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1.  Hematopoietic Cell Transplantation for Children with Acute Lymphoblastic Leukemia in Second Complete Remission: Similar Outcomes in Recipients of Unrelated Marrow and Umbilical Cord Blood versus Marrow from HLA Matched Sibling Donors 
Transplant decisions for children with acute lymphoblastic leukemia (ALL) in second complete remission (CR2) are often based on the type of available donor. In many cases, allogeneic hematopoietic cell transplantation (HCT) is considered only if a human leukocyte antigen (HLA) matched sibling donor (MSD) is available. The role of unrelated donor (URD) HCT in this patient population is not well established. As advances in supportive care and donor selection have improved, the use of URD HCT in such patients should be reevaluated. We analyzed the outcomes of 87 consecutive children with ALL in CR2 who underwent allogeneic HCT at the University of Minnesota between 1990 and 2007. Donor sources included MSD bone marrow (n = 32), well and partially matched (M, n = 18) and mismatched (MM, n = 16) URD bone marrow and URD umbilical cord blood (UCB, n = 21). Although the incidence of neutrophil recovery was similar in all groups, the overall incidence of grades II–IV acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD) was 37% and 9%, respectively, with a higher incidence of aGVHD in recipients of URD grafts. Leukemia-free survival (LFS) at 5 years was lower in recipients of MM-URD grafts, but was comparable in all other groups. Although relapse at 5 years was highest in recipients of MSD (50%), results were not significantly different compared to recipients of M-URD (17%), MM-URD (6%), and UCB (33%) (P =.17). The development of grades II–IV aGVHD and a first remission >3 years were associated with a lower risk of relapse (relative risk [RR] 0.2, P =.03; RR 0.2. P =.01 respectively). Together, these results support the continued investigation of URD HCT for ALL in CR2, and suggest the timing of HCT in these children should be based primarily on the risk of relapse with conventional chemotherapy and not on the type of donor available.
PMCID: PMC5225985  PMID: 19660721
Acute lymphoblastic leukemia; Second complete remission; Unrelated donor hematopoietic cell transplantation; Umbilical cord blood
2.  Acute kidney injury and the risk of mortality in children undergoing hematopoietic stem cell transplantation 
Acute kidney injury (AKI) is a well-documented complication of pediatric hematopoietic stem cell transplantation (HSCT). Dialysis after HSCT is associated with a lower overall survival (OS); however, the association between less severe AKI and OS is unclear.
We retrospectively studied 205 consecutive pediatric HSCT patients to determine the incidence and impact of all stages of AKI on OS in pediatric HSCT recipients. We used the peak pRIFLE grade during the first 100 days to classify AKI (R=risk, I= injury, F= failure, L= loss of function, E= End-stage renal disease) and used the modified Schwartz formula to estimate glomerular filtration rate.
AKI was observed in 173 of the 205 patients (84%). The 1-year OS decreased significantly with an increasing severity of pRIFLE grades (p < 0.01). There was no difference in the OS between patients without AKI and the R/I group. Regardless of the dialysis status, stages F/L/E had significantly lower OS compared with patients without AKI or R/I (p < 0.01). There was no difference in OS among patients with dialysis and F/L/E without dialysis (p 0.65). Stages F/L/E predicted mortality independent of acute graft versus host disease, gender, and malignancy.
The OS of children after HSCT decreases significantly with an increasing severity of AKI within the first 100 days posttransplant. While our data did not show an increased risk of mortality with stages R/I, stages F/L/E predicted mortality regardless of dialysis. Prevention and minimization of AKI may improve survival after pediatric HSCT.
PMCID: PMC5178146  PMID: 27034153
3.  tRNA-dependent alanylation of diacylglycerol and phosphatidylglycerol in Corynebacterium glutamicum 
Molecular microbiology  2015;98(4):681-693.
Aminoacyl-phosphatidylglycerol synthases (aaPGSs) are membrane proteins that utilize aminoacylated tRNAs to modify membrane lipids with amino acids. Aminoacylation of membrane lipids alters the biochemical properties of the cytoplasmic membrane, and enables bacteria to adapt to changes in environmental conditions. aaPGSs utilize alanine, lysine, and arginine as modifying amino acids, and the primary lipid recipients have heretofore been defined as phosphatidylglycerol (PG) and cardiolipin. Here we identify a new pathway for lipid aminoacylation, conserved in many Actinobacteria, which results in formation of Ala-PG and a novel alanylated lipid, Ala-diacylglycerol (Ala-DAG). Ala-DAG formation in Corynebacterium glutamicum is dependent on the activity of an aaPGS homolog, while formation of Ala-PG requires the same enzyme acting in concert with a putative esterase encoded upstream. The presence of alanylated lipids is sufficient to enhance the bacterial fitness of C. glutamicum cultured in the presence of certain antimicrobial agents, and elucidation of this system expands the known repertoire of membrane lipids acting as substrates for amino acid modification in bacterial cells.
