Background: Hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) is the most common biologic subtype of breast cancer. Although adjuvant therapy has demonstrated a survival benefi...Background: Hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) is the most common biologic subtype of breast cancer. Although adjuvant therapy has demonstrated a survival benefit in clinical trials, its use is poorly understood in the real-world among elderly breast cancer patients since age is a barrier to receiving adjuvant therapy. An examination of treatment patterns and outcomes associated with receipt of adjuvant/neoadjuvant therapy among elderly HR + HER2-breast cancer patients was undertaken. Methods: There were 18,470 HR + HER2-breast cancer patients from the linked SEER-Medicare database. Patients were diagnosed with stage I-III disease between 1/1/2007-12/31/2011, ≥66 years, enrolled in Medicare Parts A, B and D, and underwent breast cancer surgery after diagnosis. Time-varying Cox proportional hazards regression assessed overall survival. Results: There were 13,670 (74%) patients treated with adjuvant/neoadjuvant therapy and 4800 (26%) untreated. Compared to treated patients, untreated patients were older, had earlier stage, lower grade, smaller tumors, poorer performance, higher comorbidity score, and less use of a 21-gene recurrence score (RS) assay (p < 0.0001). In the survival model, increasing age, stage, tumor size, tumor grade, comorbidity score and poor performance were significantly associated with higher mortality risks, while use of an RS assay was associated with lower risks. The Cox model showed a 48% higher risk of death in untreated compared to treated patients. In a subset of 8967 patients with stage I disease, tumor size < 2.0 cm and grade 1/2;untreated patients had a 22% higher risk of death compared to treated patients. Conclusions: Older patients with favorable clinical characteristics (earlier stage, smaller tumor, lower grade) are less likely to be treated and have a higher risk of death compared to adjuvant/neoadjuvant treated patients. An unmet need among older breast cancer patients persists.展开更多
Significant progress has been made in understanding pharmacokinetics (PK),pharmacodynamics (PD),as well as toxicity profiles of therapeutic proteins in animals and humans,which have been in commercial development for ...Significant progress has been made in understanding pharmacokinetics (PK),pharmacodynamics (PD),as well as toxicity profiles of therapeutic proteins in animals and humans,which have been in commercial development for more than three decades.However,in the PK arena,many fundamental questions remain to be resolved.Investigative and bioanalytical tools need to be established to improve the translation of PK data from animals to humans,and from in vitro assays to in vivo readouts,which would ultimately lead to a higher success rate in drug development.In toxicology,it is known,in general,what studies are needed to safely develop therapeutic proteins,and what studies do not provide relevant information.One of the major complicating factors in nonclinical and clinical programs for therapeutic proteins is the impact of immunogenicity.In this review,we will highlight the emerging science and technology,as well as the challenges around the pharmacokinetic-and safety-related issues in drug development of mAbs and other therapeutic proteins.展开更多
Accurate DNA quantitation is a prerequisite in many biomedical and pharmaceutical studies.Here we established a new DNA quantitation method by nuclease P1 digestion and UPLC-MS/MS analysis.DNA fragments can be efficie...Accurate DNA quantitation is a prerequisite in many biomedical and pharmaceutical studies.Here we established a new DNA quantitation method by nuclease P1 digestion and UPLC-MS/MS analysis.DNA fragments can be efficiently hydrolyzed to single deoxyribonucleotides by nuclease P1 in a short time.The decent stabilities of all the four deoxyribonucleotides were confirmed under different conditions.Deoxyadenosine monophosphate(dAMP)was selected as the surrogate for DNA quantitation because dAMP showed the highest sensitivity among the four deoxyribonucleotides in the UPLC-MS/MS analysis.The linear range in DNA quantitation by this method is 1.2-5000 ng/mL.In the validation,the inter-day and intra-day accuracies were within 90%-110%,and the inter-day and intra-day precision were acceptable(RSD<10%).The validated method was successfully applied to quantitate DNA isolated from tumors and organs of a mouse xenograft model.Compared to the quantitation methods using UV absorbance,the reported method provides an enhanced sensitivity,and it allows for the accurate quantitation of isolated DNA with contamination of RNA and ribonucleotide.展开更多
