History of Medicine Schedule and Abstracts 2009-2010

From Genes to Genome: An historical perspective (David Wheeler) Ignaz Semmelweis: Medical Prophet Without Honor (Ronald L. Young) Why Lewis Thomas, MD is Not a Bore: The Life of a Biology Watcher (Steven Greenberg) Doctors from Hell: The Horrific Account of Nazi Experiments on Humans (Vivien Spitz) Illuminating Autism: Passing the Torch from the Twentieth Century (Student Essay Contest Winners) (Lynn Yudofsky) Healing Beyond Hippocrates: The Temples of Asclepius and Public Health Care in Ancient Greece (Andrew Baldwin) Iron Wills and Iron Lungs: The Polio Years in Texas (Heather Green Wooten) William Osler and the Inspirational Uses of History (Michael Bliss) Working Too Hard and Achieving Too Much: The Cost of Being Harvey Cushing (Michael Bliss) Medicine in Ancient Egypt (Gene Boisaubin) The History of Diabetes (Jeff Unger)

Houston History of Medicine Society 2008-2009 Schedule and Abstracts

The National Library of Medicine and the Continuing Legacy of Michael E. DeBakey, M.D. (Stephen B. Greenberg) The Legacy of William Osler: North America’s most famous physician (Robert E. Rakel) A Lady Alone: Elizabeth Blackwell: First American Woman Doctor (Linda Gray Kelley, Charlton) A Mariner with Crippling Arthritis and Bleeding Eyes: The Chronic Arthritis of Christopher Columbus (Frank C. Arnett) Generation C(affeine): A History of Caffeine Consumption and its Medical Implications (Student Essay Contest winners) (Priti Dangayach) Our Artificial Fitness? Relaxed Selection Leads to Medical Dependence (Student Essay Contest winners) Philip Boone Remembering John P. McGovern, M.D. (1921-2007) (Bryant Boutwell) Who Was Albert Schweitzer? (Bryant Boutwell) Disease, Doctors and the Duty to Treat in American History (Thomas R. Cole) Vaccinating Freedom: The African-American Experience of Smallpox Prophylaxis in Old Philadelphia, 1723-1923 (Dayle B. Delancey) The Royal Hemophilia (The Royal Hemophilia)

The Role of Cell Sterilization in Population Based Studies of Radiogenic Second Cancers Following Radiation Therapy

Advances in radiotherapy have generated increased interest in comparative studies of treatment techniques and their effectiveness. In this respect, pediatric patients are of specific interest because of their sensitivity to radiation induced second cancers. However, due to the rarity of childhood cancers and the long latency of second cancers, large sample sizes are unavailable for the epidemiological study of contemporary radiotherapy treatments. Additionally, when specific treatments are considered, such as proton therapy, sample sizes are further reduced due to the rareness of such treatments. We propose a method to improve statistical power in micro clinical trials. Specifically, we use a more biologically relevant quantity, cancer equivalent dose (DCE), to estimate risk instead of mean absorbed dose (DMA). Our objective was to demonstrate that when DCE is used fewer subjects are needed for clinical trials. Thus, we compared the impact of DCE vs. DMA on sample size in a virtual clinical trial that estimated risk for second cancer (SC) in the thyroid following craniospinal irradiation (CSI) of pediatric patients using protons vs. photons. Dose reconstruction, risk models, and statistical analysis were used to evaluate SC risk from therapeutic and stray radiation from CSI for 18 patients. Absorbed dose was calculated in two ways: with (1) traditional DMA and (2) with DCE. DCE and DMA values were used to estimate relative risk of SC incidence (RRCE and RRMA, respectively) after proton vs. photon CSI. Ratios of RR for proton vs. photon CSI (RRRCE and RRRMA) were then used in comparative estimations of sample size to determine the minimal number of patients needed to maintain 80% statistical power when using DCE vs. DMA. For all patients, we found that protons substantially reduced the risk of developing a second thyroid cancer when compared to photon therapy. Mean RRR values were 0.052±0.014 and 0.087±0.021 for RRRMA and RRRCE, respectively. However, we did not find that use of DCE reduced the number of patents needed for acceptable statistical power (i.e, 80%). In fact, when considerations were made for RRR values that met equipoise requirements and the need for descriptive statistics, the minimum number of patients needed for a micro-clinical trial increased from 17 using DMA to 37 using DCE. Subsequent analyses revealed that for our sample, the most influential factor in determining variations in sample size was the experimental standard deviation of estimates for RRR across the patient sample. Additionally, because the relative uncertainty in dose from proton CSI was so much larger (on the order of 2000 times larger) than the other uncertainty terms, it dominated the uncertainty in RRR. Thus, we found that use of corrections for cell sterilization, in the form of DCE, may be an important and underappreciated consideration in the design of clinical trials and radio-epidemiological studies. In addition, the accurate application of cell sterilization to thyroid dose was sensitive to variations in absorbed dose, especially for proton CSI, which may stem from errors in patient positioning, range calculation, and other aspects of treatment planning and delivery.

