Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, Jan 27, 2016
Survival in older adults with cancer varies given differences in functional status, comorbidities... more Survival in older adults with cancer varies given differences in functional status, comorbidities, and nutrition. Prediction of factors associated with mortality, especially in hospitalized patients, allows physicians to better inform their patients about prognosis during treatment decisions. Our objective was to analyze factors associated with survival in older adults with cancer following hospitalization. Through a retrospective cohort study, we reviewed 803 patients who were admitted to Barnes-Jewish Hospital's Oncology Acute Care of Elders (OACE) unit from 2000 to 2008. Data collected included geriatric assessments from OACE screening questionnaires as well as demographic and medical history data from chart review. The primary end point was time from index admission to death. The Cox proportional hazard modeling was performed. The median age was 72.5 years old. Geriatric syndromes and functional impairment were common. Half of the patients (50.4 %) were dependent in one or m...
WMJ : official publication of the State Medical Society of Wisconsin, 2007
To examine the relationship between neighborhood factors and adolescent victimization for low- an... more To examine the relationship between neighborhood factors and adolescent victimization for low- and high-risk areas of Milwaukee, Wis. In this cross-sectional study, we compared neighborhood characteristics based on the US Census Database by rates of adolescent victim rates as measured through victim client enrollment in an adolescent violence intervention program. Multiple regression procedures were used to analyze the data. The mean adolescent assault victim rate was 34.31 per 10,000 population (Standard deviation [SD] = 29.71) with range from 0.00 to 105.09 per 10,000 population in 35 ZIP-code areas in Milwaukee County. Neighborhood ZIP codes with low median household income and high rates of grandparents serving as heads of household were associated with high rates of adolescent assault victims (R2 = 0.75). Urban areas with higher rates of grandparent head of household and low median household income are associated with higher rates of adolescent assault victims.
In many medical conditions subjects can experience recurrent incidents. A common feature for the ... more In many medical conditions subjects can experience recurrent incidents. A common feature for the recurrent events data and multi-stage failure time observations is that the events are naturally ordered and occur in a certain sequence over time. To analyze such data, conventional methods based on either the frequency of events or the time to the first event or overall survival time is often inefficient and unsophisticated. If data have repeated events over a period with censored failure time in longitudinal studies, more complex analytic approaches are needed to obtain accurate estimates and efficient inferences, because adjustment is necessary for existing correlation between recurrent failure times within a subject. For analyzing different kinds of recurrent event data we review the existing models-multiple failure time models and frailty models, which allow use of all the available information to accurately estimate the relative risks of recurrences in a given dataset. Using the Pediatric Firearm Victim's Emergency Department Visit Study, the results from the proposed models are compared, and applicability and appropriateness of each model are discussed.
Our goal was to determine the optimal timing for repair of bile duct injuries sustained during ch... more Our goal was to determine the optimal timing for repair of bile duct injuries sustained during cholecystectomy. Bile duct injury during cholecystectomy is a serious complication that often requires surgical repair. There is heterogeneity in the literature regarding the optimal timing of surgical repair, and it remains unclear to what extent timing determines postoperative morbidity and long-term anastomotic function. A single institution prospective database was queried for all E1 to E4 injuries from 1989 to 2014 using a standardized tabular reporting format. Timing was stratified into 3 groups [early (<7 days), intermediate (8 days until 6 weeks), and late (>6 weeks) after injury]. Analysis was stratified between those who had a previous bile duct repair or not, including postoperative complications and anastomotic failure as outcome variables in 2 separate multivariate logistic regression models. There were 614 patients included in the study. The mean age was 41 years (range, 15-85 yrs), and the majority were female (80%). The mean follow-up time was 40.5 months. Side-to-side hepaticojejunostomy was performed in 94% of repairs. Intermediate repair was associated with a higher risk of postoperative complications [odd ratio = 3.7, 95% confidence interval (1.3-10.2), P = 0.01] when compared with early and late in those with a previous repair attempt. Sepsis control and avoidance of biliary stents were protective factors against anastomotic failure. Adequate sepsis control and delayed repair of biliary injuries should be considered for patients presenting between 8 days and 6 weeks after injury to prevent complications, if a previous bile duct repair was attempted.
Cancer-selective drug delivery is an important concept in improving treatment while minimizing of... more Cancer-selective drug delivery is an important concept in improving treatment while minimizing off-site toxicities, and sigma-2 receptors, which are overexpressed in solid tumors, represent attractive pharmacologic targets. Select sigma-2 ligands have been shown to be rapidly internalized selectively into cancer cells while retaining the capacity to deliver small molecules as drug cargoes. We utilized the sigma-2-based drug delivery concept to convert Erastin, a clinically underperforming drug, into a potent pancreatic cancer therapeutic. The Erastin derivative des-methyl Erastin (dm-Erastin) was chemically linked to sigma-2 ligand SV119 to create SW V-49. Conjugation increased the killing capacity of dm-Erastin by nearly 35-fold in vitro and reduced the size of established tumors and doubled the median survival in syngeneic and patient-derived xenograft models when compared to non-targeted dm-Erastin. Mechanistic analyses demonstrated that cell death was associated with robust reactive oxygen species production and could be efficiently antagonized with antioxidants. Mass spectrometry was employed to demonstrate selective uptake into pancreatic cancer cells. Thus, targeted delivery of dm-Erastin via conjugation to the sigma-2 ligand SV119 produced efficient tumor control and prolonged animal survival with minimal off-target toxicities, and SW V-49 represents a promising new therapeutic with the potential to advance the fight against pancreatic cancer.