PMCID: PMC4639916  PMID: 26235234
phospholipids; multiple peptide resistance factor (MprF); Actinobacteria; diacylglycerol; phosphatidylglycerol; aminoacyl-tRNA synthetase; transfer RNA (tRNA); amino acid; lipids; membrane proteins
4.  Neoadjuvant chemotherapy administration and time to cystectomy for muscle-invasive bladder cancer: An evaluation of transitions between academic and community settings 
Urologic oncology  2015;33(9):386.e1-386.e6.
Neoadjuvant chemotherapy (NAC) before radical cystectomy is the standard of care for muscle-invasive bladder cancer (MIBC). Many patients are referred to an academic medical center (AMC) for cystectomy but receive NAC in the community setting. This study examines if administration of NAC in the community is associated with differences in type of NAC received, pathologic response rate (pT0), and time to cystectomy as compared to NAC administered at an AMC.
We performed a retrospective study of patients with MIBC (cT2a-T4-Nx-M0) referred to a single AMC between 1/2012 and 1/2014 who received NAC. We analyzed chemotherapy received, time to cystectomy, pT0, and survival in patients who received NAC in our AMC compared to those treated in the community.
In all, 47 patients were analyzed. A similar total dose of cisplatin (median: 280 mg/m2 for both groups, P =0.82) and pT0 rate (25% vs. 29%, P =0.72) were seen in patients treated in our AMC and the community. However, administration of NAC in the community was associated with a prolonged time to cystectomy compared with that in our AMC (median number of days 162 vs. 128, P < 0.01). This remained significant after adjusting for stage, comorbidity status, and distance to the AMC (P =0.02). Disease-free survival and overall survival did not differ.
Patients with MIBC treated with NAC in the community as compared to an AMC received similar chemotherapy and achieved comparable pT0 rates, indicating effective implementation of NAC in the community. However, NAC in the community was associated with longer time to cystectomy, suggesting a delay in the transition of care between settings.
PMCID: PMC5084688  PMID: 26122712
Cystectomy; Neoadjuvant therapy; Urinary bladder neoplasms; Time factors; Quality indicators
5.  Factors Associated with Hematopoietic Cell Transplantation (HCT) Among Patients in a Population Based Study of Myelodysplastic Syndrome (MDS) in Minnesota 
Annals of hematology  2015;94(10):1667-1675.
Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disorder characterized by dysplastic changes in the bone marrow, ineffective erythropoiesis and an increased risk of developing acute myeloid leukemia. Treatment planning for patients with MDS is a complex process and we sought to better characterize HCT outcomes and the factors that play into decision-making regarding referral of adults with MDS for definitive therapy with hematopoietic cell transplantation (HCT). Patients enrolled in a population based study of MDS between April 2010 and January 2013 who underwent HCT within the first year after enrollment were included in this analysis. Age and risk matched MDS patient controls also enrolled during that time period were used as a comparison. Survival was significantly better in the HCT group (48% vs. 21%, log-rank p-value 0.009). Non-HCT patients were more likely to have comorbidities and HCT patients were more likely to have a college degree and an income >$80,000. All three of these variables were independently associated with HCT, but none impacted survival. Patients with MDS in our study who underwent HCT had better survival than a comparable group of patients who did not undergo HCT. With refined treatment techniques more patients may be able to be considered for this therapy. More work needs to be done to determine why education and income appear to impact the decision to pursue HCT, but these factors may impact referral to an academic center where aggressive therapy like HCT is more likely to be considered.
PMCID: PMC4725732  PMID: 26063191
MDS; myelodysplastic syndrome; hematopoietic cell transplantation; epidemiology
6.  Nutritional Predictors of Complications Following Radical Cystectomy 
World journal of urology  2014;33(8):1129-1137.
To determine the impact of preoperative nutritional status on the development of surgical complications following cystectomy using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP).
We performed a retrospective review of the NSQIP 2005–2012 Participant Use Data Files. ACS-NSQIP collects data on 135 variables, including pre- and intraoperative data and 30-day post-operative complications and mortality on all major surgical procedures at participating institutions. Preoperative albumin (<3.5 or >3.5 g/dl), weight loss 6 months before surgery (>10%), and BMI were identified as nutritional variables within the database. The overall complication rate was calculated and predictors of complications were identified using multivariable logistic regression models.
1,213 patients underwent cystectomy for bladder cancer between 2005–2012. The overall 30-day complication rate was 55.1% (n=668). While 14.7% (n=102) had a preoperative albumin <3.5 g/dL, 3.4% had >10% weight loss in the 6 months prior to surgery, and the mean BMI was 28 kg/m2. After controlling for age, sex, medical comorbidities, medical resident involvement, operation year, operative time and prior operation, only albumin <3.5g/dl was a significant predictor of experiencing a postoperative complication (p=0.03). This remained significant when albumin was evaluated as a continuous variable (p=0.02)
Poor nutritional status measured by serum albumin is predictive of an increased rate of surgical complications following radical cystectomy. This finding supports the importance of preoperative nutritional status in this population and highlights the need for the development of effective nutritional interventions in the preoperative setting.