TP53 as a Biomarker in Head and Neck Squamous Cell Carcinoma

Currently, there are no molecular biomarkers that guide treatment decisions for patients with head and neck squamous cell carcinoma (HNSCC). Several retrospective studies have evaluated TP53 in HNSCC, and results have suggested that specific mutations are associated with poor outcome. However, there exists heterogeneity among these studies in the site and stage of disease of the patients reviewed, the treatments rendered, and methods of evaluating TP53 mutation. Thus, it remains unclear as to which patients and in which clinical settings TP53 mutation is most useful in predicting treatment failure. In the current study, we reviewed the records of a cohort of patients with advanced, resectable HNSCC who received surgery and post-operative radiation (PORT) and had DNA isolated from fresh tumor tissue obtained at the time of surgery. TP53 mutations were identified using Sanger sequencing of exons 2-11 and the associated splice regions of the TP53 gene. We have found that the group of patients with either non-disruptive or disruptive TP53 mutations had decreased overall survival, disease-free survival, and an increased rate of distant metastasis. When examined as an independent factor, disruptive mutation was strongly associated with the development of distant metastasis. As a second aim of this project, we performed a pilot study examining the utility of the AmpliChip® p53 test as a practical method for TP53 sequencing in the clinical setting. AmpliChip® testing and Sanger sequencing was performed on a separate cohort of patients with HNSCC. Our study demonstrated the ablity of the AmpliChip® to call TP53 mutation from a single formalin-fixed paraffin-embedded slide. The results from AmpliChip® testing were identical with the Sanger method in 11 of 19 cases, with a higher rate of mutation calls using the AmpliChip® test. TP53 mutation is a potential prognostic biomarker among patients with advanced, resectable HNSCC treated with surgery and PORT. Whether this subgroup of patients could benefit from the addition of concurrent or induction chemotherapy remains to be evaluated in prospective clinical trials. Our pilot study of the p53 AmpliChip® suggests this could be a practical and reliable method of TP53 analysis in the clinical setting.

Mechanisms of Ad-p53 induced apoptosis in human malignant glioma

Malignant brain tumors are one of the most challenging cancers affecting society today. In a recent survey, an estimated 17,000 annual cases were recorded with a staggering total of 13,300 deaths. A unique degree of heterogeneity typifies glial tumors and presents a challenge for solitary anti-neoplastic treatments. Tumors subsist as heterogeneous masses that progress through dysplasia to astrocytomas, mixed glioma and glioblastoma multiforme. Although traditional therapeutic approaches have provided increments of success, the median survival time remains 12 months. The urgency to improve upon current clinical protocols has encouraged alternative experimental strategies such as p53 adenoviral gene therapy (Ad-p53). This study addresses the efficacy of Ad-p53 for the treatment of glioma. Our model presents a tumor response that is unique among human cancers. Ad-p53 effectively induces apoptosis in mutant p53 expressing cells yet fails to do so in those with wildtype p53. In order to adopt Adp53 as a standard anti-cancer modality, we characterized the role of the tumor suppressor gene p53 in mediating apoptosis. We demonstrate that altering cellular p53 status through the introduction of a dominant negative mutant p53 (175H, 248W, 273H) sensitized cells to Ad-p53. We discovered that wild-type p53 expressing glioma cells retain the apoptotic machinery necessary to accomplish cell death, but have developed mechanisms that interfere with p53 signaling. Earlier studies have not addressed the mechanisms of Ad-p53 apoptosis nor the resistance exhibited by wild-type p53 glioma. To explain the divergent phenotypes, we identified apoptotic pathways activated and effectors of the response. We illustrated that modulation of the death receptor Fas/APO-1 is a principal means of Ad-p53 signaling that is impaired in wild-type p53 glioma. Moreover, the apoptotic response was found to be a multi-faceted process that engaged several caspases, most notably caspases -1, -3 and -8. Lastly, we assessed the ability of anti-apoptotic molecules Bcl-2 and CrmA to inhibit Ad-p53 apoptosis. These studies revealed that Ad-p53 is a powerful tool for inducing apoptosis that can be delayed but not inhibited by anti-apoptotic means. This work is critical for understanding the development of glioma and the phenotypic and genotypic alterations that account for tumor resistance. ^

