Mcl-1, an anti-apoptotic member of the Bcl-2 family whose degradation is regulated by Usp9X, causes rapid death in human MPNST cell lines. Although both Usp9X and Mcl-1 knockdown elicited some features of apoptosis, broad spectrum caspase inhibition was ineffective in preventing knockdown-induced MPNST cell death suggesting that caspase-independent death pathways were also activated. Ultrastructural examination of MPNST cells following either Usp9X interference or pharmacological inhibition showed extensive cytoplasmic vacuolization and swelling of endoplasmic reticulum (ER) and mitochondria most consistent with paraptotic cell death. Finally, the Usp9X pharmacological inhibitor WP1130 significantly reduced human MPNST growth and induced tumor cell death in an in vivo xenograft model. In total, these findings indicate that Usp9X and Mcl-1 play significant roles in maintaining human MPNST cell viability and that pharmacological inhibition of Usp9X deubiquitinase activity could be a therapeutic target for MPNST treatment.

Correction to: Cardiopulmonary exercise testing (CPET) in the United Kingdom-a national survey of the structure, conduct, interpretation and funding.

[This corrects the article DOI: 10.1186/s13741-017-0082-3.].

Cardiopulmonary exercise testing (CPET) in the United Kingdom-a national survey of the structure, conduct, interpretation and funding.

BACKGROUND: Cardiopulmonary exercise testing (CPET) is an exercise stress test with concomitant expired gas analysis that provides an objective, non-invasive measure of functional capacity under stress. CPET-derived variables predict postoperative morbidity and mortality after major abdominal and thoracic surgery. Two previous surveys have reported increasing utilisation of CPET preoperatively in England. We aimed to evaluate current CPET practice in the UK, to identify who performs CPET, how it is performed, how the data generated are used and the funding models. METHODS: All anaesthetic departments in trusts with adult elective surgery in the UK were contacted by telephone to obtain contacts for their pre-assessment and CPET service leads. An online survey was sent to all leads between November 2016 and March 2017. RESULTS: The response rate to the online survey was 73.1% (144/197) with 68.1% (98/144) reporting an established clinical service and 3.5% (5/144) setting up a service. Approximately 30,000 tests are performed a year with 93.0% (80/86) using cycle ergometry. Colorectal surgical patients are the most frequently tested (89.5%, 77/86). The majority of tests are performed and interpreted by anaesthetists. There is variability in the methods of interpretation and reporting of CPET and limited external validation of results. CONCLUSIONS: This survey has identified the continued expansion of perioperative CPET services in the UK which have doubled since 2011. The vast majority of CPET tests are performed and reported by anaesthetists. It has highlighted variation in practice and a lack of standardised reporting implying a need for practice guidelines and standardised training to ensure high-quality data to inform perioperative decision making.

The effect of intensive care unit admission on smokers' attitudes and their likelihood of quitting smoking.

We sought to estimate the proportion of patients admitted to a metropolitan intensive care unit (ICU) who were current smokers, and the relationships between ICU survivors who smoked and smoking cessation and/or reduction six months post-ICU discharge. We conducted a prospective cohort study at a metropolitan level III ICU in Melbourne, Victoria. One hundred consecutive patients who met the inclusion criteria were included in the study. Inclusion criteria consisted of patients who were smokers at time of ICU admission, had an ICU length of stay greater than one day, survived to ICU discharge, and provided written informed consent. A purpose-designed questionnaire which included the Fagerstrom test for nicotine dependence and evaluation of patients' attitude towards smoking cessation was completed by participants following ICU discharge and prior to hospital discharge. Participants were re-interviewed over the phone at six months post-ICU discharge. Of the 1,062 patients admitted to ICU, 253 (23%) were current smokers and 100 were enrolled. Six months post-ICU discharge, 28 (33%) of the 86 participants who were alive and contactable had quit smoking and 35 (41%) had reduced smoking. The median number of reported cigarettes smoked per day reduced by 40%. Participants who initially believed their ICU admission was smoking-related were more likely to have quit six months post-ICU discharge (odds ratio 2.98; 95% confidence interval 1.07 to 8.26; P=0.036). Six months post-ICU discharge, 63/86 (74%) of participants had quit or reduced their smoking. Further research into targeted smoking cessation counselling for ICU survivors is indicated.