Background Preoperative skin antisepsis has the potential to decrease the risk of surgical-site i... more Background Preoperative skin antisepsis has the potential to decrease the risk of surgical-site infection. However, evidence is limited to guide the choice of antiseptic agent at cesarean delivery, which is the most common major surgical procedure among women in the United States. Methods In this single-center, randomized, controlled trial, we evaluated whether the use of chlorhexidine-alcohol for preoperative skin antisepsis was superior to the use of iodine-alcohol for the prevention of surgical-site infection after cesarean delivery. We randomly assigned patients undergoing cesarean delivery to skin preparation with either chlorhexidine-alcohol or iodine-alcohol. The primary outcome was superficial or deep surgical-site infection within 30 days after cesarean delivery, on the basis of definitions from the Centers for Disease Control and Prevention. Results From September 2011 through June 2015, a total of 1147 patients were enrolled; 572 patients were assigned to chlorhexidine-al...
CXCL8 (Interleukin-8, IL-8) plays an important role in angiogenesis and wound healing by promptin... more CXCL8 (Interleukin-8, IL-8) plays an important role in angiogenesis and wound healing by prompting endothelial cell migration. It has been suggested that heparan sulfate (HS) could provide binding sites on endothelial cells to retain and activate highly diffusible cytokines and inflammatory chemokines. In the present study, we aimed to test the hypothesis that HS is essential for enhancement of endothelial cell migration by CXCL8, and to explore the underlying mechanism by detecting the changes in expression and activity of Rho GTPases and in the organization of actin cytoskeleton after enzymatic removal of HS on human umbilical vein endothelial cells (HUVECs) by using heparinase III. Our results revealed that the wound healing induced by CXCL8 was greatly attenuated by removal of HS. The CXCL8-upregulated Rho GTPases including Cdc42, Rac1, and RhoA, and CXCL8-increased Rac1/Rho activity were suppressed by removal of HS. The polymerization and polarization of actin cytoskeleton, and the increasing of stress fibers induced by CXCL8 were also abolished by heparinase III. Taken together, our results demonstrated an essential role of HS in mediating CXCL8-induced endothelial cell migration, and highlighted the biological importance of the interaction between CXCL8 and heparan sulfate in wound healing.
Sheng wu yi xue gong cheng xue za zhi = Journal of biomedical engineering = Shengwu yixue gongchengxue zazhi, 2015
To study the potential molecular mechanism of tumor angiogenesis in its microenvironment, we inve... more To study the potential molecular mechanism of tumor angiogenesis in its microenvironment, we investigated the effects of HepG2 conditioned medium on the proliferation of vascular endothelial cell and vascular angiogenesis in our laboratory. Human umbilical vein endothelial EA. hy926 cells were co-cultured with HepG2 conditioned medium in vitro. The proliferation and the tubulogenesis of EA. hy926 cells were detected by teramethylazo salt azole (MTT) and tube formation assay, respectively. The results showed that the survival rate of the EA. hy926 cells was significantly increased under the co-culture condition. HepG2 conditioned medium also enhanced the angiogenesis ability of EA. hy926 cells. In addition, the expressions of intracellular VEGF and extracellular VEGFR (Flk-1) were regulated upward in a time-dependent manner. In conclusion, the proliferation of vascular endothelial cells and Vascula angiogenesis were improved under the condition of indirect co-culture.
To consolidate literature reports of serious late gastrointestinal toxicities after hypofractiona... more To consolidate literature reports of serious late gastrointestinal toxicities after hypofractionated radiation treatment of pancreatic cancer and attempt to derive normal tissue complication probability (NTCP) parameters using the Lyman-Kutcher-Burman model. Published reports of late grade 3 or greater gastrointestinal toxicity after hypofractionated treatment of pancreatic cancer were reviewed. The biologically equivalent dose in 1.8 Gy fractions was calculated using the EQD model. NTCP parameters were calculated using the LKB model assuming 1-5 % of the normal tissue volume was exposed to the prescription dose with α/β ratios of 3 or 4. A total of 16 human studies were examined encompassing a total of 1160 patients. Toxicities consisted of ulcers, hemorrhages, obstructions, strictures, and perforations. Non-hemorrhagic and non-perforated ulcers occurred at a rate of 9.1 % and were the most commonly reported toxicity. Derived NTCP parameter ranges were as follows: n = 0.38-0.63, m ...