Cancer stem cells （CSCs） are a rare subpopulation of phenotypically distinct cancer cells exhibiting stem cell characteristics. They are tumourigenic, meanwhile capable of self-renewal and forming differentiated pro...Cancer stem cells （CSCs） are a rare subpopulation of phenotypically distinct cancer cells exhibiting stem cell characteristics. They are tumourigenic, meanwhile capable of self-renewal and forming differentiated progenies. CSCs are believed to be resistant to the standard therapeutics, and provide the cell reservoir for tumour initiation.1 Understanding CSCs or in another word, tumour-initiating cells, is of critical therapeutic importance.展开更多
Background: Bendamustine-based regimens are often used in the management of patients with chronic lymphocytic leukemia (CLL) but few studies have analyzed the comorbidity- and/or adverse event (CAE)-related healthcare...Background: Bendamustine-based regimens are often used in the management of patients with chronic lymphocytic leukemia (CLL) but few studies have analyzed the comorbidity- and/or adverse event (CAE)-related healthcare costs in patients receiving these regimens in a real-world setting. Aims: To describe all-cause and CAE-related healthcare costs in relapse/refractory (R/R) elderly patients with CLL treated with bendamustine-based regimens in a real-world setting. Methods: Adult patients with R/R CLL who received bendamustine-based regimens on/after January 2010 were selected from the Medicare Limited Data Set (LDS) 5% Standard Analytic Files. Selected patients were classified into cohorts based on the two most prevalent bendamustine-based regimens observed (index treatment): 1) bendamustine + rituximab (BR cohort) and 2) bendamustine monotherapy (B-mono cohort). For each cohort, all-cause and CAE-related healthcare costs, while on treatment, were reported per-patient-per-month (PPPM). Overall survival (OS) rates following initiation of the index treatment were described using age- and gender-adjusted Kaplan-Meier curves. Results: A total of 275 patients were included in the BR cohort and 100 patients in the B-mono cohort. Most patients were male and the mean age was approximately 75 years old. During treatment, total all-cause healthcare costs were $14,520 PPPM for the BR cohort and $13,125 PPPM for the B-mono cohort—outpatient costs (mainly driven by CLL-drug costs) represented 86.1% of the total all-cause healthcare costs for the BR cohort and 69.8% for the B-mono cohort. CAE costs accounted for 58.3% of the total all-cause healthcare costs for the BR cohort and 66.9% for the B-mono cohort. Median OS was 35 months in the BR cohort and 21 months in the B-mono cohort. Conclusion: In this population of elderly patients with R/R CLL treated with bendamustine-based regimens, CAEs were common and translated into important medical costs. Median OS was also relatively short suggesting an unmet medical need.展开更多
Objective: To examine whether differences in treatment patterns and health care costs exist among chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma (NHL) patients receiving rituximab in a hospital outpati...Objective: To examine whether differences in treatment patterns and health care costs exist among chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma (NHL) patients receiving rituximab in a hospital outpatient setting versus those receiving rituximab in a physician office/community clinic setting. Methods: This retrospective database study used medical and pharmacy claims (1/2007-7/2012) from a large US health plan. Patients ≥18 years with ≥2 rituximab claims and ≥2 claims for either NHL or CLL were identified. The date of the first rituximab claim were set as the index date, and differences in treatment patterns and health care costs were examined during the period following the index date. Costs were adjusted for patient characteristics using a multivariate regression model. Results: A total of 4441 patients were identified;3167 received rituximab in the office/clinic setting, and 1274 in the hospital outpatient setting. From 2007 to 2012, the percentage of patients receiving rituximab in the hospital outpatient setting increased from 22% to 39%. Patients treated in the hospital outpatient setting vs. the office/clinic setting had fewer average counts of rituximab infusions (5.60 vs. 7.49, p 0.001), higher total health care costs (cost ratio = 1.325, p 0.001), higher infusion day drug and administration costs (cost ratio = 1.509, p 0.001), and higher rates of ER visits and inpatient stays (both p 0.001). Conclusions: These findings suggest that site of care may impact treatment patterns and costs of patients receiving rituximab, and additional research is needed to better understand the reason(s) for these differences by site of service.展开更多