PMCID: PMC5015441  PMID: 25240535
nutrition; albumin; cystectomy; outcomes assessment; urinary bladder neoplasms
7.  21-Gene recurrence score decreases receipt of chemotherapy in ER+ early-stage breast cancer: an analysis of the NCDB 2010–2013 
The purpose of this study was to determine if receipt of chemotherapy was associated with utilization of the 21-gene recurrence score assay (RS assay) or with recurrence score (RS) in eligible patients. Using the National Cancer Data Base (NCDB), we identified female patients eligible for RS assay based on National Comprehensive Cancer Network (NCCN) guidelines: age 18–70, ER-positive and HER2-negative early-stage breast cancer diagnosed during 2010–2013. We excluded patients not meeting testing guidelines. Inclusion required result of RS in patients who underwent RS assay and status for receipt of chemotherapy. Multivariable logistic regression models and propensity matched analysis were used to determine associations between RS assay and RS with receipt of chemotherapy. Among 129,765 patients who were eligible, 74,778 underwent RS assay and had results available. Of these, 59.5 % (44,505) had low-risk, 32.0 % (23,920) had intermediate-risk, and 8.5 % (6353) had high-risk RS. Patients with intermediate- and high-risk RS were more likely to receive chemotherapy [OR 12.9 (CI 12.2–13.6), p <0.001 and OR 87.2 (CI 79.6–95.6), p <0.0001], respectively. In both low- and intermediate-risk groups, increasing RS score was significantly associated with increasing odds of receiving chemotherapy [OR 1.10 (CI 1.09–1.12), p <0.0001 and OR 1.26 (CI 1.25–1.27), p <0.0001, respectively, for each point increase in RS]. Receipt of chemotherapy was more likely in patients who did not undergo RS assay compared to those who did, OR 1.21 (CI 1.175–1.249) p <0.0001. The utilization of RS assay and the RS were both strongly associated with chemotherapy receipt. Patients eligible for chemotherapy, based on NCCN criteria, were more likely to receive chemotherapy if they did not undergo RS assay or they had a high RS.
PMCID: PMC5012154  PMID: 27507245
Breast cancer; 21-Gene RS; Oncotype Dx; NCDB; Adjuvant chemotherapy
8.  Riboswitch RNAs 
RNA biology  2010;7(1):104-110.
Riboswitches are cis-encoded, cis-acting RNA elements that directly sense a physiological signal. Signal response results in a change in RNA structure that impacts gene expression. Elements of this type play an important role in bacteria, where they regulate a variety of fundamental cellular pathways. Riboswitch-mediated gene regulation most commonly occurs by effects on transcription attenuation, to control whether a full-length transcript is synthesized, or on translation initiation, in which case the transcript is constitutively synthesized but binding of the translation initiation complex is modulated. An overview of the role of riboswitch RNAs in bacterial gene expression will be provided, and a few examples are described in more detail to illustrate the types of mechanisms that have been uncovered.
PMCID: PMC4959611  PMID: 20061810
transcription attenuation; antitermination; translation control; RNA aptamer; regulation
9.  Assessing Sexually Intrusive Thoughts: Parsing Unacceptable Thoughts on the Dimensional Obsessive-Compulsive Scale 
Behavior therapy  2015;46(4):544-556.
Sexual obsessions are a common symptom of obsessive-compulsive disorder (OCD), often classified in a broader symptom dimension that includes aggressive and religious obsessions, as well. Indeed, the Dimensional Obsessive-Compulsive Scale (DOCS) Unacceptable Thoughts Scale includes obsessional content relating to sexual, violent, and religious themes associated with rituals that are often covert. However, there is reason to suspect that sexual obsessions differ meaningfully from other types of unacceptable thoughts. We conducted two studies to evaluate the factor structure, initial psychometric characteristics, and associated clinical features of a new DOCS scale for sexually intrusive thoughts (SIT). In the first study, nonclinical participants (N = 475) completed the standard DOCS with additional SIT questions and we conducted an exploratory factor analysis on all items and examined clinical and cognitive correlates of the different scales, as well as test-retest reliability. The SIT Scale was distinct from the Unacceptable Thoughts Scale and was predicted by different obsessional cognitions. It had good internal consistency and there was evidence for convergent and divergent validity. In the second study, we examined the relationships among the standard DOCS and SIT scales, as well as types of obsessional cognitions and symptom severity, in a clinical sample of individuals with OCD (N = 54). There were indications of both convergence and divergence between the Unacceptable Thoughts and SIT scales, which were strongly correlated with each other. Together, the studies demonstrate the potential utility of assessing sexually intrusive thoughts separately from the broader category of unacceptable thoughts.
PMCID: PMC4809189  PMID: 26163717
OCD; sexual obsessions; unacceptable thoughts; assessment; symptom dimensions
10.  Resident Involvement and Experience Do Not Affect Peri-Operative Complications Following Robotic Prostatectomy 
World journal of urology  2014;33(6):793-799.
