Dissecting the Role of a lncRNA and Involvement of <em>Plasmodium</em> Infections in the Innate Immune Response: A Dissertation
The innate immune system is a multicomponent response governed by intricate mechanisms of induction, regulation and resolution to elicit antimicrobial defenses. In recent years, the complexity of eukaryotic transcriptomes has become the subject of intense scrutiny and curiosity. It has been established, that RNA polymerase II (RNAPII) transcribes hundreds to thousands of long noncoding RNAs (lncRNAs), often in a stimulus and cell-type specific manner. However, the functional significance of these transcripts has been particularly controversial. While the number of identified lncRNAs is growing, our understanding of how lncRNAs themselves regulate other genes is quite limited. In chapter 2, a novel lncRNA is identified, more specifically, a natural antisense transcript, that mediates the transcription of the pro-inflammatory cytokine IL-1α. Through loss-of-function studies, I report the necessity of this transcript in mediating IL-1α mRNA expression by affecting RNAPII binding to the IL-1α promoter after toll-like receptor signaling. For the first time, I show that IL-1α is regulated at the transcriptional level. As a second independent component of this thesis, we explore the role of the innate immune response after infection by the malaria-causing parasite, Plasmodium berghei ANKA (PbA), and how innate immune components are both beneficial and detrimental to the host depending on when and where inflammation is triggered during infection. We attempt to identify the “malarial toxin” responsible for aberrations in the immune response that is detrimental for disease outcomes and the innate signaling pathways that are involved. Many pathogens induce pathological inflammatory conditions that lead to irreparable homeostatic imbalances and become fatal to the host. Here, type I Interferon signaling is required to dampen parasite load during liver-stage infections, but leads to host mobidity if these pathways are activated in the erythrocytic phase of infection. Together, this thesis provides new insights on how components of the innate immune system are regulated, and how dysregulation of immunity can potentially lead to adverse effects during active infections.
Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies in the United States, with an average five-year survival rate of just 6.7%. One unifying aspect of PDAC is mutational activation of the KRAS oncogene, which occurs in over 90% of PDAC. Therefore, inhibiting KRAS function is likely an effective therapeutic strategy for this disease, and current research in our lab and others is focused on identifying downstream effectors of KRAS signaling that may be therapeutic targets. miRNAs are powerful regulators of gene expression that can behave as oncogenes or tumor suppressors. Dysregulation of miRNA expression is commonly observed in human tumors, including PDAC. The mir-17~92 cluster of miRNAs is an established oncogene in a variety of tumor contexts, and members of the mir-17~92 cluster are upregulated in PDAC, but their role has not been explored in vivo. This dissertation encompasses two studies exploring the role of miRNAs in pancreatic tumorigenesis. In Chapter II, I demonstrate that deletion of the mir-17~92 cluster impairs PDAC precursor lesion formation and maintenance, and correlates with reduced ERK signaling in these lesions. mir-17~92 deficient tumors and cell lines are also less invasive, which I attribute to the loss of the miR-19 family of miRNAs. In Chapter III, I find that Dicer heterozygosity inhibits PDAC metastasis, and that this phenotype is attributable to an increased sensitivity to anoikis. Ongoing experiments will determine whether shifts in particular miRNA signatures between cell lines can be attributed to this phenotype. Together these findings illustrate the importance of miRNA biogenesis, and the mir-17~92 cluster in particular, in supporting PDAC development and progression.
Neurons comprise the main information processing cells of the nervous system. To integrate and transmit information, neurons elaborate dendritic structures to receive input and axons to relay that information to other cells. Due to their intricate structures, dendrites and axons are susceptible to damage whether by physical means or via disease mechanisms. Studying responses to axon injury, called Wallerian degeneration, in the neuronal processes of Drosophila melanogaster has allowed the identification of genes that are required for injury responses. Screens in Drosophila have identified dsarm and highwire as two genes required for axon degeneration; when these genes are mutated axons fail to degenerate after injury, even when completely cut off from the neuronal cell body. We found that these genes are also required for dendrite degeneration after injury in vivo. Further, we reveal differences between axon and dendrite injury responses using in vivo timelapse recordings and GCaMP indicators of intracellular and mitochondrial calcium transients. These data provide insights into the neuronal responses to injury, and better define novel targets for the treatment of neurodegenerative diseases.