The use of administrative billing data may enable large-scale assessments of treatment outcomes f... more The use of administrative billing data may enable large-scale assessments of treatment outcomes for Chiari Malformation type I (CM-1). However, to utilize such data sets, validated International Classification of Diseases, Ninth Revision (ICD-9-CM) code algorithms for identifying CM-1 surgery are needed. To validate 2 ICD-9-CM code algorithms identifying patients undergoing CM-1 decompression surgery. We retrospectively analyzed the validity of 2 ICD-9-CM code algorithms for identifying adult CM-1 decompression surgery performed at 2 academic medical centers between 2001 and 2013. Algorithm 1 included any discharge diagnosis code of 348.4 (CM-1), as well as a procedure code of 01.24 (cranial decompression) or 03.09 (spinal decompression, or laminectomy). Algorithm 2 restricted this group to patients with a primary diagnosis of 348.4. The positive predictive value (PPV) and sensitivity of each algorithm were calculated. Among 340 first-time admissions identified by Algorithm 1, the o...
Outcomes research on Chiari malformation type 1 (CM-1) is impeded by a reliance on small, single-... more Outcomes research on Chiari malformation type 1 (CM-1) is impeded by a reliance on small, single-center cohorts. To study the complications and resource use associated with adult CM-1 surgery using administrative data. We used a recently validated International Classification of Diseases, Ninth Revision, Clinical Modification code algorithm to retrospectively study adult CM-1 surgeries from 2004 to 2010 in California, Florida, and New York using State Inpatient Databases. Outcomes included complications and resource use within 30 and 90 days of treatment. We used multivariable logistic regression to identify risk factors for morbidity and negative binomial models to determine risk-adjusted costs. We identified 1947 CM-1 operations. Surgical complications were more common than medical complications at both 30 days (14.3% vs 4.4%) and 90 days (18.7% vs 5.0%) postoperatively. Certain comorbidities were associated with increased morbidity; for example, hydrocephalus increased the risk for surgical (odds ratio [OR] = 4.51) and medical (OR = 3.98) complications. Medical but not surgical complications were also more common in older patients (OR = 5.57 for oldest vs youngest age category) and male patients (OR = 3.19). Risk-adjusted hospital costs were $22530 at 30 days and $24852 at 90 days postoperatively. Risk-adjusted 90-day costs were more than twice as high for patients experiencing surgical ($46264) or medical ($65679) complications than for patients without complications ($18880). Complications after CM-1 surgery are common, and surgical complications are more frequent than medical complications. Certain comorbidities and demographic characteristics are associated with increased risk for complications. Beyond harming patients, complications are also associated with substantially higher hospital costs. These results may help guide patient management and inform decision making for patients considering surgery. CM-1, Chiari malformation type 1ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical ModificationOR, odds ratioSID, State Inpatient Database.
International Journal of Gynecological Cancer, 2015
This study compares surgical and survival outcomes of women with stage IV uterine serous carcinom... more This study compares surgical and survival outcomes of women with stage IV uterine serous carcinoma (USC) treated with neoadjuvant chemotherapy (NAC) and interval cytoreduction to women treated with primary cytoreductive surgery (PCS) followed by adjuvant chemotherapy. This retrospective dual cohort study included women diagnosed with stage IV USC at a single academic institution. Kruskal-Wallis and Fisher exact tests were used to compare demographics and surgical outcomes. Progression-free survival (PFS) and overall survival (OS) were estimated by using Kaplan-Meier methods. Comparison between study groups was tested by log-rank statistics. Ten women with stage IV USC who received NAC and 34 who underwent PCS met inclusion criteria. Neoadjuvant chemotherapy patients had a lower mean body mass index and were more often African American. Compared with PCS, the NAC cohort had shorter mean operative times (137 ± 66 vs 203 ± 80 minutes, P = 0.025) and were discharged from the hospital earlier (median length of stay, 3 vs 5 days; P = 0.002). Rates of debulking to no gross residual disease (70% NAC vs 32.3% PCS) or less than 1 cm of disease (30% NAC vs 50% PCS) did not differ (P = 0.10). Median follow-up time was 17.5 months. There was no difference in median PFS (10.4 vs 12 months, P = 0.29) or OS (17.3 vs 20.7 months, P = 0.23) for NAC and PCS cohorts. Women receiving NAC for stage IV USC had shorter surgeries and hospital stays than did those receiving PCS. There was no difference in PFS or OS, although our sample size was small. Neoadjuvant chemotherapy may be an appropriate therapy for select patients with advanced-stage USC.
Background: Use of a stylet during EUS-guided FNA (EUS-FNA) is believed to improve the quality an... more Background: Use of a stylet during EUS-guided FNA (EUS-FNA) is believed to improve the quality and diagnostic yield of specimens.
Clinical Journal of the American Society of Nephrology, 2013
Background and objectives To reduce racial disparities in transplant, modifiable patient characte... more Background and objectives To reduce racial disparities in transplant, modifiable patient characteristics associated with completion of transplant evaluation and receipt of living donor kidney transplant must be identified.
Cancer patients often do not make informed decisions regarding clinical trial participation. This... more Cancer patients often do not make informed decisions regarding clinical trial participation. This study evaluated whether a web-based decision aid (DA) could support trial decisions compared with our cancer center's website. Adults diagnosed with cancer in the past 6 months who had not previously participated in a cancer clinical trial were eligible. Participants were randomized to view the DA or our cancer center's website (enhanced usual care [UC]). Controlling for whether participants had heard of cancer clinical trials and educational attainment, multivariable linear regression examined group on knowledge, self-efficacy for finding trial information, decisional conflict (values clarity and uncertainty), intent to participate, decision readiness, and trial perceptions. Two hundred patients (86%) consented between May 2014 and April 2015. One hundred were randomized to each group. Surveys were completed by 87 in the DA group and 90 in the UC group. DA group participants re...