Paleoecology and paleoceanography of the Athel silicilyte, Ediacaran-Cambrian boundary, Sultanate of Oman.

The Athel silicilyte is an enigmatic, hundreds of meters thick, finely laminated quartz deposit, in which silica precipitated in deep water (>~100-200 m) at the Ediacaran-Cambrian boundary in the South Oman Salt Basin. In contrast, Meso-Neoproterozoic sinks for marine silica were dominantly restricted to peritidal settings. The silicilyte is known to contain sterane biomarkers for demosponges, which today are benthic, obligately aerobic organisms. However, the basin has previously been described as permanently sulfidic and time-equivalent shallow-water carbonate platform and evaporitic facies lack silica. The Athel silicilyte thus represents a unique and poorly understood depositional system with implications for late Ediacaran marine chemistry and paleoecology. To address these issues, we made petrographic observations, analyzed biomarkers in the solvent-extractable bitumen, and measured whole-rock iron speciation and oxygen and silicon isotopes. These data indicate that the silicilyte is a distinct rock type both in its sedimentology and geochemistry and in the original biology present as compared to other facies from the same time period in Oman. The depositional environment of the silicilyte, as compared to the bounding shales, appears to have been more reducing at depth in sediments and possibly bottom waters with a significantly different biological community contributing to the preserved biomarkers. We propose a conceptual model for this system in which deeper, nutrient-rich waters mixed with surface seawater via episodic mixing, which stimulated primary production. The silica nucleated on this organic matter and then sank to the seafloor, forming the silicilyte in a sediment-starved system. We propose that the silicilyte may represent a type of environment that existed elsewhere during the Neoproterozoic. These environments may have represented an important locus for silica removal from the oceans.

ANG1005 for breast cancer brain metastases: correlation between 18F-FLT-PET after first cycle and MRI in response assessment.

PURPOSE: Improved therapies and imaging modalities are needed for the treatment of breast cancer brain metastases (BCBM). ANG1005 is a drug conjugate consisting of paclitaxel covalently linked to Angiopep-2, designed to cross the blood-brain barrier. We conducted a biomarker substudy to evaluate 18F-FLT-PET for response assessment. METHODS: Ten patients with measurable BCBM received ANG1005 at a dose of 550 mg/m2 IV every 21 days. Before and after cycle 1, patients underwent PET imaging with 18F-FLT, a thymidine analog, retention of which reflects cellular proliferation, for comparison with gadolinium-contrast magnetic resonance imaging (Gd-MRI) in brain metastases detection and response assessment. A 20 % change in uptake after one cycle of ANG1005 was deemed significant. RESULTS: Thirty-two target and twenty non-target metastatic brain lesions were analyzed. The median tumor reduction by MRI after cycle 1 was -17.5 % (n = 10 patients, lower, upper quartiles: -25.5, -4.8 %) in target lesion size compared with baseline. Fifteen of twenty-nine target lesions (52 %) and 12/20 nontarget lesions (60 %) showed a ≥20 % decrease post-therapy in FLT-PET SUV change (odds ratio 0.71, 95 % CI: 0.19, 2.61). The median percentage change in SUVmax was -20.9 % (n = 29 lesions; lower, upper quartiles: -42.4, 2.0 %), and the median percentage change in SUV80 was also -20.9 % (n = 29; lower, upper quartiles: -49.0, 0.0 %). Two patients had confirmed partial responses by PET and MRI lasting 6 and 18 cycles, respectively. Seven patients had stable disease, receiving a median of six cycles. CONCLUSIONS: ANG1005 warrants further study in BCBM. Results demonstrated a moderately strong association between MRI and 18F-FLT-PET imaging.

Questioning the use of an age-adjusted D-dimer threshold to exclude venous thromboembolism: analysis of individual patient data from two diagnostic studies.