The effect of thyroxine and triiodothyronine on fatigue, depression, and memory in a hypothyroid population

Background. This study was planned at a time when important questions were being raised about the adequacy of using one hormone to treat hypothyroidism instead of two. Specifically, this trial aimed to replicate prior findings which suggested that substituting 12.5 μg of liothyronine for 50 μg of levothyroxine might improve mood, cognition, and physical symptoms. Additionally, this trial aimed to extend findings to fatigue. ^ Methods. A randomized, double-blind, two-period, crossover design was used. Hypothyroid patients stabilized on levothyroxine were invited to participate. Thirty subjects were recruited and randomized. Sequence one received their standard levothyroxine dose in one capsule and placebo in another during the first six weeks. Sequence two received their usual levothyroxine dose minus 50 μg in one capsule and 10 μg of liothyronine in another. At the end of the first six week period, subjects were crossed over. T tests were used to assess carry-over and treatment effects. ^ Results. Twenty-seven subjects completed the trial. The majority of completers had an autoimmune etiology. Mean baseline levothyroxine dose was 121 μg/d (±26.0). Subjects reported small increases in fatigue as measured by the Piper Fatigue Scale (0.9, p = 0.09) and in symptoms of depression measured by the Beck Depression Inventory-II (2.3, p = 0.16) as well as the General Health Questionnaire-30 (4.7, p = 0.14) while treated with substitution treatment. However, none of these differences was statistically significant. Measures of working memory were essentially unchanged between treatments. Thyroid stimulating hormone was about twice as high during substitution treatment (p = 0.16). Free thyroxine index was reduced by 0.7 (p < 0.001), and total serum thyroxine was reduced by 3.0 (p < 0.001) while serum triiodothyronine was increased by 20.5 (p < 0.001) on substitution treatment. ^ Conclusions. Substituting an equivalent amount of liothyronine for a portion of levothyroxine in patients with hypothyroidism does not decrease fatigue, symptoms of depression, or improve working memory. However, due to changes in serum hormone levels and small increments in fatigue and depression symptoms on substitution treatment, a question was raised about the role of T3 in the serum. ^

The normal range of the leukocyte count: Implications for surveillance of occupational and environmental exposure and the practice of preventive medicine

Leukopenia, the leukocyte count, and prognosis of disease are interrelated; a systematic search of the literature was undertaken to ascertain the strength of the evidence. One hundred seventy-one studies were found from 1953 onward pertaining to the predictive capabilities of the leukocyte count. Of those studies, 42 met inclusion criteria. An estimated range of 2,200cells/μL to 7,000cells/μL was determined as that which indicates good prognosis in disease and indicates the least amount of risk to an individual overall. Tables of the evidence are included indicating the disparate populations examined and the possible degree of association. ^

Safety, pharmacokinetics, and antiretroviral activity of multiple doses of ibalizumab (formerly TNX-355), an anti-CD4 monoclonal antibody in HIV-1 infected adults