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, Jan 27, 2016
Survival in older adults with cancer varies given differences in functional status, comorbidities... more Survival in older adults with cancer varies given differences in functional status, comorbidities, and nutrition. Prediction of factors associated with mortality, especially in hospitalized patients, allows physicians to better inform their patients about prognosis during treatment decisions. Our objective was to analyze factors associated with survival in older adults with cancer following hospitalization. Through a retrospective cohort study, we reviewed 803 patients who were admitted to Barnes-Jewish Hospital's Oncology Acute Care of Elders (OACE) unit from 2000 to 2008. Data collected included geriatric assessments from OACE screening questionnaires as well as demographic and medical history data from chart review. The primary end point was time from index admission to death. The Cox proportional hazard modeling was performed. The median age was 72.5 years old. Geriatric syndromes and functional impairment were common. Half of the patients (50.4 %) were dependent in one or m...
Donor lymphocyte infusion (DLI) without prophylactic immunosuppression has been used for relapsed... more Donor lymphocyte infusion (DLI) without prophylactic immunosuppression has been used for relapsed AML after allogeneic stem cell transplant (allo-SCT). However DLI is associated with an increased incidence of acute Graft vs. Host Disease (aGVHD). In mice, administration of azacitidine (AzaC) on days 4, 6, 8, and 10 post DLI increases regulatory T cell (Treg) numbers and prevents GVHD without hindering Graft vs. Leukemia (GVL). Based on these findings, we conducted a phase 1 study of AzaC post DLI for AML relapse post allo-SCT. AzaC was administered on days 4, 6, 8 and 10 post-DLI. Dose escalation was done using a 3+3 design with three AzaC dose levels: 30mg/m(2) (level -1), 45mg/m(2) (level 1) and 75mg/m(2) (level 2). Three patients were treated in the 45mg/m(2) dose level and 5 patients were treated in the 75mg/m(2) dose level; no DLTs or grade 3-5 treatment related toxicities were observed. After a median follow-up of 5.2 months, no patients developed grade III-IV aGVHD and no pat...
Journal of Neurology, Neurosurgery & Psychiatry, 2016
Understanding the natural history of familial amyotrophic lateral sclerosis (ALS) caused by SOD1 ... more Understanding the natural history of familial amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations (ALS(SOD1)) will provide key information for optimising clinical trials in this patient population. To establish an updated natural history of ALS(SOD1). Retrospective cohort study from 15 medical centres in North America evaluated records from 175 patients with ALS with genetically confirmed SOD1 mutations, cared for after the year 2000. Age of onset, survival, ALS Functional Rating Scale (ALS-FRS) scores and respiratory function were analysed. Patients with the A4V (Ala-Val) SOD1 mutation (SOD1(A4V)), the largest mutation population in North America with an aggressive disease progression, were distinguished from other SOD1 mutation patients (SOD1(non-A4V)) for analysis. Mean age of disease onset was 49.7±12.3 years (mean±SD) for all SOD1 patients, with no statistical significance between SOD1(A4V) and SOD1(non-A4V) (p=0.72, Kruskal-Wallis). Total SOD1 patient median survival was 2.7 years. Mean disease duration for all SOD1 was 4.6±6.0 and 1.4±0.7 years for SOD1(A4V). SOD1(A4V) survival probability (median survival 1.2 years) was significantly decreased compared with SOD1(non-A4V) (median survival 6.8 years; p<0.0001, log-rank). A statistically significant increase in ALS-FRS decline in SOD1(A4V) compared with SOD1(non-A4V) participants (p=0.02) was observed, as well as a statistically significant increase in ALS-forced vital capacity decline in SOD1(A4V) compared with SOD1(non-A4V) (p=0.02). SOD1(A4V) is an aggressive, but relatively homogeneous form of ALS. These SOD1-specific ALS natural history data will be important for the design and implementation of clinical trials in the ALS(SOD1) patient population.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, Jan 26, 2016
Allogeneic stem cell transplant (allo-SCT) is a potentially curative treatment for high risk acut... more Allogeneic stem cell transplant (allo-SCT) is a potentially curative treatment for high risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). For patients with relapsed disease after transplant intensive chemotherapy followed by donor lymphocyte infusion (DLI) or a second allo-SCT may result in a durable response in some patients. High intensity chemotherapy and less aggressive therapy with hypomethylating agents (HA) with and without DLI are often used for post allo-SCT relapse. Here we compared the treatment outcomes of intensive chemotherapy with that of HA in relapsed AML and MDS post allo-SCT. Patients who had received a second SCT within 90 days of the relapse date were excluded. The primary endpoints were overall response rate (ORR) and overall survival (OS). Secondary endpoints were complete remission (CR) rate and progression free survival (PFS). A total of 100 patients were included: 73 patients received chemotherapy and 27 patients received a HA. Fifty-six...
