Estimating a Treatment Effect in Residual Time Quantiles Under the Additive Hazards Model

For randomized clinical trials where the endpoint of interest is a time-to-event subject to censoring, estimating the treatment effect has mostly focused on the hazard ratio from the Cox proportional hazards model. Since the model’s proportional hazards assumption is not always satisfied, a useful alternative, the so-called additive hazards model, may instead be used to estimate a treatment effect on the difference of hazard functions. Still, the hazards difference may be difficult to grasp intuitively, particularly in a clinical setting of, e.g., patient counseling, or resource planning. In this paper, we study the quantiles of a covariate’s conditional survival function in the additive hazards model. Specifically, we estimate the residual time quantiles, i.e., the quantiles of survival times remaining at a given time t, conditional on the survival times greater than t, for a specific covariate in the additive hazards model. We use the estimates to translate the hazards difference into the difference in residual time quantiles, which allows a more direct clinical interpretation. We determine the asymptotic properties, assess the performance via Monte-Carlo simulations, and demonstrate the use of residual time quantiles in two real randomized clinical trials.     

The impact of HER2-directed targeted therapy on HER2-positive DCIS of the breast

BackgroundIn invasive breast cancer, HER2 is a well-established negative prognostic factor. However, its significance on the prognosis of ductal carcinoma in situ (DCIS) of the breast is unclear. As a result, the impact of HER2-directed therapy on HER2-positive DCIS is unknown and is currently the subject of ongoing clinical trials. In this study, we aim to determine the possible impact of HER 2-directed targeted therapy on survival outcomes for HER2-positive DCIS patients.Materials and methodsThe National Cancer Data Base (NCDB) was used to retrieve patients with biopsy-proven DCIS diagnosed from 2004–2015. Patients were divided into two groups based on the adjuvant therapy they received: systemic HER2-directed targeted therapy or no systemic therapy. Statistics included multivariable logistic regression to determine factors predictive of receiving systemic therapy, Kaplan-Meier analysis to evaluate overall survival (OS), and Cox proportional hazards modeling to determine variables associated with OS.ResultsAltogether, 1927 patients met inclusion criteria; 430 (22.3%) received HER2-directed targeted therapy; 1497 (77.7%) did not. Patients who received HER2-directed targeted therapy had a higher 5-year OS compared to patients that did not (97.7% vs. 95.8%, p = 0.043). This survival benefit remained on multivariable analysis. Factors associated with worse OS on multivariable analysis included Charlson-Deyo Comorbidity Score ≥ 2 and no receipt of hormonal therapy.ConclusionIn this large study evaluating HER2-positive DCIS patients, the receipt of HER2-directed targeted therapy was associated with an improvement in OS. The results of currently ongoing clinical trials are needed to confirm this finding.     

Concordance of Results from Randomized and Observational Analyses within the Same Study: A Re-Analysis of the Women’s Health Initiative Limited-Access Dataset

Background

Observational studies (OS) and randomized controlled trials (RCTs) often report discordant results. In the Women’s Health Initiative Calcium and Vitamin D (WHI CaD) RCT, women were randomly assigned to CaD or placebo, but were permitted to use personal calcium and vitamin D supplements, creating a unique opportunity to compare results from randomized and observational analyses within the same study.

Methods

WHI CaD was a 7-year RCT of 1g calcium/400IU vitamin D daily in 36,282 post-menopausal women. We assessed the effects of CaD on cardiovascular events, death, cancer and fracture in a randomized design- comparing CaD with placebo in 43% of women not using personal calcium or vitamin D supplements- and in a observational design- comparing women in the placebo group (44%) using personal calcium and vitamin D supplements with non-users. Incidence was assessed using Cox proportional hazards models, and results from the two study designs deemed concordant if the absolute difference in hazard ratios was ≤0.15. We also compared results from WHI CaD to those from the WHI Observational Study(WHI OS), which used similar methodology for analyses and recruited from the same population.

Results

In WHI CaD, for myocardial infarction and stroke, results of unadjusted and 6/8 covariate-controlled observational analyses (age-adjusted, multivariate-adjusted, propensity-adjusted, propensity-matched) were not concordant with the randomized design results. For death, hip and total fracture, colorectal and total cancer, unadjusted and covariate-controlled observational results were concordant with randomized results. For breast cancer, unadjusted and age-adjusted observational results were concordant with randomized results, but only 1/3 other covariate-controlled observational results were concordant with randomized results. Multivariate-adjusted results from WHI OS were concordant with randomized WHI CaD results for only 4/8 endpoints.

Conclusions

Results of randomized analyses in WHI CaD were concordant with observational analyses for 5/8 endpoints in WHI CaD and 4/8 endpoints in WHI OS.     