Background: Major depression is one of the most prevalent, disabling, and costly illnesses worldwide. Despite a 400% increase in antidepressant medication use since 1988, fewer than half of treated depression patients experience a clinically meaningful reduction in symptoms and uncertainty exists regarding how to successfully obtain symptom remission. Identifying homogenous subgroups based on clinically observable characteristics could improve the ability to efficiently predict who will benefit from which treatments.
Methods: Latent class analysis and latent transition analysis (LTA) were applied to data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study to explore how to efficiently identify subgroups comprised of the multiple dimensions of depression and examine changes in subgroup membership during treatment. The specific aims of this dissertation were to: 1) evaluate latent depression subgroups for men and women prior to antidepressant treatment; 2) examine transitions in these subgroups over 12 weeks of citalopram treatment; and 3) examine differences in functional impairment between women’s depression subgroups throughout treatment.
Results: Four subgroups of depression were identified for men and women throughout this work. Men’s subgroups were distinguished by depression severity and psychomotor agitation and retardation. Severity, appetite changes, insomnia, and psychomotor disturbances characterized women’s subgroups. Psychiatric comorbidities, especially anxiety disorders, were related to increased odds of membership in baseline moderate and severe depression subgroups for men and women. After 12 weeks of citalopram treatment, depression severity and psychomotor agitation were related to men’s chances of improving. Severity and appetite changes were related to women’s likelihood of improving during treatment. When functional impairment was incorporated in LTA models for women, baseline functional impairment levels were related to both depression subgroups at baseline and chances of moving to a different depression subgroup after treatment.
Conclusion: Depression severity, psychomotor disturbances, appetite changes, and insomnia distinguished depression subgroups in STAR*D. Gender, functional impairment, comorbid psychiatric disorders, and likelihood of transitioning to subgroups characterized by symptom improvement differed between these subgroups. The results of this work highlight how relying solely on summary symptom rating scale scores during treatment obscures changes in depression that might be informative for improving treatment response.
Nursing homes are an essential yet understudied provider of cancer-related care for those with complex health needs. Nine percent of nursing home residents have a cancer diagnosis at admission, and it is estimated that one-third of them experience pain on a daily basis. Although pain management is an essential component of disease treatment, few studies have evaluated analgesic medication use among adults with cancer in this setting. Use of opioids, which are the mainstay of pain management in older adults because of their effectiveness in controlling moderate to severe pain, may be significantly related to coverage by the Medicare Part D prescription drug benefit. However, little is known about Medicare Part D’s effects on opioid use in this patient population. A limited body of evidence also suggests that despite known risks of overdose and respiratory depression in opioid-naïve patients treated with long-acting opioids, use of these agents may be common in nursing homes.
This dissertation examined access to appropriate and effective pain-related health care services among US nursing home residents, with a special focus on those with cancer. Objectives of this dissertation were to: 1) estimate the prevalence, and identify resident-level correlates, of pain and receipt of analgesic medications; 2) use a quasi-experimental research design to examine the relationship between implementation of Medicare Part D and changes in the use of fentanyl patches and other opioids; and 3) to estimate the prevalence, and identify resident-level correlates, of naïve initiation of long-acting opioids. Data on residents’ health status from the Resident Assessment Instrument/Minimum Data Set (versions 2.0 and 3.0) were linked with prescription drug transaction data from a nationwide long-term care pharmacy (January 2005–June 2007) and the Centers for Medicare and Medicaid Services (January–December 2011).
From 2006 to 2007, more than 65% of residents of nursing homes throughout the US with cancer experienced pain (28.3% on a daily basis), among whom 13.5% reported severe pain. More than 17% of these residents who experienced daily pain received no analgesics (95% confidence interval [CI]: 16.0–19.1%), and treatment was negatively associated among those with advanced age, cognitive impairment, feeding tubes, and restraints. These findings coincided with changing patterns in opioid use among residents with cancer, including relatively abrupt 10% and 21% decreases in use of fentanyl patches and other strong opioids, respectively, after the 2006 implementation of Medicare Part D. In the years since Medicare Part D was introduced, some treatment practices in nursing homes have not been concordant with clinical guidelines for pain management among older adults. Among a contemporary population of long-stay nursing home residents with and without cancer, 10.0% (95% CI: 9.4–10.6%) of those who began receiving a long-acting opioid after nursing home admission had not previously received opioid therapy. Odds of naïve initiation of these potent opioids were increased among residents with terminal prognosis, functional impairment, feeding tubes, and cancer.