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, Jan 27, 2016
Survival in older adults with cancer varies given differences in functional status, comorbidities... more Survival in older adults with cancer varies given differences in functional status, comorbidities, and nutrition. Prediction of factors associated with mortality, especially in hospitalized patients, allows physicians to better inform their patients about prognosis during treatment decisions. Our objective was to analyze factors associated with survival in older adults with cancer following hospitalization. Through a retrospective cohort study, we reviewed 803 patients who were admitted to Barnes-Jewish Hospital's Oncology Acute Care of Elders (OACE) unit from 2000 to 2008. Data collected included geriatric assessments from OACE screening questionnaires as well as demographic and medical history data from chart review. The primary end point was time from index admission to death. The Cox proportional hazard modeling was performed. The median age was 72.5 years old. Geriatric syndromes and functional impairment were common. Half of the patients (50.4 %) were dependent in one or m...
WMJ : official publication of the State Medical Society of Wisconsin, 2007
To examine the relationship between neighborhood factors and adolescent victimization for low- an... more To examine the relationship between neighborhood factors and adolescent victimization for low- and high-risk areas of Milwaukee, Wis. In this cross-sectional study, we compared neighborhood characteristics based on the US Census Database by rates of adolescent victim rates as measured through victim client enrollment in an adolescent violence intervention program. Multiple regression procedures were used to analyze the data. The mean adolescent assault victim rate was 34.31 per 10,000 population (Standard deviation [SD] = 29.71) with range from 0.00 to 105.09 per 10,000 population in 35 ZIP-code areas in Milwaukee County. Neighborhood ZIP codes with low median household income and high rates of grandparents serving as heads of household were associated with high rates of adolescent assault victims (R2 = 0.75). Urban areas with higher rates of grandparent head of household and low median household income are associated with higher rates of adolescent assault victims.
In many medical conditions subjects can experience recurrent incidents. A common feature for the ... more In many medical conditions subjects can experience recurrent incidents. A common feature for the recurrent events data and multi-stage failure time observations is that the events are naturally ordered and occur in a certain sequence over time. To analyze such data, conventional methods based on either the frequency of events or the time to the first event or overall survival time is often inefficient and unsophisticated. If data have repeated events over a period with censored failure time in longitudinal studies, more complex analytic approaches are needed to obtain accurate estimates and efficient inferences, because adjustment is necessary for existing correlation between recurrent failure times within a subject. For analyzing different kinds of recurrent event data we review the existing models-multiple failure time models and frailty models, which allow use of all the available information to accurately estimate the relative risks of recurrences in a given dataset. Using the Pediatric Firearm Victim's Emergency Department Visit Study, the results from the proposed models are compared, and applicability and appropriateness of each model are discussed.
Our goal was to determine the optimal timing for repair of bile duct injuries sustained during ch... more Our goal was to determine the optimal timing for repair of bile duct injuries sustained during cholecystectomy. Bile duct injury during cholecystectomy is a serious complication that often requires surgical repair. There is heterogeneity in the literature regarding the optimal timing of surgical repair, and it remains unclear to what extent timing determines postoperative morbidity and long-term anastomotic function. A single institution prospective database was queried for all E1 to E4 injuries from 1989 to 2014 using a standardized tabular reporting format. Timing was stratified into 3 groups [early (<7 days), intermediate (8 days until 6 weeks), and late (>6 weeks) after injury]. Analysis was stratified between those who had a previous bile duct repair or not, including postoperative complications and anastomotic failure as outcome variables in 2 separate multivariate logistic regression models. There were 614 patients included in the study. The mean age was 41 years (range, 15-85 yrs), and the majority were female (80%). The mean follow-up time was 40.5 months. Side-to-side hepaticojejunostomy was performed in 94% of repairs. Intermediate repair was associated with a higher risk of postoperative complications [odd ratio = 3.7, 95% confidence interval (1.3-10.2), P = 0.01] when compared with early and late in those with a previous repair attempt. Sepsis control and avoidance of biliary stents were protective factors against anastomotic failure. Adequate sepsis control and delayed repair of biliary injuries should be considered for patients presenting between 8 days and 6 weeks after injury to prevent complications, if a previous bile duct repair was attempted.
Cancer-selective drug delivery is an important concept in improving treatment while minimizing of... more Cancer-selective drug delivery is an important concept in improving treatment while minimizing off-site toxicities, and sigma-2 receptors, which are overexpressed in solid tumors, represent attractive pharmacologic targets. Select sigma-2 ligands have been shown to be rapidly internalized selectively into cancer cells while retaining the capacity to deliver small molecules as drug cargoes. We utilized the sigma-2-based drug delivery concept to convert Erastin, a clinically underperforming drug, into a potent pancreatic cancer therapeutic. The Erastin derivative des-methyl Erastin (dm-Erastin) was chemically linked to sigma-2 ligand SV119 to create SW V-49. Conjugation increased the killing capacity of dm-Erastin by nearly 35-fold in vitro and reduced the size of established tumors and doubled the median survival in syngeneic and patient-derived xenograft models when compared to non-targeted dm-Erastin. Mechanistic analyses demonstrated that cell death was associated with robust reactive oxygen species production and could be efficiently antagonized with antioxidants. Mass spectrometry was employed to demonstrate selective uptake into pancreatic cancer cells. Thus, targeted delivery of dm-Erastin via conjugation to the sigma-2 ligand SV119 produced efficient tumor control and prolonged animal survival with minimal off-target toxicities, and SW V-49 represents a promising new therapeutic with the potential to advance the fight against pancreatic cancer.