Introduction: Chronic lymphocytic leukemia (CLL) is a disease of the elderly. Elderly patients often have increased comorbidity burden and loss of organ reserve that may impact their ability to tolerate cancer therapy...Introduction: Chronic lymphocytic leukemia (CLL) is a disease of the elderly. Elderly patients often have increased comorbidity burden and loss of organ reserve that may impact their ability to tolerate cancer therapy. We described realworld characteristics of typical CLL patients and identified factors predictive of receiving treatment. Methods: A retrospective cohort analysis of 8343 first primary CLL patients was performed using the linked Surveillance, Epidemiology, and End Results-Medicare database. Patients were diagnosed from 1/1/1998 to 12/31/2007, >66 years, and continuously enrolled in Medicare Parts A and B in the year prior to diagnosis. Comorbidity was examined using the National Cancer Institute comorbidity index and the Cumulative Illness Rating Scale. Cox and Logistic regression modeling assessed patient characteristics predictive of receiving treatment within the first year after diagnosis. Results: Median follow-up time from diagnosis was 782 days. During the study time period, there were 3366 (40%) treated patients and 4977 (60%) untreated. Even among those diagnosed with advanced stage (n = 4213), 57% were not treated. Treated patients were younger at diagnosis compared to untreated (76 vs. 79;p < 0.0001). In general, as age increased, the incidence and severity of comorbidities increased. In multivariate regression analyses, the treatment rate was significantly lower among patients >80 years, females, and with early stage disease;and significantly decreased with increasing comorbidity burden. Conclusions: Age, gender, comorbidity and stage were predictive of receiving treatment. Among patients with advanced stage, 57% were not being treated possibly due to older age and/or higher comorbidity burden.展开更多
Advanced basal cell carcinoma (aBCC) includes metastatic and locally advanced BCC that is inoperable (or with surgery contraindicated). We describe patient characteristics and treatment history for aBCC cases from com...Advanced basal cell carcinoma (aBCC) includes metastatic and locally advanced BCC that is inoperable (or with surgery contraindicated). We describe patient characteristics and treatment history for aBCC cases from community oncology. Nine cases of aBCC were found within the ACORN Data Warehouse, a community oncology database of >180,000 cancer patients. Data were summarized descriptively. Three illustrative case histories are presented. Patients were predominantly Caucasian (8/9), male (6/9), and over 60 (6/9). Four had metastatic disease;five had aBCC without metastasis. Five had a history of treatment for early stage BCC, including surgery (5/5), radiation (1/5), and none had chemotherapy. Those with history of early stage BCC had periods of apparent lack of follow-up and treatment. One had chemotherapy for aBCC (platinum based with radiation) and eight had radiation without chemotherapy. Patients had multiple comorbid serious medical conditions. Six were deceased, but only one was documented to have aBCC as cause of death. Advanced BCC is rare in community oncology settings. There appear to be gaps in the care and follow-up of patients with initial early stage BCC. More data and larger samples are needed from multi-specialty databases such as dermatology and head and neck surgery.展开更多
Purpose: Triple negative breast cancer is more aggressive than other breast cancer subtypes and accounts for up to 20% of all breast cancers. Despite the poorer prognosis, there are no approved targeted treatments ava...Purpose: Triple negative breast cancer is more aggressive than other breast cancer subtypes and accounts for up to 20% of all breast cancers. Despite the poorer prognosis, there are no approved targeted treatments available and chemotherapy remains the only choice. We examined treatment patterns and outcomes among elderly metastatic triple-negative breast cancer (mTNBC) patients in routine clinical practice. Methods: Patients were identified from the linked SEER-Medicare database between 1/1/2001 and 12/31/2013 and included de novo Stage IV (n = 776) and patients with distant metastasis followed an initial diagnosis of Stage I - III disease (n = 1851). Kaplan-Meier analyses and time-varying Cox proportional hazards regression were used to assess overall survival (OS). Results: The mean age at metastatic diagnosis was 77.6 years and 1259 (48%) patients received chemotherapy. Compared to <70 year olds, ≥70 year olds had worse performance status, higher comorbidity burden, and were less likely to receive chemotherapy (45% vs. 66%). Patients treated with chemotherapy had increased OS compared to untreated patients, and the survival advantage was more pronounced in the -month longer unadjusted OS compared to the ≥70 cohort (log rank p < 0.0001). This finding was supported in the adjusted multivariate model which showed a 46% increased risk of death for untreated patients in the <70 year olds and a 17% increased risk of death for untreated patients in the ≥70 year olds (vs. treated). Conclusions: In this real-world analysis, 48% of elderly mTNBC patients did not receive chemotherapy and a greater proportion were untreated in the ≥70 year old cohort (55%). Although the survival benefits of chemotherapy were greater in the younger cohort, the benefits of treatment persisted in ≥70 year olds. These findings suggest opportunities exist to improve the clinical treatment of elderly mTNBC patients.展开更多