Context: Despite tremendous strides in HIV treatment over the past decade, resistance remains a major problem. A growing number of patients develop resistance and require new therapies to suppress viral replication. ^ Objective: To assess the safety of multiple administrations of the anti-CD4 receptor (anti-CD4) monoclonal antibody ibalizumab given as intravenous (IV) infusions, in three dosage regimens, in subjects infected with human immunodeficiency virus (HIV-1). ^ Design: Phase 1, multi-center, open-label, randomized clinical trial comparing the safety, pharmacokinetics and antiviral activity of three dosages of ibalizumab. ^ Setting: Six clinical trial sites in the United States. ^ Participants: A total of twenty-two HIV-positive patients on no anti-retroviral therapy or a stable failing regimen. ^ Intervention: Randomized to one of two treatment groups in Arms A and B followed by non-randomized enrollment in Arm C. Patients randomized to Arm A received 10 mg/kg of ibalizumab every 7 days, for a total of 10 doses; patients randomized to Arm B received a total of six doses of ibalizumab; a single loading dose of 10 mg/kg on Day 1 followed by five maintenance doses of 6 mg/kg every 14 days, starting at Week 1. Patients assigned to Arm C received 25 mg/kg of ibalizumab every 14 days for a total of 5 doses. All patients were followed for safety for an additional 7 to 8 weeks. ^ Main Outcome Measures: Clinical and laboratory assessments of safety and tolerability of multiple administrations of ibalizumab in HIV-infected patients. Secondary measures of efficacy include HIV-1 RNA (viral load) measurements. ^ Results: 21 patients were treatment-experienced and 1 was naïve to HIV therapy. Six patients were failing despite therapy and 15 were on no current HIV treatment. Mean baseline viral load (4.78 log 10; range 3.7-5.9) and CD4+ cell counts (332/μL; range 89-494) were similar across cohorts. Mean peak decreases in viral load from baseline of 0.99 log10(1.11 log10, and 0.96 log 10 occurred by Wk 2 in Cohorts A, B and C, respectively. Viral loads decreased by >1.0 log10 in 64%; 4 patients viral loads were suppressed to < 400 copies/mL. Viral loads returned towards baseline by Week 9 with reduced susceptibility to ibalizumab. CD4+ cell counts rose transiently and returned toward baseline. Maximum median elevations above BL in CD4+ cell counts for Cohorts A, B and C were +257, +198 and +103 cells/μL, respectively and occurred within 3 Wks in 16 of 22 subjects. The half-life of ibalizumab was 3-3.5 days and elimination was characteristic of capacity-limited kinetics. Administration of ibalizumab was well tolerated. Four serious adverse events were reported during the study. None of these events were related to study drug. Headache, nausea and cough were the most frequently reported treatment emergent adverse events and there were no laboratory abnormalities related to study drug. ^ Conclusions: Ibalizumab administered either weekly or bi-weekly was safe, well tolerated, and demonstrated antiviral activity. Further studies with ibalizumab in combination with standard antiretroviral treatments are warranted.^

Is family medicine meeting the HIV/AIDS challenge? A national survey of family physicians' beliefs, clinical competence, and experience regarding HIV disease

A national sample of family physicians was surveyed to (1) assess family physicians' beliefs about the human immunodeficiency virus (HIV) and individuals at risk for infection, their clinical competence regarding HIV-related issues, and their experiences with HIV disease; (2) present conclusions to the American Academy of Family Physicians (AAFP) to effect the development of an early clinical care protocol and a continuing medical education curriculum; and (3) collect base-line data for use in the evaluation of an early clinical care protocol and a continuing medical education curriculum, in the case that such programs are developed and disseminated. After considering retired or deceased respondents, of the 2,660 physicians surveyed, 1,678 (63.7%) responded. The resulting sample was representative of the active members of the AAFP. About 77% of the respondents were unable to accurately identify the universal precautions for blood and body fluids to prevent occupational transmission of HIV or hepatitis B virus (HBV). Residency trained and board certified physicians expressed fewer "external constraints," such as fear of losing patients, obviating them from providing treatment to individuals with HIV disease (p =.004 and p $<$.001, respectively). These physicians also manifested fewer "internal constraints" to the provision of HIV treatment, such as fear of becoming infected (p $<$.001 and p =.012, respectively). Residency trained physicians also expressed a greater comfort with discussing sexually-related topics with their patients than did non-residency trained physicians (p $<$.001). There were 67.1% of the physicians surveyed who reported never providing treatment to an individual with HIV disease. Residency trained and board certified physicians expressed a greater likelihood to provide treatment to HIV-infected patients (p $<$.001) than non-residency trained and non-board certified physicians.^ Among the various primary care specialties, family medicine is especially vulnerable to the current challenges of HIV/AIDS. These challenges are augmented by the epidemiologic pattern that characterizes AIDS. For the past several years, we have seen AIDS in this country assume a similar pattern to that seen in most other countries; HIV is becoming increasingly prevalent in the heterosexual population as well as in locations removed from metropolitan centers. This current phase of the epidemic generates greater pressures upon primary care physicians, particularly family physicians, to become better acquainted with the means to provide early care to HIV/AIDS patients and to prevent HIV/AIDS among their patients. Family medicine is especially appropriate for providing care to HIV patients because family medicine involves treatment to all age groups and conditions; other primary care specialties focus on limited patient populations or specific conditions. Family physicians should be armed with the expertise to confront HIV/AIDS. However, family physicians' clinical competence and experience with HIV is not known. The data collected in this survey describes their competencies, attitudes, and experiences. ^