Background Preoperative skin antisepsis has the potential to decrease the risk of surgical-site i... more Background Preoperative skin antisepsis has the potential to decrease the risk of surgical-site infection. However, evidence is limited to guide the choice of antiseptic agent at cesarean delivery, which is the most common major surgical procedure among women in the United States. Methods In this single-center, randomized, controlled trial, we evaluated whether the use of chlorhexidine-alcohol for preoperative skin antisepsis was superior to the use of iodine-alcohol for the prevention of surgical-site infection after cesarean delivery. We randomly assigned patients undergoing cesarean delivery to skin preparation with either chlorhexidine-alcohol or iodine-alcohol. The primary outcome was superficial or deep surgical-site infection within 30 days after cesarean delivery, on the basis of definitions from the Centers for Disease Control and Prevention. Results From September 2011 through June 2015, a total of 1147 patients were enrolled; 572 patients were assigned to chlorhexidine-al...
CXCL8 (Interleukin-8, IL-8) plays an important role in angiogenesis and wound healing by promptin... more CXCL8 (Interleukin-8, IL-8) plays an important role in angiogenesis and wound healing by prompting endothelial cell migration. It has been suggested that heparan sulfate (HS) could provide binding sites on endothelial cells to retain and activate highly diffusible cytokines and inflammatory chemokines. In the present study, we aimed to test the hypothesis that HS is essential for enhancement of endothelial cell migration by CXCL8, and to explore the underlying mechanism by detecting the changes in expression and activity of Rho GTPases and in the organization of actin cytoskeleton after enzymatic removal of HS on human umbilical vein endothelial cells (HUVECs) by using heparinase III. Our results revealed that the wound healing induced by CXCL8 was greatly attenuated by removal of HS. The CXCL8-upregulated Rho GTPases including Cdc42, Rac1, and RhoA, and CXCL8-increased Rac1/Rho activity were suppressed by removal of HS. The polymerization and polarization of actin cytoskeleton, and the increasing of stress fibers induced by CXCL8 were also abolished by heparinase III. Taken together, our results demonstrated an essential role of HS in mediating CXCL8-induced endothelial cell migration, and highlighted the biological importance of the interaction between CXCL8 and heparan sulfate in wound healing.
Sheng wu yi xue gong cheng xue za zhi = Journal of biomedical engineering = Shengwu yixue gongchengxue zazhi, 2015
To study the potential molecular mechanism of tumor angiogenesis in its microenvironment, we inve... more To study the potential molecular mechanism of tumor angiogenesis in its microenvironment, we investigated the effects of HepG2 conditioned medium on the proliferation of vascular endothelial cell and vascular angiogenesis in our laboratory. Human umbilical vein endothelial EA. hy926 cells were co-cultured with HepG2 conditioned medium in vitro. The proliferation and the tubulogenesis of EA. hy926 cells were detected by teramethylazo salt azole (MTT) and tube formation assay, respectively. The results showed that the survival rate of the EA. hy926 cells was significantly increased under the co-culture condition. HepG2 conditioned medium also enhanced the angiogenesis ability of EA. hy926 cells. In addition, the expressions of intracellular VEGF and extracellular VEGFR (Flk-1) were regulated upward in a time-dependent manner. In conclusion, the proliferation of vascular endothelial cells and Vascula angiogenesis were improved under the condition of indirect co-culture.
To consolidate literature reports of serious late gastrointestinal toxicities after hypofractiona... more To consolidate literature reports of serious late gastrointestinal toxicities after hypofractionated radiation treatment of pancreatic cancer and attempt to derive normal tissue complication probability (NTCP) parameters using the Lyman-Kutcher-Burman model. Published reports of late grade 3 or greater gastrointestinal toxicity after hypofractionated treatment of pancreatic cancer were reviewed. The biologically equivalent dose in 1.8 Gy fractions was calculated using the EQD model. NTCP parameters were calculated using the LKB model assuming 1-5 % of the normal tissue volume was exposed to the prescription dose with α/β ratios of 3 or 4. A total of 16 human studies were examined encompassing a total of 1160 patients. Toxicities consisted of ulcers, hemorrhages, obstructions, strictures, and perforations. Non-hemorrhagic and non-perforated ulcers occurred at a rate of 9.1 % and were the most commonly reported toxicity. Derived NTCP parameter ranges were as follows: n = 0.38-0.63, m ...