Pre-clinical studies suggest carboxyamidotriazole orotate (CTO) demonstrates anti-tumor activity through modulation of multiple tyrosine kinase signaling pathways and interactions with the tumor microenvironment. We d...Pre-clinical studies suggest carboxyamidotriazole orotate (CTO) demonstrates anti-tumor activity through modulation of multiple tyrosine kinase signaling pathways and interactions with the tumor microenvironment. We determined the safety and tolerability, pharmacokinetic profile, maximum tolerated dose, and recommended Phase II dose of CTO monotherapy in patients with advanced solid tumors. In this first-in-human Phase I clinical trial, eligible patients with advanced solid tumors were enrolled to receive a once-daily dose of CTO following a standard 3 + 3 Phase I design (starting at 50 mg/m2/day) with dose escalations of 30% - 100%. Dose limiting toxicity (DLT) was defined in the first cycle of treatment. Measurable disease and response were defined by RECIST version 1.1. Forty-four patients were evaluable for safety. CTO-related grade 3 toxicities included diarrhea (2.5%), fatigue (5.0%), lymphopenia (2.5%) and transient creatine phosphokinase (CPK) elevation (2.5%). There were no grade 4 or 5 toxicities. Steady state plasma levels of CAI (CTO metabolite) were achieved by day 12 with a half life estimate of 55 hr. Although no objective response rates were observed, nine patients with rapidly progressive and treatment-refractory tumors achieved stable disease (SD) durable for up to 14 months. The maximum tolerated dose for CTO alone was 427 mg/m2/day. The dose-limiting toxicity was grade 3 fatigue. CTO is orally bioavailable, safe, well tolerated and produces disease stabilization in a broad range of heavily treated refractory tumors. Combination trials of CTO with other antineoplastic agents are ongoing.展开更多
Die filling is a critical stage during powder compaction,which can significantly affect the product quality and efficiency.In this paper,a forced feeder is introduced attempting to improve the filling performance of a...Die filling is a critical stage during powder compaction,which can significantly affect the product quality and efficiency.In this paper,a forced feeder is introduced attempting to improve the filling performance of a lab-scale die filling system.The die filling process is analysed with a graphics processing units(GPU)enhanced discrete element method(DEM).Various stirrer designs are assessed for a wide range of process settings(i.e.,stirrer speed,filling speed)to explore their influence on the die filling performance of free-flowing powder.Numerical results show that die filing with the novel helical-ribbon(i.e.,type D)stirrer design exhibits the highest filling ratio,implying that it is the most robust stirrer design for the feeder configuration considered.Furthermore,die filling performance with the type D stirrer design is a function of the stirrer speed and the filling speed.A positive variation of filling ratio(ηf>0%)can be ensured over the whole range of filling speed by adjusting the stirrer speed(i.e.,increasing the stirrer speed).The approach used in this study can not only help understand how the stirrer design affects the die filling performance but also guide the optimization of feeder system and process settings.展开更多
The FAIR data guiding principles have been recently developed and widely adopted to improve the Findability,Accessibility,Interoperability,and Reuse of digital assets in the face of an exponential increase of data vol...The FAIR data guiding principles have been recently developed and widely adopted to improve the Findability,Accessibility,Interoperability,and Reuse of digital assets in the face of an exponential increase of data volume and complexity.The FAIR data principles have been formulated on a general level and the technological implementation of these principles remains up to the industries and organizations working on maximizing the value of their data.Here,we describe the data management and curation methodologies and best practices developed for FAIRification of clinical exploratory biomarker data collected from over 250 clinical studies.We discuss the data curation effort involved,the resulting output,and the business and scientific impact of our work.Finally,we propose prospective planning for FAIR data to optimize data management efforts and maximize data value.展开更多
