Combination antiangiogenic therapy in advanced breast cancer: a phase 1 trial of vandetanib, a VEGFR inhibitor, and metronomic chemotherapy, with correlative platelet proteomics

This phase 1 study evaluated the safety and tolerability of antiangiogenic therapy using vandetanib and metronomic cyclophosphamide and methotrexate in metastatic breast cancer. Eligible patients had metastatic breast cancer with 0?C4 prior chemotherapy regimens. All received cyclophosphamide 50?mg daily, methotrexate 2.5?mg?days 1?C2?weekly, and vandetanib daily in 3 dose-escalation cohorts: 100?mg (C1), 200?mg (C2), and 300?mg (C3). The primary endpoint was safety and tolerability; secondary endpoints included response rate and evaluation of platelet-associated proteins. Twenty three patients were treated and evaluable for toxicity. Common mild toxicities included nausea, vomiting, LFTs abnormalities, fatigue, and rash. Three episodes of dose-limiting toxicity occurred in C3. In all cohorts, 1/3 of patients required vandetanib dose reduction, and 22?% ended therapy for toxicity. Of the 20 response-evaluable patients, 10?% demonstrated partial response and 15?% stable disease ??24?weeks. Proteomic analyses demonstrated changes in platelet content of angiogenesis regulators, including vascular endothelial growth factor and platelet factor 4, with exposure to therapy. This regimen was tolerable at a maximum vandetanib dose of 200?mg; modest clinical activity was observed in this heavily pretreated population. Changes in the platelet proteome may serve as pharmacodynamic markers of angiogenesis inhibition. Metronomic chemotherapy is an attractive partner with biologics and deserves further study in metastatic breast cancer.     

Adverse events in cancer genetic testing: medical, ethical, legal, and financial implications

ABSTRACT: Cancer genetic counseling and testing are now integral services in progressive cancer care. There has been much debate over whether these services should be delivered by providers with specialized training in genetics or by all clinicians. Adverse outcomes resulting from cancer genetic counseling and testing performed by clinicians without specialization in genetics have been reported, but formal documentation is sparse. In this review, we present a series of national cases illustrating major patterns of errors in cancer genetic counseling and testing and the resulting impact on medical liability, health care costs, and the patients and their families.     

Chemokine Ligand 5 (CCL5) and chemokine receptor (CCR5) genetic variants and prostate cancer risk among men of African Descent: a case-control study

Background

Chemokine and chemokine receptors play an essential role in tumorigenesis. Although chemokine-associated single nucleotide polymorphisms (SNPs) are associated with various cancers, their impact on prostate cancer (PCA) among men of African descent is unknown. Consequently, this study evaluated 43 chemokine-associated SNPs in relation to PCA risk. We hypothesized inheritance of variant chemokine-associated alleles may lead to alterations in PCA susceptibility, presumably due to variations in antitumor immune responses.

Methods

Sequence variants were evaluated in germ-line DNA samples from 814 African-American and Jamaican men (279 PCA cases and 535 controls) using Illumina’s Goldengate genotyping system.

Results

Inheritance of CCL5 rs2107538 (AA, GA+AA) and rs3817655 (AA, AG, AG+AA) genotypes were linked with a 34-48% reduction in PCA risk. Additionally, the recessive and dominant models for CCR5 rs1799988 and CCR7 rs3136685 were associated with a 1.52-1.73 fold increase in PCA risk. Upon stratification, only CCL5 rs3817655 and CCR7 rs3136685 remained significant for the Jamaican and U.S. subgroups, respectively.

Conclusions

In summary, CCL5 (rs2107538, rs3817655) and CCR5 (rs1799988) sequence variants significantly modified PCA susceptibility among men of African descent, even after adjusting for age and multiple comparisons. Our findings are only suggestive and require further evaluation and validation in relation to prostate cancer risk and ultimately disease progression, biochemical/disease recurrence and mortality in larger high-risk subgroups. Such efforts will help to identify genetic markers capable of explaining disproportionately high prostate cancer incidence, mortality, and morbidity rates among men of African descent.     

Phase II trial of syncopated thalidomide, lenalidomide, and weekly dexamethasone in patients with newly diagnosed multiple myeloma

IntroductionOver the past decade, the novel agents thalidomide, lenalidomide, and bortezomib have emerged as effective treatment in patients with multiple myeloma (MM). Initially used in the relapse setting, these agents have been incorporated into frontline treatment algorithms. They have been combined in doublets with corticosteroids, in triplets with alkylators, or with each other. Because thalidomide and lenalidomide have different clinical activity and toxicity profiles, we designed a trial to evaluate a syncopated schedule of thalidomide and lenalidomide with weekly dexamethasone in patients with newly diagnosed MM to determine response and toxicity.Patients and MethodsTwenty-two patients with newly diagnosed MM were treated with syncopated thalidomide (200 mg on days 1-7 and 15-21), lenalidomide (25 mg on days 8-14 and 22-28 for the first cycle and 50 mg on the same schedule for subsequent cycles) with weekly dexamethasone (40 mg). Each cycle lasted 28 days. MM parameters were assessed at the end of each cycle. It was intended that the patients proceed to stem cell mobilization and autologous transplantation after 4 cycles of therapy.ResultsThe median number of cycles administered was 3.5. The overall response was 68%. The regimen was well tolerated by the majority of the patients; only patient discontinued treatment because of toxicity.ConclusionWe conclude that a syncopated schedule of thalidomide and lenalidomide with weekly dexamethasone was tolerated well, with no unexpected toxicities. However the response rate, even using lenalidomide at 50 mg, was not superior to standard dosing of thalidomide or lenalidomide plus dexamethasone.     