Most urologic training programs use robotic prostatectomy (RP) as an introduction to teach residents appropriate robotic technique. However, concerns may exist regarding differences in RP outcomes with resident involvement. Our objective was therefore to evaluate whether resident involvement affects complications, operative time, or length of stay following RP.
Using the National Surgical Quality Improvement Program database (2005 – 2011), we identified patients who underwent RP, stratified them by resident presence or absence during surgery, and compared hospital length of stay (LOS), operative time, and postoperative complications using bivariable and multivariable analyses. A secondary analysis comparing outcomes of interest across postgraduate year (PGY) levels was also performed.
5,087 patients who underwent RPs were identified, in which residents participated in 56%, during the study period. After controlling for potential confounders, resident present and absent groups were similar in 30-day mortality (0.0% vs. 0.2%, p = 0.08), serious morbidity (1.8% vs. 2.1%, p = 0.33), and overall morbidity (5.1% vs. 5.4%, p = 0.70). While resident involvement did not affect LOS, operative time was longer when residents were present (median: 208 vs. 183 minutes, p < 0.001). Similar findings were noted when assessing individual PGY levels.
Regardless of PGY level, resident involvement in RPs appears safe and does not appear to affect postoperative complications or length of stay. While resident involvement in RPs does result in longer operative times, this is necessary for the learning process.
PMCID: PMC4282627  PMID: 24985554
residents; surgical training; robotics; prostatectomy; complications
11.  Endovascular coil retrieval using a TrevoProVue stentriever 
BMJ Case Reports  2014;2014:bcr2014011181.
A 65-year-old man with a left cavernous internal carotid artery cerebral aneurysm experienced a premature detachment of the first framing coil (10 mm×40 cm Penumbra Complex Standard) during a coil embolization procedure. The coil herniated into the anterior cerebral artery and pericallosal artery. Multiple attempts to retrieve the coil using both a 2 and 4 mm Microsnare (Amplatz GooseNeck) failed. A Trevo ProVue retrievable stent was then used to retrieve the coil without any adverse events. This case report highlights a novel use of a stent for the removal of a foreign body from the cerebrovascular system.
PMCID: PMC4009877  PMID: 24759162
Aneurysm; Coil; Stent; Complication
12.  Provider-based research networks and the diffusion of surgical technologies among patients with early-stage kidney cancer 
Cancer  2014;121(6):836-843.
Provider-based research networks, such as the National Cancer Institute’s Community Clinical Oncology Program (CCOP), have been shown to facilitate the translation of evidence-based cancer care into clinical practice. As such, we compared utilization of laparoscopy and partial nephrectomy among patients with early-stage kidney cancer according to exposure to CCOP-affiliated providers.
Using linked SEER-Medicare data, we identified patients with T1aN0M0 kidney cancer treated with nephrectomy from 2000–2007. For each patient, we determined receipt of care from a CCOP physician or hospital and treatment with laparoscopy or partial nephrectomy. Adjusting for patient characteristics (e.g., age, gender, marital status) and other organizational features (e.g., community hospital, NCI-designated cancer center), we used multivariable logistic regression to estimate the association between each surgical innovation and CCOP affiliation.
Over the study interval, we identified 1,578 (26.8%) patients treated by a provider with CCOP affiliation. Trends in laparoscopy and partial nephrectomy utilization remained similar between affiliated and non-affiliated providers (p≥0.05). Adjusting for patient characteristics, organizational features, and clustering, we noted no association between CCOP affiliation and the use of laparoscopy (OR 1.11, 95% CI 0.81–1.53) or partial nephrectomy (OR 1.04, 95% CI 0.82–1.32) despite the relatively higher receipt of these treatments in academic settings (p-values<0.05).
At a population-level, patients treated by providers affiliated with CCOP were no more likely to receive at least one of two surgical innovations for treatment of their kidney cancer, indicating perhaps a more limited scope to provider-based research networks as they pertain to translational efforts in cancer care.
PMCID: PMC4352108  PMID: 25410684
kidney neoplasm; translation research; diffusion of innovation; provider-based research networks; laparoscopy; nephrectomy
13.  Evaluation and Management of the Geriatric Urologic Oncology Patient 
Current geriatrics reports  2014;4(1):7-15.
The geriatric population presents a unique set of challenges in urologic oncology. In addition to the known natural history of disease, providers must also consider patient factors such as functional and nutritional status, comorbidities and social support when determining the treatment plan. The development of frailty measures and biomarkers to estimate surgical risk shows promise, with several assessment tools predictive of surgical complications. Decreased dependence on chronologic age is important when assessing surgical fitness, as age cutoffs prevent appropriate treatment of many elderly patients who would benefit from surgery. Within bladder, kidney and prostate cancers, continued refinement of surgical techniques offers a broader array of options for the geriatric patient than previously available.
PMCID: PMC4321682  PMID: 25678987
Elderly; frailty; comorbidity; risk assessment; geriatric assessment; competing risks; active surveillance; prostate cancer; bladder cancer; kidney cancer
14.  Exploring the Burden of Inpatient Readmissions After Major Cancer Surgery 
Journal of Clinical Oncology  2014;33(5):455-464.