Upon recognition of foreign antigens,naïve B cells undergo rapid activation,growth,and proliferation.How B-cell growth and proliferation are coupled with activation remains poorly understood.Combining CRISPR/Cas9...Upon recognition of foreign antigens,naïve B cells undergo rapid activation,growth,and proliferation.How B-cell growth and proliferation are coupled with activation remains poorly understood.Combining CRISPR/Cas9-mediated functional analysis and mouse genetics approaches,we found that Dhx33,an activation-induced RNA helicase,plays a critical role in coupling B-cell activation with growth and proliferation.Mutant mice with B-cell-specific deletion of Dhx33 exhibited impaired B-cell development,germinal center reactions,plasma cell differentiation,and antibody production.Dhx33-deficient B cells appeared normal in the steady state and early stage of activation but were retarded in growth and proliferation.Mechanistically,Dhx33 played an indispensable role in activation-induced upregulation of ribosomal DNA(rDNA)transcription.In the absence of Dhx33,activated B cells were compromised in their ability to ramp up 47S ribosomal RNA(rRNA)production and ribosome biogenesis,resulting in nucleolar stress,p53 accumulation,and cellular death.Our findings demonstrate an essential role for Dhx33 in coupling B-cell activation with growth and proliferation and suggest that Dhx33 inhibition is a potential therapy for lymphoma and antibody-mediated autoimmune diseases.展开更多
文摘Background: Hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) is the most common biologic subtype of breast cancer. Although adjuvant therapy has demonstrated a survival benefit in clinical trials, its use is poorly understood in the real-world among elderly breast cancer patients since age is a barrier to receiving adjuvant therapy. An examination of treatment patterns and outcomes associated with receipt of adjuvant/neoadjuvant therapy among elderly HR + HER2-breast cancer patients was undertaken. Methods: There were 18,470 HR + HER2-breast cancer patients from the linked SEER-Medicare database. Patients were diagnosed with stage I-III disease between 1/1/2007-12/31/2011, ≥66 years, enrolled in Medicare Parts A, B and D, and underwent breast cancer surgery after diagnosis. Time-varying Cox proportional hazards regression assessed overall survival. Results: There were 13,670 (74%) patients treated with adjuvant/neoadjuvant therapy and 4800 (26%) untreated. Compared to treated patients, untreated patients were older, had earlier stage, lower grade, smaller tumors, poorer performance, higher comorbidity score, and less use of a 21-gene recurrence score (RS) assay (p < 0.0001). In the survival model, increasing age, stage, tumor size, tumor grade, comorbidity score and poor performance were significantly associated with higher mortality risks, while use of an RS assay was associated with lower risks. The Cox model showed a 48% higher risk of death in untreated compared to treated patients. In a subset of 8967 patients with stage I disease, tumor size < 2.0 cm and grade 1/2;untreated patients had a 22% higher risk of death compared to treated patients. Conclusions: Older patients with favorable clinical characteristics (earlier stage, smaller tumor, lower grade) are less likely to be treated and have a higher risk of death compared to adjuvant/neoadjuvant treated patients. An unmet need among older breast cancer patients persists.
文摘Significant progress has been made in understanding pharmacokinetics (PK),pharmacodynamics (PD),as well as toxicity profiles of therapeutic proteins in animals and humans,which have been in commercial development for more than three decades.However,in the PK arena,many fundamental questions remain to be resolved.Investigative and bioanalytical tools need to be established to improve the translation of PK data from animals to humans,and from in vitro assays to in vivo readouts,which would ultimately lead to a higher success rate in drug development.In toxicology,it is known,in general,what studies are needed to safely develop therapeutic proteins,and what studies do not provide relevant information.One of the major complicating factors in nonclinical and clinical programs for therapeutic proteins is the impact of immunogenicity.In this review,we will highlight the emerging science and technology,as well as the challenges around the pharmacokinetic-and safety-related issues in drug development of mAbs and other therapeutic proteins.
文摘Accurate DNA quantitation is a prerequisite in many biomedical and pharmaceutical studies.Here we established a new DNA quantitation method by nuclease P1 digestion and UPLC-MS/MS analysis.DNA fragments can be efficiently hydrolyzed to single deoxyribonucleotides by nuclease P1 in a short time.The decent stabilities of all the four deoxyribonucleotides were confirmed under different conditions.Deoxyadenosine monophosphate(dAMP)was selected as the surrogate for DNA quantitation because dAMP showed the highest sensitivity among the four deoxyribonucleotides in the UPLC-MS/MS analysis.The linear range in DNA quantitation by this method is 1.2-5000 ng/mL.In the validation,the inter-day and intra-day accuracies were within 90%-110%,and the inter-day and intra-day precision were acceptable(RSD<10%).The validated method was successfully applied to quantitate DNA isolated from tumors and organs of a mouse xenograft model.Compared to the quantitation methods using UV absorbance,the reported method provides an enhanced sensitivity,and it allows for the accurate quantitation of isolated DNA with contamination of RNA and ribonucleotide.