HOUSE-TO-HOUSE SURVEY OF ACCESS TO AND USE OF PUBLIC HEALTH FACILITIES IN METROPOLITAN LAGOS, NIGERIA

One of the broad objectives of the Nigerian health service, vigorously being pursued at all levels of government, is to make comprehensive health care available and accessible to the population at the lowest possible cost, within available resources. Some state governments in the federation have already introduced free medical service as a practical way to remove financial barriers to access and in turn to encourage greater utilization of publicly funded care facilities.^ To aid health planners and decision makers in identifying a shorter corridor through which urban dwellers can gain access to comprehensive health care, a health interview survey of the metropolitan Lagos was undertaken. The primary purpose was to ascertain the magnitude of access problems which urban households face in seeking care from existing public facilities at the time of need. Six categories of illness chosen from the 1975 edition of the International Classification of Disease were used as indicators of health need.^ Choice of treatment facilities in response to illness episode was examined in relation to distance, travel time, time of use and transportation experiences. These were graphically described. The overall picture indicated that distance and travel time coexist with transportation problems in preventing a significant segment of those in need of health care from benefitting in the free medical service offered in public health facilities. Within this milieu, traditional medicine and its practitioners became the most preferred alternative. Recommendations were offered for action with regard to decentralization of general practitioner (GP) consultations in general hospitals and integration of traditional medicine and its practitioners into public health service. ^

ALLERGEN SENSITIZATION AND IMMUNOMODULATION BY SYNTHETIC LIGANDS, PUL-042, IN AN ALLERGEN-INDUCED ASTHMA MURINE MODEL

Allergen-induced asthma is the leading form of asthma and a chronic condition worldwide. Common allergens are known to contribute to the pathogenesis of this disease. Murine models of allergic asthma have mostly used an intraperitoneal route of sensitization (not airway) to study this disease. Allergic asthma pathophysiology involves the activation of TH2-specific cells, which triggers production of IgE antibodies, the up-regulation of TH2-specific cytokines (i.e. IL-4, IL-5, IL-9 and IL-13), increased airway eosinophilia, and mucin hypersecretion. Although there are several therapeutics currently treating asthmatic patients, some of these treatments can result in drug tolerance and may be linked to increased mortality. CpG oligodeoxynucleotides (ODNs) is a synthetic ligand that targets Toll-like Receptor (TLR) 9. It has been evaluated as a therapeutic agent for the treatment of cancer, infectious diseases, and for treating allergy and asthma. PUL-042 is also a synthetic TLR ligand and is composed of two agonists against TLR2/6 heterodimer and TLR9. Previous studies have evaluated PUL-042 for its ability to confer resistance against bacterial and viral lung infection. These findings, combined with studies performed using CpG ODNs, led to speculation that PUL-042 dampens the immune response in allergen-induced asthma. My thesis research investigated airway route sensitization and airway delivery of PUL-042 to evaluate its effects in reducing an allergen-induced asthma phenotype in a murine model. The results of this study contribute to the foundation for future investigations to evaluate the efficacy of PUL-042 as a novel therapy in allergic-asthma disease.