Travel distances to care have increased substantially with centralization of complex cancer procedures at high-volume centers. We hypothesize that longer travel distances are associated with higher rates of postoperative readmission and poorer outcomes.
SEER-Medicare patients with bladder, lung, pancreas, or esophagus cancer who were diagnosed in 2001 to 2007 and underwent extirpative surgery were included. Readmission rates and survival were calculated using Kaplan-Meier functions. Multivariable negative binomial models were used to examine factors associated with readmission.
Four thousand nine hundred forty cystectomies, 1,573 esophagectomies, 20,362 lung resections, and 2,844 pancreatectomies were included. Thirty- and 90-day readmission rates ranged from 13% to 29% and 23% to 43%, respectively, based on tumor type. Predictors of readmission were discharge to somewhere other than home, longer length of stay, comorbidities, higher stage at diagnosis, and longer travel distance (P < .001 for each). Patients who lived farther from the index hospital also had increased emergency room visits and were more likely to be readmitted to a hospital other than the index hospital (P < .001). Of readmitted patients, 31.9% were readmitted more than once. Long-term survival was worse and costs of care higher for patients who were readmitted (P < .001 for all).
The burden of readmissions after major cancer surgery is high, resulting in substantially poorer patient outcomes and higher costs. Risk of readmission was most strongly associated with length of stay and discharge destination. Travel distance also has an impact on patterns of readmission. Interventions targeted at higher risk individuals could potentially decrease the population burden of readmissions after major cancer surgery.
PMCID: PMC4314594  PMID: 25547502
15.  Readability of American Online Patient Education Materials in Urologic Oncology: a Need for Simple Communication 
Urology  2014;85(2):351-356.
To determine readability levels of reputable cancer and urologic websites addressing bladder, prostate, kidney and testicular cancers.
Online patient education materials (PEMs) for bladder, prostate, kidney and testicular malignancies were evaluated from the American Cancer Society, American Society of Clinical Oncology (ASCO), National Cancer Institute (NCI), Urology Care Foundation (AUA-UCF), Bladder Cancer Advocacy Network (BCAN), Prostate Cancer Foundation (PCF), Kidney Cancer Association (KCA), and Testicular Cancer Resource Center (TCRC). Grade level was determined using several readability indices, and analyses were performed based on cancer type, website, and content area (general, causes, risk factors and prevention, diagnosis and staging, treatment, and post-treatment).
Estimated grade level of online PEMs ranged from 9.2 to 14.2 with an overall mean of 11.7. Websites for kidney cancer had the least difficult readability (11.3) and prostate cancer had the most difficult readability (12.1). Among specific websites, the most difficult readability levels were noted for the AUA-UCF website for bladder and prostate cancer and the KCA and TCRC for kidney and testes cancer. Readability levels within content areas varied based on disease and website.
Online PEMs in urologic oncology are written at a level above the average American reader. Simplification of these resources are necessary to improve patient understanding of urologic malignancy.
PMCID: PMC4308671  PMID: 25623686
readability; health literacy; urologic oncology; urinary bladder neoplasms; kidney neoplasms; testicular neoplasms; prostatic neoplasms
16.  Geriatric Assessment in Surgical Oncology: A Systematic Review 
The Journal of surgical research  2014;193(1):265-272.
The comprehensive geriatric assessment (CGA) has developed as an important prognostic tool to risk stratify older adults and has recently been applied to the surgical field. In this systematic review, we examined the utility of CGA components as predictors of adverse outcomes among geriatric patients undergoing major oncologic surgery.
Materials and Methods
MEDLINE, Embase, and the Cochrane Library were searched for prospective studies examining the association of components of the CGA with specific outcomes among geriatric patients undergoing elective oncologic surgery. Outcome parameters included 30-day post-operative complications, mortality, and discharge to a non-home institution.
The initial search identified 178 potentially relevant articles, with six studies meeting inclusion criteria. Deficiencies in instrumental activities of daily living (IADLs), ADLs, fatigue, cognition, frailty, and cognitive impairment were associated with increased post-operative complications. No CGA predictors were identified for post-operative mortality while frailty, deficiencies in IADLs, and depression predicted discharge to a non-home institution.
Across a variety of surgical oncologic populations and cancer types, components of the CGA appear to be predictive of post-operative complications and discharge to a non-home institution. These results argue for inclusion of focused geriatric assessments as part of routine pre-operative care in the geriatric surgical oncology population.
PMCID: PMC4267910  PMID: 25091339
cancer surgery; geriatric assessment; treatment outcome; survival; complication
17.  The somatic genomic landscape of chromophobe renal cell carcinoma 
Cancer cell  2014;26(3):319-330.