文摘Cancer stem cells （CSCs） are a rare subpopulation of phenotypically distinct cancer cells exhibiting stem cell characteristics. They are tumourigenic, meanwhile capable of self-renewal and forming differentiated progenies. CSCs are believed to be resistant to the standard therapeutics, and provide the cell reservoir for tumour initiation.1 Understanding CSCs or in another word, tumour-initiating cells, is of critical therapeutic importance.
文摘Background: Bendamustine-based regimens are often used in the management of patients with chronic lymphocytic leukemia (CLL) but few studies have analyzed the comorbidity- and/or adverse event (CAE)-related healthcare costs in patients receiving these regimens in a real-world setting. Aims: To describe all-cause and CAE-related healthcare costs in relapse/refractory (R/R) elderly patients with CLL treated with bendamustine-based regimens in a real-world setting. Methods: Adult patients with R/R CLL who received bendamustine-based regimens on/after January 2010 were selected from the Medicare Limited Data Set (LDS) 5% Standard Analytic Files. Selected patients were classified into cohorts based on the two most prevalent bendamustine-based regimens observed (index treatment): 1) bendamustine + rituximab (BR cohort) and 2) bendamustine monotherapy (B-mono cohort). For each cohort, all-cause and CAE-related healthcare costs, while on treatment, were reported per-patient-per-month (PPPM). Overall survival (OS) rates following initiation of the index treatment were described using age- and gender-adjusted Kaplan-Meier curves. Results: A total of 275 patients were included in the BR cohort and 100 patients in the B-mono cohort. Most patients were male and the mean age was approximately 75 years old. During treatment, total all-cause healthcare costs were $14,520 PPPM for the BR cohort and $13,125 PPPM for the B-mono cohort—outpatient costs (mainly driven by CLL-drug costs) represented 86.1% of the total all-cause healthcare costs for the BR cohort and 69.8% for the B-mono cohort. CAE costs accounted for 58.3% of the total all-cause healthcare costs for the BR cohort and 66.9% for the B-mono cohort. Median OS was 35 months in the BR cohort and 21 months in the B-mono cohort. Conclusion: In this population of elderly patients with R/R CLL treated with bendamustine-based regimens, CAEs were common and translated into important medical costs. Median OS was also relatively short suggesting an unmet medical need.
文摘Objective: To examine whether differences in treatment patterns and health care costs exist among chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma (NHL) patients receiving rituximab in a hospital outpatient setting versus those receiving rituximab in a physician office/community clinic setting. Methods: This retrospective database study used medical and pharmacy claims (1/2007-7/2012) from a large US health plan. Patients ≥18 years with ≥2 rituximab claims and ≥2 claims for either NHL or CLL were identified. The date of the first rituximab claim were set as the index date, and differences in treatment patterns and health care costs were examined during the period following the index date. Costs were adjusted for patient characteristics using a multivariate regression model. Results: A total of 4441 patients were identified;3167 received rituximab in the office/clinic setting, and 1274 in the hospital outpatient setting. From 2007 to 2012, the percentage of patients receiving rituximab in the hospital outpatient setting increased from 22% to 39%. Patients treated in the hospital outpatient setting vs. the office/clinic setting had fewer average counts of rituximab infusions (5.60 vs. 7.49, p 0.001), higher total health care costs (cost ratio = 1.325, p 0.001), higher infusion day drug and administration costs (cost ratio = 1.509, p 0.001), and higher rates of ER visits and inpatient stays (both p 0.001). Conclusions: These findings suggest that site of care may impact treatment patterns and costs of patients receiving rituximab, and additional research is needed to better understand the reason(s) for these differences by site of service.