Essentials It is unclear if raising the D-dimer level to exclude venous thrombosis in older patients is valid. We compared this 'age-adjusted' strategy with other ways of interpreting D-dimer results. A non-age adjusted increase, and using higher thresholds in younger patients, was just as accurate. Age-adjustment of D-dimer thresholds does not appear to be appropriate. Click to hear Prof. le Gal's presentation on controversies in venous thromboembolism diagnosis SUMMARY: Background Using a progressively higher D-dimer level to exclude venous thromboembolism (VTE) with increasing age has been proposed but is not well validated. Objective To determine whether it is appropriate to use a progressively higher D-dimer level to exclude VTE with increasing age. Patients/methods We analyzed clinical data and blood samples from 1649 patients with a first suspected deep vein thrombosis or pulmonary embolism. We compared the negative predictive values (NPVs) for VTE, and the proportions of patients with a negative D-dimer result, by using three D-dimer interpretation strategies: a progressively higher D-dimer threshold with increasing age (age-adjusted strategy); the same higher D-dimer threshold in all patients (mean D-dimer strategy); and a progressively higher D-dimer threshold with decreasing age (inverse age-adjusted strategy). Results The NPV with the age-adjusted strategy (99.6%; 95% confidence interval [CI] 99.0-99.9%) was not different from that with the mean D-dimer strategy (99.7%; 95% CI 99.0-99.9%) or that with the inverse age-adjusted strategy (99.8%; 95% CI 99.1-99.9%). The proportion of patients with a negative result with the age-adjusted strategy (50.9%; 95% CI 48.5-53.4%) was not different from the proportion of patients with a negative result with the mean D-dimer strategy (51.7%; 95% CI 49.3-54.1%) or with the inverse age-adjusted strategy (49.5%; 95% CI 47.1-51.9%). Conclusions Our analysis does not support the use of a progressively higher D-dimer level to exclude VTE with increasing age.

Rapid quantitative D-dimer to exclude pulmonary embolism: a prospective cohort management study.

UNLABELLED: ESSENTIALS: It is not known if D-dimer testing alone can safely exclude pulmonary embolism (PE). We studied the safety of using a quantitative latex agglutination D-dimer to exclude PE in 808 patients. 52% of patients with suspected PE had a negative D-dimer test and were followed for 3 months. The negative predictive value of D-dimer testing alone was 99.8%, suggesting it may safely exclude PE. BACKGROUND: Strategies are needed to exclude pulmonary embolism (PE) efficiently without the need for imaging tests. Although validated rules for clinical probability assessment can be combined with D-dimer testing to safely exclude PE, the rules can be complicated or partially subjective, which limits their use. OBJECTIVES: To determine if PE can be safely excluded in patients with a negative D-dimer without incorporating clinical probability assessment. PATIENTS/METHODS: We enrolled consecutive outpatients and inpatients with suspected PE from four tertiary care hospitals. All patients underwent D-dimer testing using the MDA D-dimer test, a quantitative latex agglutination assay. PE was excluded in patients with a D-dimer less than 750 µg FEU L(-1) without further testing. PATIENTS: with D-dimer levels of 750 µg FEU L(-1) or higher underwent standardized imaging tests for PE. All patients in whom PE was excluded had anticoagulant therapy withheld and were followed for 3 months for venous thromboembolism (VTE). Suspected events during follow-up were adjudicated centrally. RESULTS: Eight hundred and eight patients were enrolled, of whom 99 (12%) were diagnosed with VTE at presentation. Four hundred and twenty (52%) patients had a negative D-dimer level at presentation and were not treated with anticoagulants; of these, one had VTE during follow-up. The negative predictive value of D-dimer testing for PE was 99.8% (95% confidence interval, 98.7-99.9%). CONCLUSIONS: A negative latex agglutination D-dimer assay is seen in about one-half of patients with suspected PE and reliably excludes PE as a stand-alone test.

The linker region of breast cancer resistance protein ABCG2 is critical for coupling of ATP-dependent drug transport.