We describe the landscape of somatic genomic alterations of 66 chromophobe renal cell carcinomas (ChRCCs) based on multidimensional and comprehensive characterization, including mitochondrial DNA (mtDNA) and whole genome sequencing. The result is consistent that ChRCC originates from the distal nephron compared to other kidney cancers with more proximal origins. Combined mtDNA and gene expression analysis implicates changes in mitochondrial function as a component of the disease biology, while suggesting alternative roles for mtDNA mutations in cancers relying on oxidative phosphorylation. Genomic rearrangements lead to recurrent structural breakpoints within TERT promoter region, which correlates with highly elevated TERT expression and manifestation of kataegis, representing a mechanism of TERT up-regulation in cancer distinct from previously-observed amplifications and point mutations.
PMCID: PMC4160352  PMID: 25155756
18.  Neoadjuvant Chemotherapy for Bladder Cancer Does Not Increase Risk of Perioperative Morbidity 
BJU international  2014;114(2):221-228.
• To determine whether neoadjuvant chemotherapy (NAC) is a predictor of post-operative complications, length of stay, or operative time after radical cystectomy f stay, or operative time after radical cystectomy (RC) for bladder cancer.
Patients and Methods
• A retrospective review of the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database was performed to identify patients receiving NAC prior to RC from 2005–2011.
• Bivariable and multivariable analyses were performed to determine whether NAC was associated with 30-day peri-operative outcomes such as complications, length of stay, and operative time.
• Of the 878 patients who underwent RC for bladder cancer in our study, 78 (8.9%) received NAC. Excluding those patients who were ineligible for NAC due to renal insufficiency, 78/642 (12.1%) received NAC.
• 457 of the 878 patients (52.1%) undergoing RC had at least 1 complication within 30 days, including 43 of 78 patients (55.1%) who received NAC and 414 of 800 patients (51.8%) who did not (p = 0.58).
• On multivariable logistic regression, NAC was not a predictor of complications (p=0.87), reoperation (p=0.16), wound infection (p=0.32), or wound dehiscence(p=0.32).
• Using multiple linear regression, NAC was not a predictor of increased operative time (p=0.24), and patients undergoing NAC had decreased hospital length of stay (p=0.02).
• Our study is the first large multi-institutional analysis specifically comparing complications after RC with and without NAC.
• Using a nationally validated, prospectively maintained database specifically designed to measure perioperative outcomes, we found no increase in perioperative complications or surgical morbidity with NAC.
• In light of these findings and the well-established overall survival benefit over surgery alone, efforts are needed to improve the uptake of NAC.
PMCID: PMC4033705  PMID: 24274722
19.  Inverse dynamics modelling of upper-limb tremor, with cross-correlation analysis 
Healthcare Technology Letters  2014;1(2):59-63.
A method to characterise upper-limb tremor using inverse dynamics modelling in combination with cross-correlation analyses is presented. A 15 degree-of-freedom inverse dynamics model is used to estimate the joint torques required to produce the measured limb motion, given a set of estimated inertial properties for the body segments. The magnitudes of the estimated torques are useful when assessing patients or evaluating possible intervention methods. The cross-correlation of the estimated joint torques is proposed to gain insight into how tremor in one limb segment interacts with tremor in another. The method is demonstrated using data from a single patient presenting intention tremor because of multiple sclerosis. It is shown that the inertial properties of the body segments can be estimated with sufficient accuracy using only the patient's height and weight as a priori knowledge, which ensures the method's practicality and transferability to clinical use. By providing a more detailed, objective characterisation of patient-specific tremor properties, the method is expected to improve the selection, design and assessment of treatment options on an individual basis.
PMCID: PMC4614064  PMID: 26609379
biomechanics; torque; diseases; patient treatment; inverse dynamics modelling; upper limb tremor; cross-correlation analysis; joint torques; limb motion; inertial properties; intention tremor; multiple sclerosis; body segments; patient treatment
20.  Effect of comorbidity on risk of venous thromboembolism in patients with renal cell carcinoma1 
Urologic oncology  2014;32(4):466-472.
Venous thromboembolism (VTE) is associated with renal cell carcinoma (RCC), but data on the effect of comorbidities are limited. Therefore, our purpose was to determine the effect of comorbidity on VTE risk among patients with RCC.
Materials and methods
A population-based cohort of all patients with RCC (n = 8,633) diagnosed in Denmark between 1995 and 2010 and a comparison cohort selected from the general population and matched on age, sex, and comorbidities (n = 83,055) were identified. Risk of subsequent VTE was estimated with 95% CI for the first 3 months, 1 year, and 5 years following cancer diagnosis. We stratified by Charlson comorbidity index (CCI) scores to estimate excess risk in patients with RCC vs. the comparison cohort within comorbidity strata. We also performed subanalyses for postoperative VTE and metastases.
VTE risk was higher in the RCC compared with comparison cohort, particularly during the initial year following diagnosis (risk difference = 9.9 per 1,000 persons [95% CI: 7.7–12.2]). After stratifying by CCI, excess risk declined with increasing comorbidities. The risk difference was 12.3 per 1,000 persons (95% CI: 9.1–15.5) for CCI = 0 and 0.5 (95% CI: 6.0–7.0) for CCI = 4. Excess risk also declined with increasing comorbidities among patients with postoperative VTE and among those with metastases.