This dissertation provides new evidence on pharmaceutical management of pain and on Medicare Part D’s impact on opioid use in nursing home residents. Results from this dissertation shed light on nursing home residents’ access to pain-related health care services and provide initial directions for targeted efforts to improve the quality of pain treatment in nursing homes.
Background: Overtreatment of localized prostate cancer (PCa) is a concern as many men die of other causes prior to experiencing a treatment benefit. This dissertation characterizes the need for assessing other cause mortality (OCM) risk in older men with PCa and informs efforts to identify patients most likely to benefit from definitive PCa treatment.
Methods: Using the linked Surveillance Epidemiology and End Results-Medicare Health Outcomes Survey database, 2,931 men (mean age=75) newly diagnosed with clinical stage T1a-T3a PCa from 1998-2009 were identified. Survival analysis methods were used to compare observed 10-year OCM by primary treatment type. Age and health factors predictive of primary treatment type were assessed with multinomial logistic regression. Predicted mortality estimates from Social Security life tables (recommended for life expectancy evaluation) and two OCM risk estimation tools were compared to observed rates. An improved OCM prediction model was developed fitting Fine and Gray competing risks models for 10-year OCM with age, sociodemographic, comorbidity, activities of daily living, and patient-reported health data as predictors. The tools’ ability to discriminate between patients who died and those who did not was evaluated with Harrell’s c-index (range 0.5-1), which also guided new model selection.
Results: Fifty-four percent of older men with localized PCa underwent radiotherapy while 13% underwent prostatectomy. Twenty-three percent of those treated with radiotherapy and 12% of those undergoing prostatectomy experienced OCM within 10 years of treatment and thus were considered overtreated. Health factors indicative of a shorter life expectancy (increased comorbidity, worse physical health, smoking) had little to no association with radiotherapy assignment but were significantly related to reductions in the likelihood of undergoing prostatectomy. Social Security life tables overestimated mortality risk and discriminated poorly between men who died and those who did not over 10 years (c-index=0.59). Existing OCM risk estimation tools were less likely to overestimate OCM rates and had limited but improved discrimination (c-index=0.64). A risk model developed with self-reported age, Charlson comorbidity index score, overall health (excellent-good/fair/poor), smoking, and marital status predictors had improved discrimination (c-index=0.70).
Conclusions: Overtreatment of older men with PCa is primarily attributable to radiotherapy and may be reduced by pretreatment assessment of mortality-related health factors. This dissertation provides a prognostic model which utilizes a set of five self-reported characteristics that better identify patients likely to die of OCM within 10 years of diagnosis than age and comorbidity-based assessments alone.
Hospital Treatment Practices, 30-Day Hospital Readmissions, and Long-Term Prognosis in Patients Hospitalized with Acute Myocardial Infarction: A Dissertation
Background: Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in the U.S. Acute myocardial infarction (AMI), with or without ST-segment elevation, is a common presentation of coronary heart disease and affected more than 800,000 American adults in 2010. The overall goal of this dissertation was to examine decade-long trends in the extent of delay in the receipt of a primary percutaneous coronary intervention (PCI) among patients hospitalized with ST-segment elevation myocardial infarction (STEMI), 30-day hospital readmission rates in patients having survived an AMI, and multiple decade long trends in 1-year post-hospital all-cause mortality, as well as factors associated with these outcomes, among patients hospitalized with AMI.
Methods: Data from the Worcester Heart Attack Study, a population-based chronic disease surveillance project that has been carried out among adult residents of the Worcester, MA, metropolitan area, hospitalized with AMI on a biennial basis from 1975 through 2009 at all medical centers in central MA, were used for this dissertation.
