Migrastatics: Redirecting R&D in Solid Cancer Towards Metastasis?

The concept of 'migrastatics' allows the development of a new drug class that is neither cytotoxic nor antiproliferative but is solely directed towards inhibition of cancer cell motility. Given that the regulatory pathway is open, and migrastatic candidates have been described, it is the right time to enter a new era of antimetastatic treatment.

Solid cancer: the new tumour spread endpoint opens novel opportunities.

Novel androgen deprivation agents delay metastasis in non-metastatic, castration-resistant, prostate cancer (nmCRPC). The recent regulatory guidance: considerations for metastasis-free survival endpoint in clinical trials, opens new opportunities in cell biology, medicinal chemistry and advanced imaging. Past failures are the likely result of equating tumour shrinkage to efficacy, rather than inhibition of tumour spread. In the future, the selection of anti-metastasis drug candidates will probably be based on anti-migratory rather than anti-proliferative potential. Oligometastatic cancer coupled with advanced imaging can serve as a clinical proof-of-concept model.

The new US and European guidelines in hypertension: A multi-dimensional analysis.

The Systolic Blood Pressure Intervention Trial (SPRINT) compared the clinical outcomes between target systolic blood pressure (SBP) levels between 140 and 120 mmHg or lower. Both,the 2017 ACC/AHA and the 2018 ESC/ESH guidelines in hypertension are derived from the SPRINT trial and advise initiation and/or intensification of treatment at lower blood pressure thresholds. The ACC/AHA guidance supersedes the 2014 Eight Joint National Committee guideline (JNC-8) which advised initiation of treatment when the BP was 140/90 mmHg or higher; in adults 60 years or over, the target was 150/90 mmHg. Compared to JNC-8, the new guidelines lower the SBP target by 10 mmHg in patients under age of 60 years, and by 20 mmHg in the elderly. We performed a qualitative multi-dimensional analysis in order to answer two key questions: will the new guidelines deliver the stated benefits? and, will translation to the clinic be simple, risk-free, and affordable? A major investment by national healthcare administrations will be necessary for the initiation and support of this program but this decision can only be justified by a valid expectation of clinical benefit. At this time, a definitive answer is not available and a "wait and see" attitude appears appropriate and reasonable. In the interim, efforts are best directed to the immediate problem of untreated hypertension worldwide.

Mortality predictors in patients with pelvic fractures from blunt trauma. / Preditores de mortalidade em pacientes com fratura de pelve por trauma contuso.

OBJECTIVE:: to analyze the association of mortality with sociodemographic and clinical variables, as well as lesions and complication in patients with pelvic trauma due to blunt trauma. METHODS:: we conducted a retrospective, observational study with five-year trauma record data. Death was considered as the main stratification variable for the analyzes. We used the Student t test to compare means, the Chi-Square or Fisher exact test for proportions, and the Wilcoxon-Mann Whitney test for medians. We analyzed the independent factors using a logistic regression model with penalized likelihood, based on the Wald tests, the Akaike Information Criterion (AIC) and the Schwarz Bayesian Information Criterion (BIC). RESULTS:: of the 28 patients with blunt trauma fracture, 23 (82.1%) were men; 16 (57.1%) were, in average, 38.8 years old (±17.3). There were 98 lesions or fractures in the 28 patients. As for severity, seven people had Injury Severity Score higher than 24 (25%). The mean hospital stay was 26.8 days (±22.4). Fifteen patients (53.6%) had ICU admission. Mortality was 21.4%. The analysis showed that age 50 years or more and presence of coagulopathy were factors independently associated with death. CONCLUSION:: pelvic fractures can have high mortality. In this study, mortality was higher than that described in the literature. Age above 50 years and the presence of coagulopathy are risk factors in this population.

Retrospective analysis of 103 diaphragmatic injuries in patients operated in a trauma center. / Análise retrospectiva de 103 casos de lesão diafragmática operados em um centro de trauma.