RCC is associated with increased risk of VTE when compared with a matched general population cohort. Risk did not appear to increase with added comorbidity burden. Clinical attention to VTE risk in patients with RCC is appropriate regardless of the presence or absence of comorbidities.
PMCID: PMC4017852  PMID: 24767684
Carcinoma; Renal cell; Venous thromboembolism; Incidence; Epidemiology; Comorbidity
21.  Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Hemoglobinopathies Using a Reduced-Intensity Conditioning Regimen and Third-Party Mesenchymal Stromal Cells 
Allogeneic hematopoietic stem cell transplantation for patients with a hemoglobinopathy can be curative but is limited by donor availability. Although positive results are frequently observed in those with an HLA-matched sibling donor, use of unrelated donors has been complicated by poor engraftment, excessive regimen-related toxicity, and graft-versus-host disease (GVHD). As a potential strategy to address these obstacles, a pilot study was designed that incorporated both a reduced-intensity conditioning and mesenchymal stromal cells (MSCs). Six patients were enrolled, including 4 with high-risk sickle cell disease (SCD) and 2 with transfusion-dependent thalassemia major. Conditioning consisted of fludarabine (150 mg/m2), melphalan (140 mg/m2), and alemtuzumab (60 mg for patients weighing > 30 kg and.9 mg/kg for patients weighing <30 kg). Two patients received HLA 7/8 allele matched bone marrow and 4 received 4-5/6 HLA matched umbilical cord blood as the source of HSCs. MSCs were of bone marrow origin and derived from a parent in 1 patient and from an unrelated third-party donor in the remaining 5 patients. GVHD prophylaxis consisted of cyclosporine A and mycophenolate mofetil. One patient had neutropenic graft failure, 2 had autologous hematopoietic recovery, and 3 had hematopoietic recovery with complete chimerism. The 2 SCD patients with autologous hematopoietic recovery are alive. The remaining 4 died either from opportunistic infection, GVHD, or intracranial hemorrhage. Although no infusion-related toxicity was seen, the cotransplantation of MSCs was not sufficient for reliable engraftment in patients with advanced hemoglobinopathy. Although poor engraftment has been observed in nearly all such trials to date in this patient population, there was no evidence to suggest that MSCs had any positive impact on engraftment. Because of the lack of improved engraftment and unacceptably high transplant-related mortality, the study was prematurely terminated. Further investigations into understanding the mechanisms of graft resistance and development of strategies to overcome this barrier are needed to move this field forward.
PMCID: PMC3998675  PMID: 24370862
Hemoglobinopathies; Sickle cell disease; Thalassemia; Hematopoietic stem cell transplant; Reduced-intensity conditioning; Mesenchymal stromal cells; Umbilical cord; Bone marrow; Engraftment; Graft-versus-host disease
22.  Transplantation Outcomes for Severe Combined Immunodeficiency, 2000–2009 
The New England journal of medicine  2014;371(5):434-446.
The Primary Immune Deficiency Treatment Consortium was formed to analyze the results of hematopoietic-cell transplantation in children with severe combined immunodeficiency (SCID) and other primary immunodeficiencies. Factors associated with a good transplantation outcome need to be identified in order to design safer and more effective curative therapy, particularly for children with SCID diagnosed at birth.
We collected data retrospectively from 240 infants with SCID who had received transplants at 25 centers during a 10-year period (2000 through 2009).
Survival at 5 years, freedom from immunoglobulin substitution, and CD3+ T-cell and IgA recovery were more likely among recipients of grafts from matched sibling donors than among recipients of grafts from alternative donors. However, the survival rate was high regardless of donor type among infants who received transplants at 3.5 months of age or younger (94%) and among older infants without prior infection (90%) or with infection that had resolved (82%). Among actively infected infants without a matched sibling donor, survival was best among recipients of haploidentical T-cell–depleted transplants in the absence of any pretransplantation conditioning. Among survivors, reduced-intensity or myeloablative pre-transplantation conditioning was associated with an increased likelihood of a CD3+ T-cell count of more than 1000 per cubic millimeter, freedom from immunoglobulin substitution, and IgA recovery but did not significantly affect CD4+ T-cell recovery or recovery of phytohemagglutinin-induced T-cell proliferation. The genetic subtype of SCID affected the quality of CD3+ T-cell recovery but not survival.
Transplants from donors other than matched siblings were associated with excellent survival among infants with SCID identified before the onset of infection. All available graft sources are expected to lead to excellent survival among asymptomatic infants. (Funded by the National Institute of Allergy and Infectious Diseases and others.)