Introduction: Understanding and influencing multilevel factors across the cancer care continuum

Health care in the United States is notoriously expensive while often failing to deliver the care recommended in published guidelines. There is, therefore, a need to consider our approach to health-care delivery. Cancer care is a good example for consideration because it spans the continuum of health-care issues from primary prevention through long-term survival and end-of-life care. In this monograph, we emphasize that health-care delivery occurs in a multilevel system that includes organizations, teams, and individuals. To achieve health-care delivery consistent with the Institute of Medicine's six quality aims (safety, effectiveness, timeliness, efficiency, patient-centeredness, and equity), we must influence multiple levels of that multilevel system. The notion that multiple levels of contextual influence affect behaviors through interdependent interactions is a well-established ecological view. This view has been used to analyze health-care delivery and health disparities. However, experience considering multilevel interventions in health care is much less robust. This monograph includes 13 chapters relevant to expanding the foundation of research for multilevel interventions in health-care delivery. Subjects include clinical cases of multilevel thinking in health-care delivery, the state of knowledge regarding multilevel interventions, study design and measurement considerations, methods for combining interventions, time as a consideration in the evaluation of effects, measurement of effects, simulations, application of multilevel thinking to health-care systems and disparities, and implementation of the Affordable Care Act of 2010. Our goal is to outline an agenda to proceed with multilevel intervention research, not because it guarantees improvement in our current approach to health care, but because ignoring the complexity of the multilevel environment in which care occurs has not achieved the desired improvements in care quality outlined by the Institute of Medicine at the turn of the millennium.     

Homeobox gene expression profile indicates HOXA5 as a candidate prognostic marker in oral squamous cell carcinoma

The search for molecular markers to improve diagnosis, individualize treatment and predict behavior of tumors has been the focus of several studies. This study aimed to analyze homeobox gene expression profile in oral squamous cell carcinoma (OSCC) as well as to investigate whether some of these genes are relevant molecular markers of prognosis and/or tumor aggressiveness. Homeobox gene expression levels were assessed by microarrays and qRT-PCR in OSCC tissues and adjacent non-cancerous matched tissues (margin), as well as in OSCC cell lines. Analysis of microarray data revealed the expression of 147 homeobox genes, including one set of six at least 2-fold up-regulated, and another set of 34 at least 2-fold down-regulated homeobox genes in OSCC. After qRT-PCR assays, the three most up-regulated homeobox genes (HOXA5, HOXD10 and HOXD11) revealed higher and statistically significant expression levels in OSCC samples when compared to margins. Patients presenting lower expression of HOXA5 had poorer prognosis compared to those with higher expression (P=0.03). Additionally, the status of HOXA5, HOXD10 and HOXD11 expression levels in OSCC cell lines also showed a significant up-regulation when compared to normal oral keratinocytes. Results confirm the presence of three significantly upregulated (>4-fold) homeobox genes (HOXA5, HOXD10 and HOXD11) in OSCC that may play a significant role in the pathogenesis of these tumors. Moreover, since lower levels of HOXA5 predict poor prognosis, this gene may be a novel candidate for development of therapeutic strategies in OSCC.     

Public perception of depression in the city of São Paulo

OBJECTIVE: To assess how the population identifies symptoms of depression as well as its causes. METHODS: A household survey with a probabilistic sample of 500 individuals, residing in the city of S?o Paulo and aged between 18 and 65 years, was conducted in 2002. A structured questionnaire including sociodemographic data and a vignette presentation describing a person with depression, according to the Diagnostic and Statistical Manual of Mental Disorders-IV and the International Classification of Diseases-10 was used during the in-person interviews carried out by trained, qualified interviewers. Two questions about the vignette's symptom identification were subsequently asked. The results were analyzed by means of logistic regression and variance analysis. RESULTS: Symptoms presented were identified as "depression" by less than half of the sample. About 20% of respondents believed it was a mental illness. Low level of education was the only variable associated with identification as mental illness (OR=2.001, 95% CI: 1.275; 3.141, p=0.003). The most relevant causes were "unemployment" and "isolation". Biological, spiritual and moral causes were considered to be less relevant. Factors that most influenced the responses about causes were level of education, gender, personal experience with mental problems and identification as mental illness. CONCLUSIONS: The population of the city of S?o Paulo in general, especially those with a higher level of education, views depression in terms of a psychosocial model that somewhat differs from the biomedical model.