COMPREHENSIVE CALCULATION-BASED IMRT QA USING R&V DATA, TREATMENT RECORDS, AND A SECOND TREATMENT PLANNING SYSTEM

Purpose: Traditional patient-specific IMRT QA measurements are labor intensive and consume machine time. Calculation-based IMRT QA methods typically are not comprehensive. We have developed a comprehensive calculation-based IMRT QA method to detect uncertainties introduced by the initial dose calculation, the data transfer through the Record-and-Verify (R&V) system, and various aspects of the physical delivery. Methods: We recomputed the treatment plans in the patient geometry for 48 cases using data from the R&V, and from the delivery unit to calculate the “as-transferred” and “as-delivered” doses respectively. These data were sent to the original TPS to verify transfer and delivery or to a second TPS to verify the original calculation. For each dataset we examined the dose computed from the R&V record (RV) and from the delivery records (Tx), and the dose computed with a second verification TPS (vTPS). Each verification dose was compared to the clinical dose distribution using 3D gamma analysis and by comparison of mean dose and ROI-specific dose levels to target volumes. Plans were also compared to IMRT QA absolute and relative dose measurements. Results: The average 3D gamma passing percentages using 3%-3mm, 2%-2mm, and 1%-1mm criteria for the RV plan were 100.0 (σ=0.0), 100.0 (σ=0.0), and 100.0 (σ=0.1); for the Tx plan they were 100.0 (σ=0.0), 100.0 (σ=0.0), and 99.0 (σ=1.4); and for the vTPS plan they were 99.3 (σ=0.6), 97.2 (σ=1.5), and 79.0 (σ=8.6). When comparing target volume doses in the RV, Tx, and vTPS plans to the clinical plans, the average ratios of ROI mean doses were 0.999 (σ=0.001), 1.001 (σ=0.002), and 0.990 (σ=0.009) and ROI-specific dose levels were 0.999 (σ=0.001), 1.001 (σ=0.002), and 0.980 (σ=0.043), respectively. Comparing the clinical, RV, TR, and vTPS calculated doses to the IMRT QA measurements for all 48 patients, the average ratios for absolute doses were 0.999 (σ=0.013), 0.998 (σ=0.013), 0.999 σ=0.015), and 0.990 (σ=0.012), respectively, and the average 2D gamma(5%-3mm) passing percentages for relative doses for 9 patients was were 99.36 (σ=0.68), 99.50 (σ=0.49), 99.13 (σ=0.84), and 98.76 (σ=1.66), respectively. Conclusions: Together with mechanical and dosimetric QA, our calculation-based IMRT QA method promises to minimize the need for patient-specific QA measurements by identifying outliers in need of further review.

Novel Use of Dual Anti-Inflammatory Therapy to Overcome Drug Resistance and Improve Functional Recovery Following Spinal Cord Injury

Over 1.2 million Americans are currently living with a traumatic spinal cord injury (SCI). Despite the need for effective therapies, there are currently no proven effective treatments that can improve recovery of function in SCI patients. Many therapeutic compounds have shown promise in preclinical models of SCI, but all of these have fallen short in clinical trials. P-glycoprotein (Pgp) is an active transporter expressed on capillary endothelial cell membranes at the blood-spinal cord barrier (BSCB). Pgp limits passive diffusion of blood-borne drugs into the CNS, by actively extruding drugs from the endothelial cell membrane. Pgp can become pathologically up-regulated, thus greatly impeding therapeutic drug delivery (‘multidrug resistance’). Importantly, many drugs that have been evaluated for the treatment of SCI are Pgp substrates. We hypothesized that Pgp-mediated drug resistance diminishes the delivery and efficacy of neuroprotective drugs following SCI. We observed a progressive, spatial spread of Pgp overexpression within the injured spinal cord. To assess Pgp function, we examined spinal cord uptake of systemically-delivered riluzole, a drug that is currently being evaluated in clinical trials as an SCI intervention. Blood-to-spinal cord riluzole penetration was reduced following SCI in wild-type but not Pgp-null rats, highlighting a critical role for Pgp in mediating spinal cord drug resistance after injury. Others have shown that pro-inflammatory signaling drives Pgp up-regulation in cancer and epilepsy. We have detected inflammation in both acutely- and chronically-injured spinal cord tissue. We therefore evaluated the ability of the dual COX-/5-LOX inhibitor licofelone to attenuate Pgp-mediated drug resistance following SCI. Licofelone treatment both reduced spinal cord Pgp levels and enhanced spinal cord riluzole bioavailability following SCI. Thus, we propose that licofelone may offer a new combinatorial treatment strategy to enhance spinal cord drug delivery following SCI. Additionally, we assessed the ability of licofelone, riluzole, or both to enhance recovery of locomotor function following SCI. We found that licofelone treatment conferred a significant improvement in hindlimb function that was sustained through the end of the study. In contrast, riluzole did not improve functional outcome. We therefore conclude that licofelone holds promise as a potential neuroprotective intervention for SCI.