Results: Between 1999 and 2009, among patients hospitalized with STEMI, the likelihood of receiving a primary PCI within 90 minutes after emergency department arrival increased dramatically from 1999/2001 (11.6%) to 2007/2009 (70.5%). Between 1999 and 2009, among hospital survivors of an AMI, the 30-day all-cause rehospitalization rates decreased from 1999/2001 (20.3%) to 2007/2009 (16.7%). The overall cause-specific 30-day rehospitalization rates due to CVD, non-CVD, and AMI were 10.1%, 7.1%, and 1.8%, respectively, during the years under study. Between 1975 and 2009, among hospital survivors for a first AMI, the 1-year post-discharge mortality rates remained relatively stable from 1975-1984 (12.9%) to 1986-1997 (12.5%), but increased during 1999-2009 (15.8%). We identified several demographic, clinical and in-hospital treatment factors associated with an increased risk of failing to receive a primary PCI within 90 minutes after emergency department arrival, 30-day readmissions, and 1-year post-discharge mortality.
Conclusions: Our findings can hopefully lead to the enhanced development of innovative, patient-centered, intervention strategies which can further improve the treatment and transitions of care, as well as short and long-term prognosis, of men and women hospitalized with AMI.
The hospitalization of a family member in an intensive care unit can be a very stressful time for the family. Family bedside rounds is one way for the care team to inform family members, answer questions, and involve them in care decisions. Few studies have examined the experiences of family members with ICU bedside rounds.
A qualitative descriptive study, undergirded by the Family Management Style Framework developed by Knafl and Deatrick (1990, 2003) and Knafl, Deatrick, and Havill (2012), was done at an academic medical center examining families who both participated and did not participate in the family bedside rounds. The majority of families who participated (80%) found the process helpful. One overarching theme emerged from the data of participating families: Making a Connection: Comfort and Confidence. Two major factors influenced how that connection was made: consistency and preparing families for the future. Three types of consistency were identified: consistency with information being shared, consistency about when rounds were being held, and
consistency with being informed of delays. The second major contributing factor was preparing families for the future. When a connection was present, families felt comfortable with the situation. When any of the factors were missing, families described feelings of anger, frustration, and fear. Family members who did not participate described feelings of disappointment and frustration about not having participated.
As healthcare providers, what we say to families matters. They need to be included in decision-making with honest, consistent, easy-to-understand information.
Sterile particles underlie the pathogenesis of numerous inflammatory diseases. These diseases can often become chronic and debilitating. Moreover, they are common, and include silicosis (silica), asbestosis (asbestos), gout (monosodium urate), atherosclerosis (cholesterol crystals), and Alzeihmer’s disease (amyloid Aβ). Central to the pathology of these diseases is a repeating cycle of particle-induced cell death and inflammation. Macrophages are the key cellular mediators thought to drive this process, as they are especially sensitive to particle-induced cell death and they are also the dominant producers of the cytokine responsible for much of this inflammation, IL-1β. In response to cytokines or microbial cues, IL-1β is synthesized in an inactive form (pro-IL-1β) and requires an additional signal to be secreted as an active cytokine. Although a multimolecular complex, called the NLRP3 inflammasome, controls the activation/secretion of IL-1β (and has been thought to also control cell death) in response to particles in vitro, the in vivo inflammatory response to particles occurs independently of inflammasomes. Therefore, I sought to better understand the mechanisms governing IL-1β production and cell death in response to particles, focusing specifically on the role of lysosomal cathepsin proteases. Inhibitor studies have suggested that one of these proteases, cathepsin B, plays a role in promoting inflammasome activation subsequent to particle-induced lysosomal damage, however genetic models of cathepsin B deficiency have argued otherwise. Through the use of inhibitors, state-of-the-art biochemical tools, and multi-cathepsin-deficient genetic models, I found that multiple redundant cathepsins promote pro-IL-1β synthesis as well as particle-induced NLRP3 activation and cell death. Importantly, I also found that particle-induced cell death does not depend on inflammasomes, suggesting that this may be why inflammasomes do not contribute to particle-induced inflammation in vivo. Therefore, my observations suggest that cathepsins may be multifaceted therapeutic targets involved in the two key pathological aspects of particle-induced inflammatory disease, IL-1β production and cell death.