The ATP-binding cassette (ABC) transporters of class G display a different domain organisation than P-glycoprotein/ABCB1 and bacterial homologues with a nucleotide-binding domain preceding the transmembrane domain. The linker region connecting these domains is unique and its function and structure cannot be predicted. Sequence analysis revealed that the human ABCG2 linker contains a LSGGE sequence, homologous to the canonical C-motif/ABC signature present in all ABC nucleotide-binding domains. Predictions of disorder and of secondary structures indicated that this C2-sequence was highly mobile and located between an α-helix and a loop similarly to the C-motif. Point mutations of the two first residues of the C2-sequence fully abolished the transport-coupled ATPase activity, and led to the complete loss of cell resistance to mitoxantrone. The interaction with potent, selective and non-competitive, ABCG2 inhibitors was also significantly altered upon mutation. These results suggest an important mechanistic role for the C2-sequence of the ABCG2 linker region in ATP binding and/or hydrolysis coupled to drug efflux.

Exclusion of deep vein thrombosis using the Wells rule in clinically important subgroups: individual patient data meta-analysis.

OBJECTIVE: To assess the accuracy of the Wells rule for excluding deep vein thrombosis and whether this accuracy applies to different subgroups of patients. DESIGN: Meta-analysis of individual patient data. DATA SOURCES: Authors of 13 studies (n = 10,002) provided their datasets, and these individual patient data were merged into one dataset. ELIGIBILITY CRITERIA: Studies were eligible if they enrolled consecutive outpatients with suspected deep vein thrombosis, scored all variables of the Wells rule, and performed an appropriate reference standard. MAIN OUTCOME MEASURES: Multilevel logistic regression models, including an interaction term for each subgroup, were used to estimate differences in predicted probabilities of deep vein thrombosis by the Wells rule. In addition, D-dimer testing was added to assess differences in the ability to exclude deep vein thrombosis using an unlikely score on the Wells rule combined with a negative D-dimer test result. RESULTS: Overall, increasing scores on the Wells rule were associated with an increasing probability of having deep vein thrombosis. Estimated probabilities were almost twofold higher in patients with cancer, in patients with suspected recurrent events, and (to a lesser extent) in males. An unlikely score on the Wells rule (≤ 1) combined with a negative D-dimer test result was associated with an extremely low probability of deep vein thrombosis (1.2%, 95% confidence interval 0.7% to 1.8%). This combination occurred in 29% (95% confidence interval 20% to 40%) of patients. These findings were consistent in subgroups defined by type of D-dimer assay (quantitative or qualitative), sex, and care setting (primary or hospital care). For patients with cancer, the combination of an unlikely score on the Wells rule and a negative D-dimer test result occurred in only 9% of patients and was associated with a 2.2% probability of deep vein thrombosis being present. In patients with suspected recurrent events, only the modified Wells rule (adding one point for the previous event) is safe. CONCLUSION: Combined with a negative D-dimer test result (both quantitative and qualitative), deep vein thrombosis can be excluded in patients with an unlikely score on the Wells rule. This finding is true for both sexes, as well as for patients presenting in primary and hospital care. In patients with cancer, the combination is neither safe nor efficient. For patients with suspected recurrent disease, one extra point should be added to the rule to enable a safe exclusion.

Primary care and population factors associated with NHS Health Check coverage: a national cross-sectional study.

INTRODUCTION: High and equitable coverage of systematic cardiovascular disease (CVD) prevention programmes, such as the NHS Health Check programme in England, is essential if they are to effectively reduce the population CVD burden. METHODS: We conducted a cross-sectional study using data from 151 English primary care trusts (PCTs) on NHS Health Check coverage during 2011-12. We examined the associations between programme coverage and primary care and population factors, including patient demographics, primary care workforce and cardiovascular health need. RESULTS: Median coverage of NHS Health Checks was 8.2%, with wide PCT-level variation (range = 0-29.8%). Coverage was significantly higher in PCTs in the most deprived areas compared with the least deprived (P = 0.035), adjusting for covariates. Significant negative associations between coverage and a higher proportion of PCT population aged 40-74 years-the eligible Health Check age group, a larger total population size and higher practice staffing levels were found in the unadjusted analyses. CONCLUSIONS: NHS Health Check coverage during 2011-12 was lower than the government projection of 18% coverage. Coverage must be increased through concerted multi-disciplinary strategies, for the programme to improve cardiovascular health in England. Considerable variation in participation between PCTs warrants attention, with enhanced support for poor performers.