Brian Hernandez

Clinical characteristics and treatment outcomes of patients with colorectal cancer who develop brain metastasis: a single institution experience

BACKGROUND The development of brain metastasis (BM) in patients with colorectal cancer (CRC) is a rare and late event. We sought to investigate the clinical characteristics, disease course and safety using biologic agents in our patients with CRC who develop brain metastases. METHODS A retrospective review of patients with CRC with brain metastases treated at our institution from 01/2005-01/2015 was performed. Survival analysis was performed using the Kaplan-Meier method. RESULTS Forty patients were included in the analysis. Median age was 55.5 years, 67.5% were males, and 28% had a KRAS mutation. Twenty-four percent were treatment-naive at the time of BM diagnosis. Patients had a median of two brain lesions. Sixty-five percent of the patients were treated with radiotherapy alone, 22.5% had both surgical resection and brain radiotherapy. Median overall survival was 3.2 months after development of BM. Overall survival was longer in patients who received combined modality local therapy compared to patients treated with surgical resection or radiotherapy alone. Patients who received systemic treatment incorporating biologics following development of BM had a median overall survival of 18.6 months. Overall, the administration of biologic agents was safe and well tolerated. CONCLUSIONS In summary, BM is an uncommon and late event in the natural history of metastatic CRC. The ability to deliver combined-modality local brain therapy as well as availability of more systemic therapy options appear to lead to improved outcomes.

IGF1R as a Key Target in High Risk, Metastatic Medulloblastoma

Risk or presence of metastasis in medulloblastoma causes substantial treatment-related morbidity and overall mortality. Through the comparison of cytokines and growth factors in the cerebrospinal fluid (CSF) of metastatic medulloblastoma patients with factors also in conditioned media of metastatic MYC amplified medulloblastoma or leptomeningeal cells, we were led to explore the bioactivity of IGF1 in medulloblastoma by elevated CSF levels of IGF1, IGF-sequestering IGFBP3, IGFBP3-cleaving proteases (MMP and tPA), and protease modulators (TIMP1 and PAI-1). IGF1 led not only to receptor phosphorylation but also accelerated migration/adhesion in MYC amplified medulloblastoma cells in the context of appropriate matrix or meningothelial cells. Clinical correlation suggests a peri-/sub-meningothelial source of IGF-liberating proteases that could facilitate leptomeningeal metastasis. In parallel, studies of key factors responsible for cell autonomous growth in MYC amplified medulloblastoma prioritized IGF1R inhibitors. Together, our studies identify IGF1R as a high value target for clinical trials in high risk medulloblastoma.

Probabilistic modeling of personalized drug combinations from integrated chemical screen and molecular data in sarcoma

Cancer patients with advanced disease exhaust available clinical regimens and lack actionable genomic medicine results, leaving a large patient population without effective treatments options when their disease inevitably progresses. To address the unmet clinical need for evidence-based therapy assignment when standard clinical approaches have failed, we have developed a probabilistic computational modeling approach which integrates sequencing data with functional assay data to develop patient-specific combination cancer treatments. This computational modeling approach addresses three major challenges in personalized cancer therapy, which we validate across multiple species via computationally-designed personalized synergistic drug combination predictions, identification of unifying therapeutic targets to overcome intra-tumor heterogeneity, and mitigation of cancer cell resistance and rewiring mechanisms. These proof-of-concept studies support the use of an integrative functional approach to personalized combination therapy prediction for the population of high-risk cancer patients lacking viable clinical options and without actionable DNA sequencing-based therapy.

Tuberculosis Patients Who Are A Potential Source for Unprotected Exposure in Health Care Systems: A Multicenter Case Control Study

Abstract Setting Five health care systems in Texas. Objective To describe the epidemiology of inadequate isolation for pulmonary tuberculosis leading to tuberculosis (TB) exposures from confirmed TB patients and the patient factors that led to the exposures. Design A retrospective cohort and case-control study of adult patients with TB resulting in exposures (cases) vs those TB patients who did not result in exposures (controls) during January 2005 to December 2012. Results There were 335 patients with pulmonary TB disease, 199 cases and 136 controls. There was no difference between groups in age (46 ± 14.6 vs 45 ± 17 years; P > .05), race, or substance abuse. Cases were more likely to be transplant recipients (adjusted odds ratio [AOR], 18.90; 95% CI, 1.9–187.76), have typical TB chest radiograph (AOR, 2.23; 95% CI, 1.1–4.51), and have positive acid-fast bacilli stains (AOR, 2.36; 95% CI, 1.31–4.27). Cases were less likely to have extrapulmonary disease (AOR, 0.47; 95% CI, 0.24–0.95). Conclusions TB exposure resulting from inadequate isolation is frequent in health care settings. Extrapulmonary involvement resulted in earlier airborne isolation. Being a transplant recipient, having chest radiograph findings typical for TB, and sputum positivity acid-fast bacilli upon staining were associated with increased risk of inadequate isolation.

Risks and benefits of phase I liver dysfunction studies: should patients with severe liver dysfunction be included in these trials?

SummaryIntroduction The goal of organ dysfunction Phase I trials is to characterize the safety and pharmacokinetics of novel agents in cancer patients with liver or kidney dysfunction, but the clinical benefit is not well established. Methods We reviewed 170 patients across 15 liver dysfunction studies at our institution, grouped based on the NCI-Organ Dysfunction Working Group criteria or Child-Pugh Score. Results The median survival for the entire cohort was two months and just one month amongst patients with severe liver dysfunction. Patients with normal or mild liver dysfunction, absence of tumor in liver, good performance status, higher serum albumin and lower bilirubin, aspartate transaminase and alkaline phosphatase had improved survival by univariate analysis. Serum albumin and liver function classification remained significant by multivariate analysis. Conclusion Given poor survival of patients with liver dysfunction, we need better criteria, such as albumin levels, for optimally selecting patients for liver dysfunction studies.