OBJECTIVE:: to analyze the factors associated with death in patients with diaphragmatic injury treated at a trauma reference hospital. METHODS:: we conducted a retrospective study of patients with diaphragm injury attended at the Risoleta Tolentino Neves Hospital of the Federal University of Minas Gerais, between January 2010 and December 2014. We used The Collector® database of trauma records (MD, USA). We gathered data on demographics, location of the diaphragmatic lesion, site and number of associated lesions, type of therapeutic approach, complications and Injury Severity Score (ISS). The variable of interest was the occurrence of death. RESULTS:: we identified 103 patients and mortality was 16.5%. Penetrating lesions occurred in 98% of patients. Univariate analysis showed a mortality higher in patients whose treatment was non-operative, without closing of the defect (p=0.023), and lower in patients submitted to diaphragmatic suturing (p<0.001). The increase in the number of lesions was associated with an increase in mortality (p=0.048). In multivariate analysis, ISS>24 (OR=4.0, p=0.029) and diaphragmatic suturing (OR=0.76, p<0.001) were associated with mortality. CONCLUSION:: The findings indicate that the traumatic rupture of the diaphragm rarely presents as an isolated lesion, being frequently associated with injuries of other organs, especially the liver and hollow viscera. Mortality was higher among those with ISS>24.

Migrastatics-Anti-metastatic and Anti-invasion Drugs: Promises and Challenges.

In solid cancers, invasion and metastasis account for more than 90% of mortality. However, in the current armory of anticancer therapies, a specific category of anti-invasion and antimetastatic drugs is missing. Here, we coin the term 'migrastatics' for drugs interfering with all modes of cancer cell invasion and metastasis, to distinguish this class from conventional cytostatic drugs, which are mainly directed against cell proliferation. We define actin polymerization and contractility as target mechanisms for migrastatics, and review candidate migrastatic drugs. Critical assessment of these antimetastatic agents is warranted, because they may define new options for the treatment of solid cancers.

Preditores de mortalidade em pacientes com fratura de pelve por trauma contuso / Mortality predictors in patients with pelvic fractures from blunt trauma

RESUMO Objetivo: analisar a associação de mortalidade com variáveis sociodemográficas, clínicas, lesões e complicações em pacientes com trauma de pelve decorrente de trauma contuso. Métodos: estudo retrospectivo e observacional com dados de registro de trauma obtidos durante cinco anos. O óbito foi a variável de estratificação das análises. Para verificar se as variáveis de interesse tinham associação com o óbito, foi realizado o teste t de Student e teste do Qui-quadrado (ou Fisher) e Wilcoxon-Mann Whitney. Os fatores independentemente associados ao óbito foram analisados por modelo logístico binomial, e com base nos testes de Wald e por Critérios de Informação de Akaike (AIC) e Bayesiano de Schwarz (BIC). Resultados: dos 28 pacientes com fratura de pelve por trauma contuso, 23 (82,1%) eram homens; 16 (57,1%) com média de idade de 38,8 anos (desvio padrão 17,3). Houve 98 lesões ou fraturas nos 28 pacientes. Quanto à gravidade, sete pacientes tiveram Injury Severity Score superior a 24 (25%). O tempo de internação hospitalar médio foi 26,8 dias (DP=22,4). Quinze pacientes (53,6%) tiveram internação em UTI. A incidência de óbito foi de 21,4%. A análise mostrou que idade igual ou maior do que 50 anos e presença de coagulopatia foram fatores independentemente associados ao óbito. Conclusão: as fraturas de pelve podem ter mortalidade elevada. Neste estudo a mortalidade foi superior ao que é descrito na literatura. A idade acima de 50 anos e a coagulopatia se revelaram fatores de risco nessa população.

ABSTRACT Objective: to analyze the association of mortality with sociodemographic and clinical variables, as well as lesions and complication in patients with pelvic trauma due to blunt trauma. Methods: we conducted a retrospective, observational study with five-year trauma record data. Death was considered as the main stratification variable for the analyzes. We used the Student t test to compare means, the Chi-Square or Fisher exact test for proportions, and the Wilcoxon-Mann Whitney test for medians. We analyzed the independent factors using a logistic regression model with penalized likelihood, based on the Wald tests, the Akaike Information Criterion (AIC) and the Schwarz Bayesian Information Criterion (BIC). Results: of the 28 patients with blunt trauma fracture, 23 (82.1%) were men; 16 (57.1%) were, in average, 38.8 years old (±17.3). There were 98 lesions or fractures in the 28 patients. As for severity, seven people had Injury Severity Score higher than 24 (25%). The mean hospital stay was 26.8 days (±22.4). Fifteen patients (53.6%) had ICU admission. Mortality was 21.4%. The analysis showed that age 50 years or more and presence of coagulopathy were factors independently associated with death. Conclusion: pelvic fractures can have high mortality. In this study, mortality was higher than that described in the literature. Age above 50 years and the presence of coagulopathy are risk factors in this population.