Role and Regulation of Autophagy During Developmental Cell Death in <i>Drosophila Melanogaster</i>: A Dissertation
Autophagy is a conserved catabolic process that traffics cellular components to the lysosome for degradation. Autophagy is required for cell survival during nutrient restriction, but it has also been implicated in programmed cell death. It is associated with several diseases, including cancer. Cancer is a disease characterized by aberrant cell growth and proliferation. To support this growth, the tumor cell often deregulates several metabolic processes, including autophagy. Interestingly, autophagy plays paradoxical roles in tumorigenesis. It has been shown to be both tumor suppressive through cell death mechanisms and tumor promoting through its cytoprotective properties. However, the mechanisms regulating the balance between cell death and cell survival, as well as the metabolic consequences of disrupting this balance, are still poorly understood. Autophagy functions in both cell survival and cell death during the development of Drosophila melanogaster, making it an ideal model for studying autophagy in vivo. My research aimed to better understand the regulation and metabolic contribution of autophagy during cell death in Drosophila. I found that the Ral GTPase pathway, important to oncogenesis, regulates autophagy specifically during cell death in Drosophila larval salivary glands. Contrary to previous studies in mammalian cell culture, Ral is dispensable for autophagy induced during nutrient deprivation suggesting that Ral regulates autophagy in a context-dependent manner. This is the first in vivo evidence of Ral regulating autophagy. I found that disrupting autophagy has an extensive impact on an organism’s metabolism. Additionally, I found that autophagy in degrading tissues is crucial for maintaining the fly’s metabolic homeostasis, and that it may be important for resource allocation amongst tissues. This research highlights the importance of understanding how pathways regulate autophagy in different cell contexts and the metabolic outcomes of manipulating those pathways. This is especially important as we investigate which pathways to target therapeutically in an effort to harness autophagy to promote cell death rather than cell survival.
Causal Inference Methods for Assessing Neurodevelopment in Children Following Prenatal Exposure to Triptan Medications: A Dissertation
Background: Migraine headache is a chronic pain condition that affects 20% of women of reproductive age, and is often treated with triptans. Triptans are serotonin 1B, 1D, and 1F receptor agonists that act as vasoconstrictors and inhibitors of the trigeminal cervical complex as well as peripheral neurons; they cross the blood brain barrier and placenta, and as such are plausible neurodevelopmental teratogens. No studies have examined risk of neurodevelopmental problems in children with prenatal triptan exposure. This dissertation had three aims: (1) to examine risk of behavioral problems in children using in the presence of time-varying confounding by concomitant medication use; (2) to examine risk of temperamental, motor, and communication disturbances associated with prenatal triptans exposure, adjusting for unmeasured confounding by migraine type and severity; and (3) to examine changes in neurodevelopment over time associated with prenatal triptan exposure.
Methods: This dissertation used data from the Norwegian Mother and Child Cohort Study, a prospective birth cohort including more than 100,000 women recruited during their first prenatal ultrasound visit. Aims 1 and 3 used marginal structural models to assess the risk of (1) neurodevelopmental problems at age 36 months (Aim 1), or (2) change in risk of neurodevelopmental problems from 18 to 36 months (Aim 3) associated with prenatal triptan exposure. Aim 2 used propensity matching and calibration to adjust for unmeasured confounding by migraine type, severity, and attitudes towards medication use in pregnancy. Neurodevelopmental outcome measures included the Child Behavior Checklist (CBCL), the Emotionality, Activity, and Temperament Scale (EAS), and the Ages and Stages Questionnaire (ASQ). Exposure to triptans was ascertained by self-report.
Results: Prenatal triptan exposure was associated with greater externalizing behavior problems at 18 and 36 months, as well as greater increases in emotionality and activity from 18 to 36 months. We observed no association between triptan exposure and motor skills or communication problems; triptan use during pregnancy was associated with migraine severity but not migraine type, and adjustment for unmeasured migraine characteristics moved effect estimates towards the null.
Conclusions: Prenatal triptan exposure is associated with externalizing-type behaviors and temperament in children, while migraine itself is associated with internalizing-type behaviors and temperament. The use of concomitant medications and the severity of the underlying condition both exerted substantial influence on observed effect estimates, and should be considered in any future studies of triptan medication use in pregnancy.
A Randomized, Double-Blind, Placebo-Controlled Trial of Adjunctive Metformin Therapy in Overweight/Obese Youth with Type 1 Diabetes
CONTEXT: Insulin resistance has been proposed as one of the causes of poor glycemic control in overweight/obese youth with type 1 diabetes (T1D). However, the role of adjunctive metformin, an insulin sensitizer, on glycemic control in these patients is unclear.
OBJECTIVE: To compare the effect of metformin vs. placebo on hemoglobin A1c (HbA1c), total daily dose (TDD) of insulin, and other parameters in overweight/obese youth with T1D.