The use of administrative billing data may enable large-scale assessments of treatment outcomes f... more The use of administrative billing data may enable large-scale assessments of treatment outcomes for Chiari Malformation type I (CM-1). However, to utilize such data sets, validated International Classification of Diseases, Ninth Revision (ICD-9-CM) code algorithms for identifying CM-1 surgery are needed. To validate 2 ICD-9-CM code algorithms identifying patients undergoing CM-1 decompression surgery. We retrospectively analyzed the validity of 2 ICD-9-CM code algorithms for identifying adult CM-1 decompression surgery performed at 2 academic medical centers between 2001 and 2013. Algorithm 1 included any discharge diagnosis code of 348.4 (CM-1), as well as a procedure code of 01.24 (cranial decompression) or 03.09 (spinal decompression, or laminectomy). Algorithm 2 restricted this group to patients with a primary diagnosis of 348.4. The positive predictive value (PPV) and sensitivity of each algorithm were calculated. Among 340 first-time admissions identified by Algorithm 1, the o...
Outcomes research on Chiari malformation type 1 (CM-1) is impeded by a reliance on small, single-... more Outcomes research on Chiari malformation type 1 (CM-1) is impeded by a reliance on small, single-center cohorts. To study the complications and resource use associated with adult CM-1 surgery using administrative data. We used a recently validated International Classification of Diseases, Ninth Revision, Clinical Modification code algorithm to retrospectively study adult CM-1 surgeries from 2004 to 2010 in California, Florida, and New York using State Inpatient Databases. Outcomes included complications and resource use within 30 and 90 days of treatment. We used multivariable logistic regression to identify risk factors for morbidity and negative binomial models to determine risk-adjusted costs. We identified 1947 CM-1 operations. Surgical complications were more common than medical complications at both 30 days (14.3% vs 4.4%) and 90 days (18.7% vs 5.0%) postoperatively. Certain comorbidities were associated with increased morbidity; for example, hydrocephalus increased the risk for surgical (odds ratio [OR] = 4.51) and medical (OR = 3.98) complications. Medical but not surgical complications were also more common in older patients (OR = 5.57 for oldest vs youngest age category) and male patients (OR = 3.19). Risk-adjusted hospital costs were $22530 at 30 days and $24852 at 90 days postoperatively. Risk-adjusted 90-day costs were more than twice as high for patients experiencing surgical ($46264) or medical ($65679) complications than for patients without complications ($18880). Complications after CM-1 surgery are common, and surgical complications are more frequent than medical complications. Certain comorbidities and demographic characteristics are associated with increased risk for complications. Beyond harming patients, complications are also associated with substantially higher hospital costs. These results may help guide patient management and inform decision making for patients considering surgery. CM-1, Chiari malformation type 1ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical ModificationOR, odds ratioSID, State Inpatient Database.
International Journal of Gynecological Cancer, 2015
This study compares surgical and survival outcomes of women with stage IV uterine serous carcinom... more This study compares surgical and survival outcomes of women with stage IV uterine serous carcinoma (USC) treated with neoadjuvant chemotherapy (NAC) and interval cytoreduction to women treated with primary cytoreductive surgery (PCS) followed by adjuvant chemotherapy. This retrospective dual cohort study included women diagnosed with stage IV USC at a single academic institution. Kruskal-Wallis and Fisher exact tests were used to compare demographics and surgical outcomes. Progression-free survival (PFS) and overall survival (OS) were estimated by using Kaplan-Meier methods. Comparison between study groups was tested by log-rank statistics. Ten women with stage IV USC who received NAC and 34 who underwent PCS met inclusion criteria. Neoadjuvant chemotherapy patients had a lower mean body mass index and were more often African American. Compared with PCS, the NAC cohort had shorter mean operative times (137 ± 66 vs 203 ± 80 minutes, P = 0.025) and were discharged from the hospital earlier (median length of stay, 3 vs 5 days; P = 0.002). Rates of debulking to no gross residual disease (70% NAC vs 32.3% PCS) or less than 1 cm of disease (30% NAC vs 50% PCS) did not differ (P = 0.10). Median follow-up time was 17.5 months. There was no difference in median PFS (10.4 vs 12 months, P = 0.29) or OS (17.3 vs 20.7 months, P = 0.23) for NAC and PCS cohorts. Women receiving NAC for stage IV USC had shorter surgeries and hospital stays than did those receiving PCS. There was no difference in PFS or OS, although our sample size was small. Neoadjuvant chemotherapy may be an appropriate therapy for select patients with advanced-stage USC.
Background: Use of a stylet during EUS-guided FNA (EUS-FNA) is believed to improve the quality an... more Background: Use of a stylet during EUS-guided FNA (EUS-FNA) is believed to improve the quality and diagnostic yield of specimens.
Clinical Journal of the American Society of Nephrology, 2013
Background and objectives To reduce racial disparities in transplant, modifiable patient characte... more Background and objectives To reduce racial disparities in transplant, modifiable patient characteristics associated with completion of transplant evaluation and receipt of living donor kidney transplant must be identified.
Cancer patients often do not make informed decisions regarding clinical trial participation. This... more Cancer patients often do not make informed decisions regarding clinical trial participation. This study evaluated whether a web-based decision aid (DA) could support trial decisions compared with our cancer center's website. Adults diagnosed with cancer in the past 6 months who had not previously participated in a cancer clinical trial were eligible. Participants were randomized to view the DA or our cancer center's website (enhanced usual care [UC]). Controlling for whether participants had heard of cancer clinical trials and educational attainment, multivariable linear regression examined group on knowledge, self-efficacy for finding trial information, decisional conflict (values clarity and uncertainty), intent to participate, decision readiness, and trial perceptions. Two hundred patients (86%) consented between May 2014 and April 2015. One hundred were randomized to each group. Surveys were completed by 87 in the DA group and 90 in the UC group. DA group participants re...