Análise retrospectiva de 103 casos de lesão diafragmática operados em um centro de trauma / Retrospective analysis of 103 diaphragmatic injuries in patients operated in a trauma center

RESUMO Objetivo: analisar os fatores associados ao óbito em pacientes com lesão diafragmática atendidos em hospital de referência para o trauma. Métodos: estudo retrospectivo de pacientes com lesão do diafragma atendidos no Hospital Risoleta Tolentino Neves da Universidade Federal de Minas Gerais entre janeiro de 2010 e dezembro de 2014. Foi utilizado o Banco de Registros de Trauma Collector® (MD, USA). Utilizaram-se dados demográficos, localização da lesão diafragmática, lesões associadas de outros órgãos, número de lesões associadas, tipo de abordagem terapêutica, complicações e o escore de gravidade Injury Severity Score (ISS). A variável de interesse foi a ocorrência de óbito. Resultados: foram identificados 103 pacientes e a incidência de óbito foi de 16,5%. Lesões penetrantes ocorreram em 98% dos pacientes. Em análise univariada a mortalidade foi maior em pacientes cujo tratamento foi não operatório, sem rafia (p=0,023), e menor em pacientes submetidos à rafia diafragmática (p<0,001). O aumento do número de lesões associou-se ao aumento da incidência de óbitos (p=0,048). Em análise multivariada, ISS>24 (OR=4,0; p=0,029) e rafia do diafragma (OR=0,76; p<0,001) associaram-se à mortalidade. Conclusão: os achados indicam que a ruptura traumática do diafragma raramente se apresenta como lesão isolada, estando associada frequentemente à lesão de outros órgãos, especialmente fígado e vísceras ocas. Pode-se afirmar que a mortalidade foi mais elevada entre aqueles com ISS>24.

ABSTRACT Objective: to analyze the factors associated with death in patients with diaphragmatic injury treated at a trauma reference hospital. Methods: we conducted a retrospective study of patients with diaphragm injury attended at the Risoleta Tolentino Neves Hospital of the Federal University of Minas Gerais, between January 2010 and December 2014. We used The Collector® database of trauma records (MD, USA). We gathered data on demographics, location of the diaphragmatic lesion, site and number of associated lesions, type of therapeutic approach, complications and Injury Severity Score (ISS). The variable of interest was the occurrence of death. Results: we identified 103 patients and mortality was 16.5%. Penetrating lesions occurred in 98% of patients. Univariate analysis showed a mortality higher in patients whose treatment was non-operative, without closing of the defect (p=0.023), and lower in patients submitted to diaphragmatic suturing (p<0.001). The increase in the number of lesions was associated with an increase in mortality (p=0.048). In multivariate analysis, ISS>24 (OR=4.0, p=0.029) and diaphragmatic suturing (OR=0.76, p<0.001) were associated with mortality. Conclusion: The findings indicate that the traumatic rupture of the diaphragm rarely presents as an isolated lesion, being frequently associated with injuries of other organs, especially the liver and hollow viscera. Mortality was higher among those with ISS>24.

Pragmatic medicine in solid cancer: a translational alternative to precision medicine.