HYPOTHESIS: Adjunctive metformin therapy will improve glycemic control in overweight/obese youth with T1D.
DESIGN, SETTING, AND PARTICIPANTS: A 9-mo randomized, double-blind, placebo controlled trial of metformin and placebo in 28 subjects (13m/15f) of ages 10-20years (y), with HbA1c >8% (64 mmol/mol), BMI >85%, and T1D > 12 months was conducted at a university outpatient facility. The metformin group consisted of 15 subjects (8 m/ 7f), of age 15.0 ± 2.5 y; while the control group was made up of 13 subjects (5m/ 8f), of age 14.5 ± 3.1y. All participants employed a self-directed treat-to-target insulin regimen based on a titration algorithm of (-2)-0-(+2) units to adjust their long-acting insulin dose every 3rd day from -3 mo through +9 mo to maintain fasting plasma glucose (FPG) between 90-120 mg/dL (5.0-6.7 mmol/L). Pubertal maturation was determined by Tanner stage.
RESULTS: Over the course of the 9 months of observation, the between-treatment differences in HbA1c of 0.4% (9.85% [8.82 to 10.88] for placebo versus 9.46% [8.47 to 10.46] for metformin) was not significant (p = 0.903). There were non-significant reduction in fasting plasma glucose (189.4 mg/dL [133.2 to 245.6] for placebo versus 170.5 mg/dL [114.3 to 226.7] for metformin), (p = 0.927); total daily dose (TDD) of short-acting insulin per kg body weight/day(p = 0.936); and the TDD of long-acting insulin per kg body weight per day (1.15 units/kg/day [0.89 to 1.41] for placebo versus 0.90 units/kg/day [0.64 to 1.16] for metformin) (p = 0.221). There was no difference in the occurrence of hypoglycemia between the groups.
CONCLUSIONS: This 9-month RCT of adjunctive metformin therapy in overweight and obese youth with T1D resulted in a 0.4% lower HbA1c value in the metformin group compared to the placebo group.
TRIAL REGISTRATION: ClinicalTrial.gov NCT01334125.
This chapter in Cancer Concepts: A Guidebook for the Non-Oncologist presents an overview of breast cancer, including etiology, screening, pathology, staging, and treatment.
This is the September 2015 issue of the UMass Center for Clinical and Translational Science Newsletter containing news and events of interest.
Comparison of diagnostic performance of CT and MRI for abdominal staging of pediatric renal tumors: a report from the Children's Oncology Group
BACKGROUND: CT and MRI are both used for abdominal staging of pediatric renal tumors. The diagnostic performance of the two modalities for local and regional staging of renal tumors has not been systematically evaluated.
OBJECTIVE: To compare the diagnostic performance of CT and MRI for local staging of pediatric renal tumors.
MATERIALS AND METHODS: The study population was derived from the AREN03B2 study of the Children's Oncology Group. Baseline abdominal imaging performed with both CT and MRI within 30 days of nephrectomy was available for retrospective review in 82 renal tumor cases. Each case was evaluated for capsular penetration, lymph node metastasis, tumor thrombus, preoperative tumor rupture, and synchronous contralateral lesions. The surgical and pathological findings at central review were the reference standard.
RESULTS: The sensitivity of CT and MRI for detecting capsular penetration was 68.6% and 62.9%, respectively (P = 0.73), while specificity was 86.5% and 83.8% (P = 1.0). The sensitivity of CT and MRI for detecting lymph node metastasis was 76.5% and 52.9% (P = 0.22), and specificity was 90.4% and 92.3% (P = 1.0). Synchronous contralateral lesions were identified by CT in 4/9 cases and by MRI in 7/9 cases.
CONCLUSION: CT and MRI have similar diagnostic performance for detection of lymph node metastasis and capsular penetration. MR detected more contralateral synchronous lesions; however these were present in a very small number of cases. Either modality can be used for initial loco-regional staging of pediatric renal tumors.
Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III Non-small-cell lung cancer: Cancer and Leukemia Group B
PURPOSE: Standard therapy for unresectable stage III non-small-cell lung cancer includes concomitant chemoradiotherapy. In Cancer and Leukemia Group B 39801, we evaluated whether induction chemotherapy before concurrent chemoradiotherapy would result in improved survival.