PROSTATE CANCER STEM CELLS: DRUG TOLERANCE, EXPERIMENTAL RECONSTITUTION AND CASTRATION RESISTANCE

Prostate cancer (PCa) is one of the leading malignancies affecting men in the Western world. Although tremendous effort has been made towards understanding PCa development and developing clinical treatments in the past decades, the exact mechanisms of PCa are still not clearly understood. Emerging evidence has postulated that a population of stem cell-like cells inside a tumor, termed ‘cancer stem cells (CSCs)’, may be the cells responsible for tumor initiation, progression, recurrence, metastasis and therapy resistance. Like CSC studies in other cancer types, it has been reported that PCa also contains CSCs. However, there remain several unresolved questions that need to be clarified. First, the relationship between prostate CSCs (PCSCs) and therapy resistance (chemo- and radio-) is not known. Herein, we have found that not all CSCs are drug-tolerant, and not all drug-tolerant cells are CSCs. Second, whether primary human PCa (HPCa) actually contain PCSCs remains unclear, due to the well-known fact that we have yet to establish a reliable assay system that can reproducibly and faithfully reconstitute tumor regeneration from single HPCa cells. Herein, after utilizing more than 114 HPCa samples we have provided evidence that immortalized bone marrow-derived stromal cells (Hs5) can help dissociated HPCa cells generate undifferentiated tumors in immunodeficient NOD/SCID-IL2Rγ-/- mice, and the undifferentiated PCa cells seem to have a survival advantage to generate tumors. Third, the evolution of PCa from androgen dependent to the lethally castration resistant (CRPC) stage remains enigmatic, and the cells responsible for CRPC development have not been identified. Herein, we have found a putative cell population, ALDH+CD44+α2β1+ PCa cells that may represent a cell-of-origin for CRPC. Taken together, our work has improved our understanding of PCSC properties, possibly highlighting a potential therapeutic target for CRPC.

Radiomics of NSCLC: Quantitative CT Image Feature Characterization and Tumor Shrinkage Prediction

Radiomics is the high-throughput extraction and analysis of quantitative image features. For non-small cell lung cancer (NSCLC) patients, radiomics can be applied to standard of care computed tomography (CT) images to improve tumor diagnosis, staging, and response assessment. The first objective of this work was to show that CT image features extracted from pre-treatment NSCLC tumors could be used to predict tumor shrinkage in response to therapy. This is important since tumor shrinkage is an important cancer treatment endpoint that is correlated with probability of disease progression and overall survival. Accurate prediction of tumor shrinkage could also lead to individually customized treatment plans. To accomplish this objective, 64 stage NSCLC patients with similar treatments were all imaged using the same CT scanner and protocol. Quantitative image features were extracted and principal component regression with simulated annealing subset selection was used to predict shrinkage. Cross validation and permutation tests were used to validate the results. The optimal model gave a strong correlation between the observed and predicted shrinkages with . The second objective of this work was to identify sets of NSCLC CT image features that are reproducible, non-redundant, and informative across multiple machines. Feature sets with these qualities are needed for NSCLC radiomics models to be robust to machine variation and spurious correlation. To accomplish this objective, test-retest CT image pairs were obtained from 56 NSCLC patients imaged on three CT machines from two institutions. For each machine, quantitative image features with concordance correlation coefficient values greater than 0.90 were considered reproducible. Multi-machine reproducible feature sets were created by taking the intersection of individual machine reproducible feature sets. Redundant features were removed through hierarchical clustering. The findings showed that image feature reproducibility and redundancy depended on both the CT machine and the CT image type (average cine 4D-CT imaging vs. end-exhale cine 4D-CT imaging vs. helical inspiratory breath-hold 3D CT). For each image type, a set of cross-machine reproducible, non-redundant, and informative image features was identified. Compared to end-exhale 4D-CT and breath-hold 3D-CT, average 4D-CT derived image features showed superior multi-machine reproducibility and are the best candidates for clinical correlation.