The precision medicine (PM) initiative is a response to the dismal outlook in solid cancer. Despite heterogeneity, common mechanistic denominators may exist across the spectrum of solid cancer. A shift from conventional research and development (R&D) toward PM will require conceptual and structural change. As individuals and as a society, we welcome innovation, but question change. We ask: In solid cancer, does PM identify and address the causes of prior failures, and, if so, are the proposed solutions feasible? And, when may we expect safer, more effective and affordable drugs in the clinic? Considerations that prompt a pragmatic rethink include a failure analysis of translational R&D in solid cancer suggesting that trials and regulations need to be aligned with the natural history of the disease. In successful therapeutic interventions in chronic, complex disease, surrogate markers and endpoints should be consistent with the Prentice's criteria. In solid cancer, drug induced tumor shrinkage, is a drug effect and not a disease response; tumor shrinkage does not reflect nor predict interruption of the disease. Overall, we support a pragmatic, multidisciplinary, and collaborative R&D, and suggest that direction be set by clinical need and utility, and by questions, not answers. PM will prove worthwhile if it could improve clinical outcomes. The lag in therapeutics relative to diagnostics is a cause for confusion. Overdiagnosis adds to fear and harm, especially in the absence of effective interventions. A revised initiative that prioritizes metastasis research could replicate the successful HIV/AIDS model in solid cancer. A pragmatic approach may further translational efforts toward meaningfully effective, generally available, and affordable solutions.

Drugs for solid cancer: the productivity crisis prompts a rethink.

Despite remarkable progress in cancer-drug discovery, the delivery of novel, safe, and sustainably effective products to the clinic has stalled. Using Src as a model, we examine key steps in drug development. The preclinical evidence on the relationship between Src and solid cancer is in sharp contrast with the modest anticancer effect noted in conventional clinical trials. Here, we consider Src inhibitors as an example of a promising drug class directed to invasion and metastasis and identify roadblocks in translation. We question the assumption that a drug-induced tumor shrinkage in preclinical and clinical studies predicts a successful outcome. Our analysis indicates that the key areas requiring attention are related, and include preclinical models (in vitro and mouse models), meaningful clinical trial end points, and an appreciation of the role of metastasis in morbidity and mortality. Current regulations do not reflect the natural history of the disease, and may be unrelated to the key complications: local invasion, metastasis, and the development of resistance. Alignment of preclinical and clinical studies and regulations based on mechanistic trial end points and platforms may help in overcoming these roadblocks. Viewed kaleidoscopically, most elements necessary and sufficient for a novel translational paradigm are in place.

Cytostatic anticancer drug development.

This review focuses on clinical trials and the approval process in order to understand the discrepancy between vibrant science and the continuing failure of mechanism-based anticancer drugs. CLINICAL TRIALS: Mechanistic trials in cancer require at least three elements: the assurance of tumor definition, knowledge of the natural history, and earlier intervention. Histologic identity is not a reliable surrogate of the functional nature or a predictor of the natural history. cDNA arrays and computational models have promise in improving diagnosis and prediction, and thereby making tailored therapy possible. The latter requires: the incorporation of initial and earlier rational combination therapy, dynamic models of disease progression, and methods to discourage the emergence of resistance. For cytostatics, and in early cancer, a delay in progression may represent a better index of survival than tumor shrinkage. APPROVAL PROCESS: Since mechanistic similarities may outweigh therapeutic predictions based on organ-and histology-defined cancer, there is a need for a revised process that would allow for tailored treatment and initial combination therapy to improve safety, efficacy, and circumvent resistance. CONCLUSION: In order to translate the major and immediate potential of cytostatic drugs, clinical trials and the approval process may need to shift to a mechanism-based framework.

New tools for cancer chemotherapy: computational assistance for tailoring treatments.

Computational models of cancer chemotherapy have the potential to streamline clinical trial design, contribute to the design of rational, tailored treatments, and facilitate our understanding of experimental results. Mechanistic models based on functional data from tumor biopsies will enable physicians to predict response to treatment for a specific patient, in contrast to statistical models in which the probability of response for a given patient may differ substantially from the population average. While microarray analyses of gene expression also show promise for guiding individualized treatments, it may be difficult to link statistical mining of microarray data with mechanistic, tailored treatments. Furthermore, gene expression does not identify how drugs should be scheduled. This review summarizes mechanistic mathematical models developed to improve the design of chemotherapy regimens. Mechanistic models that incorporate both genetic resistance and cell cycle-mediated resistance during treatment with multiple drugs will be most useful in designing treatment regimens tailored for individuals. Because there are already a number of papers that address the applications of microarray technology, we will limit our discussion to the contrasts between mechanistic computational models and microarray technology, and how these two approaches may complement one another.