PATIENTS AND METHODS: Between July 1998 and May 2002, 366 patients were randomly assigned to arm A, which involved immediate concurrent chemoradiotherapy with carboplatin area under the concentration-time curve (AUC) of 2 and paclitaxel 50 mg/m2 given weekly during 66 Gy of chest radiotherapy, or arm B, which involved two cycles of carboplatin AUC 6 and paclitaxel 200 mg/m2 administered every 21 days followed by identical chemoradiotherapy. The accrual goal was 360 patients.
RESULTS: Thirty-four percent of patients were female, 66% were male, and the median age was 63 years. Grade 3 or 4 toxicities during induction chemotherapy on arm B consisted mainly of neutropenia (18% and 20%, respectively). During concurrent chemoradiotherapy, there was no difference in severity of in-field toxicities of esophagitis (grade 3 and 4 were, respectively, 30% and 2% for arm A v 28% and 8% for arm B) and dyspnea (grade 3 and 4 were, respectively, 11% and 3% for arm A v 15% and 4% for arm B). Survival differences were not statistically significant (P = .3), with a median survival on arm A of 12 months (95% CI, 10 to 16 months) versus 14 months (95% CI, 11 to 16 months) on arm B and a 2-year survival of 29% (95% CI, 22% to 35%) and 31% (95% CI, 25% to 38%). Age, weight loss before therapy, and performance status were statistically significant predictive factors.
CONCLUSION: The addition of induction chemotherapy to concurrent chemoradiotherapy added toxicity and provided no survival benefit over concurrent chemoradiotherapy alone. The median survival achieved in each of the treatment groups is low, and the routine use of weekly carboplatin and paclitaxel with simultaneous radiotherapy should be re-examined.
Developing a multi-institutional PACS archive and designing processes to manage the shift from a film to a digital-based archive
The Quality Assurance Review Center (QARC) works to improve the standards of care in treating cancer by improving the quality of clinical trials medicine. QARC operates as a data management and review center providing quality assurance services for multiple external groups including cooperative groups and pharmaceutical companies. As the medical world migrates from analog film to digital files, QARC has developed an innovative and unique digital imaging management system to accommodate this trend. As QARC acquires electronic data from institutions across six continents, the system is continually developed to accommodate Digital Imaging and Communications in Medicine (DICOM) imaging originating from a wide variety of Picture Archival and Communications System (PACS) manufacturers, thus creating one of the largest and most diverse multi-institutional imaging archives in the cancer research community.
The effect of radiation timing on patients with high-risk features of parameningeal rhabdomyosarcoma: an analysis of IRS-IV and D9803
PURPOSE: Radiation therapy remains an essential treatment for patients with parameningeal rhabdomyosarcoma (PMRMS), and early radiation therapy may improve local control for patients with intracranial extension (ICE).
METHODS AND MATERIALS: To address the role of radiation therapy timing in PMRMS in the current era, we reviewed the outcome from 2 recent clinical trials for intermediate-risk RMS: Intergroup Rhabdomyosarcoma Study (IRS)-IV and Children's Oncology Group (COG) D9803. The PMRMS patients on IRS-IV with any high-risk features (cranial nerve palsy [CNP], cranial base bony erosion [CBBE], or ICE) were treated immediately at day 0, and PMRMS patients without any of these 3 features received week 6-9 radiation therapy. The D9803 PMRMS patients with ICE received day 0 X-Ray Therapy (XRT) as well; however, those with either CNP or CBBE had XRT at week 12.
RESULTS: Compared with the 198 PMRMS patients from IRS-IV, the 192 PMRMS patients from D9803 had no difference (P < .05) in 5-year local failure (19% vs 19%), failure-free-survival (70% vs 67%), or overall survival (75% vs 73%) in aggregate. The 5-year local failure rates by subset did not differ when patients were classified as having no risk features (None, 15% vs 19%, P = .25), cranial nerve palsy/cranial base of skull erosion (CNP/CBBE, 15% vs 28%, P = .22), or intracranial extension (ICE, 21% vs 15%, P = .27). The D9083 patients were more likely to have received initial staging by magnetic resonance imaging (71% vs 53%).
CONCLUSIONS: These data support that a delay in radiation therapy for high-risk PMRMS features of CNP/CBBE does not compromise clinical outcomes.