文摘Introduction: Chronic lymphocytic leukemia (CLL) is a disease of the elderly. Elderly patients often have increased comorbidity burden and loss of organ reserve that may impact their ability to tolerate cancer therapy. We described realworld characteristics of typical CLL patients and identified factors predictive of receiving treatment. Methods: A retrospective cohort analysis of 8343 first primary CLL patients was performed using the linked Surveillance, Epidemiology, and End Results-Medicare database. Patients were diagnosed from 1/1/1998 to 12/31/2007, >66 years, and continuously enrolled in Medicare Parts A and B in the year prior to diagnosis. Comorbidity was examined using the National Cancer Institute comorbidity index and the Cumulative Illness Rating Scale. Cox and Logistic regression modeling assessed patient characteristics predictive of receiving treatment within the first year after diagnosis. Results: Median follow-up time from diagnosis was 782 days. During the study time period, there were 3366 (40%) treated patients and 4977 (60%) untreated. Even among those diagnosed with advanced stage (n = 4213), 57% were not treated. Treated patients were younger at diagnosis compared to untreated (76 vs. 79;p < 0.0001). In general, as age increased, the incidence and severity of comorbidities increased. In multivariate regression analyses, the treatment rate was significantly lower among patients >80 years, females, and with early stage disease;and significantly decreased with increasing comorbidity burden. Conclusions: Age, gender, comorbidity and stage were predictive of receiving treatment. Among patients with advanced stage, 57% were not being treated possibly due to older age and/or higher comorbidity burden.
文摘Advanced basal cell carcinoma (aBCC) includes metastatic and locally advanced BCC that is inoperable (or with surgery contraindicated). We describe patient characteristics and treatment history for aBCC cases from community oncology. Nine cases of aBCC were found within the ACORN Data Warehouse, a community oncology database of >180,000 cancer patients. Data were summarized descriptively. Three illustrative case histories are presented. Patients were predominantly Caucasian (8/9), male (6/9), and over 60 (6/9). Four had metastatic disease;five had aBCC without metastasis. Five had a history of treatment for early stage BCC, including surgery (5/5), radiation (1/5), and none had chemotherapy. Those with history of early stage BCC had periods of apparent lack of follow-up and treatment. One had chemotherapy for aBCC (platinum based with radiation) and eight had radiation without chemotherapy. Patients had multiple comorbid serious medical conditions. Six were deceased, but only one was documented to have aBCC as cause of death. Advanced BCC is rare in community oncology settings. There appear to be gaps in the care and follow-up of patients with initial early stage BCC. More data and larger samples are needed from multi-specialty databases such as dermatology and head and neck surgery.
文摘Purpose: Triple negative breast cancer is more aggressive than other breast cancer subtypes and accounts for up to 20% of all breast cancers. Despite the poorer prognosis, there are no approved targeted treatments available and chemotherapy remains the only choice. We examined treatment patterns and outcomes among elderly metastatic triple-negative breast cancer (mTNBC) patients in routine clinical practice. Methods: Patients were identified from the linked SEER-Medicare database between 1/1/2001 and 12/31/2013 and included de novo Stage IV (n = 776) and patients with distant metastasis followed an initial diagnosis of Stage I - III disease (n = 1851). Kaplan-Meier analyses and time-varying Cox proportional hazards regression were used to assess overall survival (OS). Results: The mean age at metastatic diagnosis was 77.6 years and 1259 (48%) patients received chemotherapy. Compared to <70 year olds, ≥70 year olds had worse performance status, higher comorbidity burden, and were less likely to receive chemotherapy (45% vs. 66%). Patients treated with chemotherapy had increased OS compared to untreated patients, and the survival advantage was more pronounced in the -month longer unadjusted OS compared to the ≥70 cohort (log rank p < 0.0001). This finding was supported in the adjusted multivariate model which showed a 46% increased risk of death for untreated patients in the <70 year olds and a 17% increased risk of death for untreated patients in the ≥70 year olds (vs. treated). Conclusions: In this real-world analysis, 48% of elderly mTNBC patients did not receive chemotherapy and a greater proportion were untreated in the ≥70 year old cohort (55%). Although the survival benefits of chemotherapy were greater in the younger cohort, the benefits of treatment persisted in ≥70 year olds. These findings suggest opportunities exist to improve the clinical treatment of elderly mTNBC patients.