PMCID: PMC4183064  PMID: 25075835
23.  Short-read, high-throughput sequencing technology for STR genotyping 
DNA-based methods for human identification principally rely upon genotyping of short tandem repeat (STR) loci. Electrophoretic-based techniques for variable-length classification of STRs are universally utilized, but are limited in that they have relatively low throughput and do not yield nucleotide sequence information. High-throughput sequencing technology may provide a more powerful instrument for human identification, but is not currently validated for forensic casework. Here, we present a systematic method to perform high-throughput genotyping analysis of the Combined DNA Index System (CODIS) STR loci using short-read (150 bp) massively parallel sequencing technology. Open source reference alignment tools were optimized to evaluate PCR-amplified STR loci using a custom designed STR genome reference. Evaluation of this approach demonstrated that the 13 CODIS STR loci and amelogenin (AMEL) locus could be accurately called from individual and mixture samples. Sensitivity analysis showed that as few as 18,500 reads, aligned to an in silico referenced genome, were required to genotype an individual (>99% confidence) for the CODIS loci. The power of this technology was further demonstrated by identification of variant alleles containing single nucleotide polymorphisms (SNPs) and the development of quantitative measurements (reads) for resolving mixed samples.
PMCID: PMC4301848  PMID: 25621315
STR; forensic; next-generation sequencing; high-throughput sequencing; Illumina; Bridge PCR; SNP; genotyping
24.  Trends in Stage-Specific Incidence Rates for Urothelial Carcinoma of the Bladder in the United States: 1988 to 2006 
Cancer  2013;120(1):86-95.
Bladder cancer is notable for a striking heterogeneity of disease-specific risks. Among the approximately 75% of incident cases found to be superficial to the muscularis propria at the time of presentation (non-muscle-invasive bladder cancer), the risk of progression to the lethal phenotype of muscle-invasive disease is strongly associated with stage and grade of disease. Given the suggestion of an increasing percentage of low-risk cases in hospital-based registry data in recent years, the authors hypothesized that population-based data may reveal changes in the stage distribution of early-stage cases.
Surveillance, Epidemiology, and End Results (SEER) data were used to examine trends for the stage-specific incidence of bladder cancer between 1988 and 2006, adjusted for age, race, and sex, using Joinpoint and nonparametric tests.
The adjusted incidence rate of papillary noninvasive (Ta) predominantly low grade (77%) disease was found to increase from 5.52 to 9.09 per 100,000 population (P <.0001), with an average annual percentage change of +3.3. Over the same period, concomitant, albeit smaller, decreases were observed for flat in situ (Tis) and lamina propria-invasive (T1) disease (2.57 to 1.19 and 6.65 to 4.61 per 100,000 population [both P <.0001]; average annual percent change of −5.0 and −1.6, respectively). The trend was most dramatic among patients in the oldest age strata, suggesting a previously unappreciated cohort phenomenon.
The findings of the current study should motivate further epidemiological investigations of differential associations of genetic and environmental factors with different bladder cancer phenotypes as well as further scrutiny of clinical practice guideline recommendations for the growing subgroup of predominantly older patients with lower-risk disease.
PMCID: PMC3964001  PMID: 24122346
bladder cancer; incidence; epidemiology; carcinogenesis; stage migration
25.  Roadmap for the Development of the University of North Carolina at Chapel Hill Genitourinary OncoLogy Database – UNC GOLD 
Urologic oncology  2013;32(1):32.e1-32.e9.
The management of genitourinary malignancies requires a multidisciplinary care team composed of urologists, medical oncologists and radiation oncologists. A genitourinary (GU) oncology clinical database is an invaluable resource for patient care and research. Although electronic medical records provide a single web-based record used for clinical care, billing and scheduling, information is typically stored in a discipline-specific manner and data extraction is often not applicable to a research setting. A GU oncology database may be used for the development of multidisciplinary treatment plans, analysis of disease-specific practice patterns, and identification of patients for research studies. Despite the potential utility, there are many important considerations that must be addressed when developing and implementing a discipline-specific database.
Methods and Materials
The creation of the GU oncology database including prostate, bladder and kidney cancers with the identification of necessary variables was facilitated by meetings of stakeholders in medical oncology, urology, and radiation oncology at the University of North Carolina (UNC) at Chapel Hill with a template data dictionary provided by the Department of Urologic Surgery at Vanderbilt University Medical Center. Utilizing Research Electronic Data Capture (REDCap, version 4.14.5), the UNC Genitourinary OncoLogy Database (UNC GOLD) was designed and implemented.
The process of designing and implementing a discipline-specific clinical database requires many important considerations. The primary consideration is determining the relationship between the database and the Institutional Review Board (IRB) given the potential applications for both clinical and research uses. Several other necessary steps include ensuring information technology security and federal regulation compliance; determination of a core complete data set; creation of standard operating procedures; standardizing entry of free text fields; use of data exports, queries, and de-identification strategies; inclusion of individual investigators’ data; and strategies for prioritizing specific projects and data entry.
A discipline-specific database requires a buy-in from all stakeholders, meticulous development, and data entry resources in order to generate a unique platform for housing information that may be used for clinical care and research with IRB approval. The steps and issues identified in the development of UNC GOLD provide a process map for others interested in developing a GU oncology database.
PMCID: PMC4058502  PMID: 23434424
Urologic Oncology; Clinical Database; Genitourinary Oncology; REDCap; Oncology Database

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