Evaluation of smoking-specific and generic quality of life measures in current and former smokers in Germany and the United States
BACKGROUND: Health-related quality of life (QOL) surveys include generic measures that enable comparisons across conditions and measures that focus more specifically on one disease or condition. We evaluated the psychometric properties of German- and English-language versions of survey scales representing both types of measures in samples of current and former smokers.
METHODS: TQOLITv1 integrates new measures of smoking-specific symptoms and QOL impact attributed to smoking with generic SF-36 Health Survey measures. For purposes of evaluation, cross-sectional data were analyzed for two independent samples. Disease-free (otherwise healthy) adults ages 23-55 used a tablet to complete surveys in a clinical trial in Germany (125 current and 54 former smokers). Online general population surveys were completed in the US by otherwise healthy current and former smokers (N = 149 and 110, respectively). Evaluations included psychometric tests of assumptions underlying scale construction and scoring, score distributions, and reliability. Tests of validity included cross-sectional correlations and analyses of variance based on a conceptual framework and hypotheses for groups differing in self-reported smoking behavior (current versus former smoker, cigarettes per day (CPD)) and severity of smoking symptoms in both samples and, in the German trial only, clinical parameters of biomarkers of exposure.
RESULTS: Tests of scaling assumptions and internal consistency reliability (alpha = 0.71-0.79) of the smoking-specific measures were satisfactory, although ceiling effects attenuated correlations for former smokers in both samples. Correlational evidence supporting validity of smoking-specific symptom and impact measures included their substantial inter-correlation and higher correlations (than generic measures) with smoking behavior (favoring former over current groups) and CPD in both samples. In the German trial, both smoking-specific measures correlated significantly (p < 0.05) with all four biomarkers. QOL impact attributed to smoking correlated with the SF-36 mental but not physical summary measures in both samples.
CONCLUSIONS: German- and English-language TQOLITv1 surveys have comparable and satisfactory psychometric properties. Cross-sectional tests, including correlations with four biomarkers, support the validity of the new smoking-specific measures for use in studies of otherwise healthy smokers. Smoking-specific measures consistently performed better than generic QOL measures in all tests of validity.
A cluster randomized Hybrid Type III trial testing an implementation support strategy to facilitate the use of an evidence-based practice in VA homeless programs
BACKGROUND: The Housing and Urban Development-Veterans Affairs Supportive Housing (HUD-VASH) program is one of the largest initiatives to end Veteran homelessness. However, mental health and substance use disorders continue to reduce client stability and impede program success. HUD-VASH programs do not consistently employ evidence-based practices that address co-occurring mental health and substance use disorders. This paper presents a study protocol to evaluate the implementation of an evidence-based, co-occurring disorder treatment called Maintaining Independence and Sobriety Through Systems Integration, Outreach, and Networking-Veterans Edition (MISSION-Vet) in HUD-VASH using an implementation strategy called Getting To Outcomes (GTO).
METHODS/DESIGN: In three large VA Medical Centers, this Hybrid Type III trial will randomize case managers and their clients by HUD-VASH sub-teams to receive either MISSION-Vet Implementation as Usual (IU-standard training and access to the MISSION-Vet treatment manuals) or MISSION-Vet implementation augmented by GTO. In addition to testing GTO, effectiveness of the treatment (MISSION-Vet) will be assessed using existing Veteran-level data from the HUD-VASH data monitoring system. This project will compare GTO and IU case managers and their clients on the following variables: (1) fidelity to the MISSION-Vet intervention; (2) proportion of time the Veteran is housed; (3) mental health, substance use, and functional outcomes among Veterans; and (4) factors key to the successful deployment of a new treatment as specified by the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) model.
DISCUSSION: This project is an important step for developing an implementation strategy to increase adoption of evidence-based practice use in VA homeless programs, and to further examine efficacy of MISSION-Vet in HUD-VASH. This project has important implications for program managers, policy makers, and researchers within the homelessness field. VA Central IRB approval for this study was granted in October 2011. The three sites were trained on MISSION-Vet and GTO in the first half of 2013. The first GTO planning meetings began after training occurred, between January 2013 and November 2013, across the three sites. The data collection-via a fidelity measure embedded into the VA Computerized Patient Record System-began as each site initiated MISSION-Vet, between April 2013 and January 2014.
TRIAL REGISTRATION: ClinicalTrials.gov: NCT01430741.