文摘Pre-clinical studies suggest carboxyamidotriazole orotate (CTO) demonstrates anti-tumor activity through modulation of multiple tyrosine kinase signaling pathways and interactions with the tumor microenvironment. We determined the safety and tolerability, pharmacokinetic profile, maximum tolerated dose, and recommended Phase II dose of CTO monotherapy in patients with advanced solid tumors. In this first-in-human Phase I clinical trial, eligible patients with advanced solid tumors were enrolled to receive a once-daily dose of CTO following a standard 3 + 3 Phase I design (starting at 50 mg/m2/day) with dose escalations of 30% - 100%. Dose limiting toxicity (DLT) was defined in the first cycle of treatment. Measurable disease and response were defined by RECIST version 1.1. Forty-four patients were evaluable for safety. CTO-related grade 3 toxicities included diarrhea (2.5%), fatigue (5.0%), lymphopenia (2.5%) and transient creatine phosphokinase (CPK) elevation (2.5%). There were no grade 4 or 5 toxicities. Steady state plasma levels of CAI (CTO metabolite) were achieved by day 12 with a half life estimate of 55 hr. Although no objective response rates were observed, nine patients with rapidly progressive and treatment-refractory tumors achieved stable disease (SD) durable for up to 14 months. The maximum tolerated dose for CTO alone was 427 mg/m2/day. The dose-limiting toxicity was grade 3 fatigue. CTO is orally bioavailable, safe, well tolerated and produces disease stabilization in a broad range of heavily treated refractory tumors. Combination trials of CTO with other antineoplastic agents are ongoing.
基金the financial support from Genentech Ltd.,the Engineering and Physical Science Research Council(Grant No.EP/M02976X)the Marie Skłodowska-Curie Individual Fellowships under European Union's Horizon 2020 research and innovation programme(Grant No.840264)。
文摘Die filling is a critical stage during powder compaction,which can significantly affect the product quality and efficiency.In this paper,a forced feeder is introduced attempting to improve the filling performance of a lab-scale die filling system.The die filling process is analysed with a graphics processing units(GPU)enhanced discrete element method(DEM).Various stirrer designs are assessed for a wide range of process settings(i.e.,stirrer speed,filling speed)to explore their influence on the die filling performance of free-flowing powder.Numerical results show that die filing with the novel helical-ribbon(i.e.,type D)stirrer design exhibits the highest filling ratio,implying that it is the most robust stirrer design for the feeder configuration considered.Furthermore,die filling performance with the type D stirrer design is a function of the stirrer speed and the filling speed.A positive variation of filling ratio(ηf>0%)can be ensured over the whole range of filling speed by adjusting the stirrer speed(i.e.,increasing the stirrer speed).The approach used in this study can not only help understand how the stirrer design affects the die filling performance but also guide the optimization of feeder system and process settings.
文摘The FAIR data guiding principles have been recently developed and widely adopted to improve the Findability,Accessibility,Interoperability,and Reuse of digital assets in the face of an exponential increase of data volume and complexity.The FAIR data principles have been formulated on a general level and the technological implementation of these principles remains up to the industries and organizations working on maximizing the value of their data.Here,we describe the data management and curation methodologies and best practices developed for FAIRification of clinical exploratory biomarker data collected from over 250 clinical studies.We discuss the data curation effort involved,the resulting output,and the business and scientific impact of our work.Finally,we propose prospective planning for FAIR data to optimize data management efforts and maximize data value.
基金the National Natural Science Foundation of China(31570882,31770950 and 32070877 to W-H.L,and 81961138008 to CX)the Fundamental Research Funds for the Central Universities of China-Xiamen University(20720170064 to CX)the Sanofi Institute for Biomedical Research(SIBR).
文摘Upon recognition of foreign antigens,naïve B cells undergo rapid activation,growth,and proliferation.How B-cell growth and proliferation are coupled with activation remains poorly understood.Combining CRISPR/Cas9-mediated functional analysis and mouse genetics approaches,we found that Dhx33,an activation-induced RNA helicase,plays a critical role in coupling B-cell activation with growth and proliferation.Mutant mice with B-cell-specific deletion of Dhx33 exhibited impaired B-cell development,germinal center reactions,plasma cell differentiation,and antibody production.Dhx33-deficient B cells appeared normal in the steady state and early stage of activation but were retarded in growth and proliferation.Mechanistically,Dhx33 played an indispensable role in activation-induced upregulation of ribosomal DNA(rDNA)transcription.In the absence of Dhx33,activated B cells were compromised in their ability to ramp up 47S ribosomal RNA(rRNA)production and ribosome biogenesis,resulting in nucleolar stress,p53 accumulation,and cellular death.Our findings demonstrate an essential role for Dhx33 in coupling B-cell activation with growth and proliferation and suggest that Dhx33 inhibition is a potential therapy for lymphoma and antibody-mediated autoimmune diseases.