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, Jan 27, 2016
Survival in older adults with cancer varies given differences in functional status, comorbidities... more Survival in older adults with cancer varies given differences in functional status, comorbidities, and nutrition. Prediction of factors associated with mortality, especially in hospitalized patients, allows physicians to better inform their patients about prognosis during treatment decisions. Our objective was to analyze factors associated with survival in older adults with cancer following hospitalization. Through a retrospective cohort study, we reviewed 803 patients who were admitted to Barnes-Jewish Hospital's Oncology Acute Care of Elders (OACE) unit from 2000 to 2008. Data collected included geriatric assessments from OACE screening questionnaires as well as demographic and medical history data from chart review. The primary end point was time from index admission to death. The Cox proportional hazard modeling was performed. The median age was 72.5 years old. Geriatric syndromes and functional impairment were common. Half of the patients (50.4 %) were dependent in one or m...
Donor lymphocyte infusion (DLI) without prophylactic immunosuppression has been used for relapsed... more Donor lymphocyte infusion (DLI) without prophylactic immunosuppression has been used for relapsed AML after allogeneic stem cell transplant (allo-SCT). However DLI is associated with an increased incidence of acute Graft vs. Host Disease (aGVHD). In mice, administration of azacitidine (AzaC) on days 4, 6, 8, and 10 post DLI increases regulatory T cell (Treg) numbers and prevents GVHD without hindering Graft vs. Leukemia (GVL). Based on these findings, we conducted a phase 1 study of AzaC post DLI for AML relapse post allo-SCT. AzaC was administered on days 4, 6, 8 and 10 post-DLI. Dose escalation was done using a 3+3 design with three AzaC dose levels: 30mg/m(2) (level -1), 45mg/m(2) (level 1) and 75mg/m(2) (level 2). Three patients were treated in the 45mg/m(2) dose level and 5 patients were treated in the 75mg/m(2) dose level; no DLTs or grade 3-5 treatment related toxicities were observed. After a median follow-up of 5.2 months, no patients developed grade III-IV aGVHD and no pat...
Journal of Neurology, Neurosurgery & Psychiatry, 2016
Understanding the natural history of familial amyotrophic lateral sclerosis (ALS) caused by SOD1 ... more Understanding the natural history of familial amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations (ALS(SOD1)) will provide key information for optimising clinical trials in this patient population. To establish an updated natural history of ALS(SOD1). Retrospective cohort study from 15 medical centres in North America evaluated records from 175 patients with ALS with genetically confirmed SOD1 mutations, cared for after the year 2000. Age of onset, survival, ALS Functional Rating Scale (ALS-FRS) scores and respiratory function were analysed. Patients with the A4V (Ala-Val) SOD1 mutation (SOD1(A4V)), the largest mutation population in North America with an aggressive disease progression, were distinguished from other SOD1 mutation patients (SOD1(non-A4V)) for analysis. Mean age of disease onset was 49.7±12.3 years (mean±SD) for all SOD1 patients, with no statistical significance between SOD1(A4V) and SOD1(non-A4V) (p=0.72, Kruskal-Wallis). Total SOD1 patient median survival was 2.7 years. Mean disease duration for all SOD1 was 4.6±6.0 and 1.4±0.7 years for SOD1(A4V). SOD1(A4V) survival probability (median survival 1.2 years) was significantly decreased compared with SOD1(non-A4V) (median survival 6.8 years; p<0.0001, log-rank). A statistically significant increase in ALS-FRS decline in SOD1(A4V) compared with SOD1(non-A4V) participants (p=0.02) was observed, as well as a statistically significant increase in ALS-forced vital capacity decline in SOD1(A4V) compared with SOD1(non-A4V) (p=0.02). SOD1(A4V) is an aggressive, but relatively homogeneous form of ALS. These SOD1-specific ALS natural history data will be important for the design and implementation of clinical trials in the ALS(SOD1) patient population.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, Jan 26, 2016
Allogeneic stem cell transplant (allo-SCT) is a potentially curative treatment for high risk acut... more Allogeneic stem cell transplant (allo-SCT) is a potentially curative treatment for high risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). For patients with relapsed disease after transplant intensive chemotherapy followed by donor lymphocyte infusion (DLI) or a second allo-SCT may result in a durable response in some patients. High intensity chemotherapy and less aggressive therapy with hypomethylating agents (HA) with and without DLI are often used for post allo-SCT relapse. Here we compared the treatment outcomes of intensive chemotherapy with that of HA in relapsed AML and MDS post allo-SCT. Patients who had received a second SCT within 90 days of the relapse date were excluded. The primary endpoints were overall response rate (ORR) and overall survival (OS). Secondary endpoints were complete remission (CR) rate and progression free survival (PFS). A total of 100 patients were included: 73 patients received chemotherapy and 27 patients received a HA. Fifty-six...
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Papers by Jingxia Liu