Association between hypertension and cutaneous melanoma,and the effect of aspirin: extended follow-up of a large randomised controlled trial

BackgroundThe association between hypertension and melanoma is unclear, and previous analyses of data from the ASPirin in Reducing Events in the Elderly (ASPREE) study demonstrated a reduced number of invasive melanoma events amongst aspirin-exposed hypertensive individuals.MethodsData from the ASPREE study which included (1) the intervention period with a median follow-up of 4.7 years, and (2) the observational period with an additional 2 years follow-up, were combined for this analysis. Logistic regression analyses examined the association between baseline hypertension and treatment status and past melanoma history. Survival analyses examined the association between hypertension and melanoma risk, and the effect of aspirin across hypertension groups. Cox proportional hazards models were used to compare incidence across groups.Results19,114 participants (median age of 74 years) were randomised to daily 100 mg aspirin or placebo. At baseline, hypertension and past melanoma history were recorded in 14,195 and 685 individuals, respectively. After adjustment for confounders, hypertension was significantly associated with past melanoma history (OR=1.34, 95%CI: 1.11–1.62). In a prospective analysis, baseline hypertension was not associated with melanoma risk. However, aspirin was associated with a reduced risk of incident melanoma amongst individuals with uncontrolled hypertension (blood pressure ≥140/90 mmHg; HR=0.63, 95%CI 0.44–0.89), but not in those with controlled hypertension (HR=1.04, 95%CI 0.74–1.46).ConclusionOur results support a reduced melanoma incidence amongst individuals with uncontrolled hypertension exposed to aspirin. Additional studies are required to confirm these findings.     

Survival among clinical stage I–III rectal cancer patients treated with different preoperative treatments: A population-based comparison

BackgroundRadical resection is regarded as the cornerstone of rectal cancer treatment. Preoperative (chemo)radiotherapy and adjuvant chemotherapy are often administered. This population-based study compares the survival in clinical stage I–III rectal cancer patients who received either preoperative radiotherapy, preoperative chemoradiotherapy or no preoperative therapy. As secondary research questions, the association of type of radical resection and adjuvant chemotherapy on survival is also investigated.MethodsPatients diagnosed between January 2006 and December 2011 with stage I–III rectal adenocarcinoma were retrieved from the Belgian Cancer Registry database. Multivariable Cox proportional hazards regression models were applied to evaluate the association of preoperative treatment, type of radical resection and use of adjuvant chemotherapy with survival, adjusting for the baseline characteristics age, gender, WHO performance status and clinical stage.ResultsA total of 5173 rectal cancer patients were identified. Preoperative treatment was as follows: none in 1354 (26.2%), radiotherapy in 797 (15.4%) and chemoradiotherapy in 3022 (58.4%) patients. The patient group who did not receive preoperative therapy or radiotherapy followed by radical resection had a lower observed survival compared to the patient group receiving preoperative chemoradiotherapy. The patient groups who underwent abdominoperineal excision and those receiving adjuvant chemotherapy had a worse observed survival compared to the patient group treated with sphincter-sparing surgery and no adjuvant therapy respectively. These effects were age-dependent. Multivariable analysis demonstrated similar findings for the observed survival conditional on surviving the first year since surgery.ConclusionIn this population-based study among clinical stage I–III rectal cancer patients treated with radical resection, a superior observed survival was noticed in the patient group receiving preoperative chemoradiotherapy compared to the patients groups receiving no or preoperative radiotherapy only, adjusting for case mix, type of radical resection and adjuvant chemotherapy. Additionally, higher adjusted observed survival was also detected for the patient groups with sphincter-sparing surgery or no adjuvant chemotherapy.     

A group sequential test for survival trials: an alternative to rank-based procedures

A method of interim monitoring is described for survival trials in which the proportional hazards assumption may not hold. This method extends the test statistics based on the cumulative weighted difference in the Kaplan-Meier estimates (Pepe and Fleming, 1989, Biometrics 45, 497-507) to the sequential setting. Therefore, it provides a useful alternative to the group sequential linear rank tests. With an appropriate weight function, the test statistic itself provides an estimator for the cumulative weighted difference in survival probabilities, which is an interpretable measure for the treatment difference, especially when the proportional hazards model fails. The method is illustrated based on the design of a real trial. The operating characteristics are studied through a small simulation.     

Vitamin D for Treatment and Prevention of Infectious Diseases; A Systematic Review of Randomized Controlled Trials

ObjectiveTo review the existing human controlled intervention studies of vitamin D as adjunctive therapy in settings of infection and provide recommendations for design and implementation of future studies in this field on the basis of the evidence reviewed.MethodsWe conducted a systematic review of randomized controlled clinical trials that studied vitamin D for treatment or prevention of infectious diseases in humans. Studies from 1948 through 2009 were identified through search terms in PubMed and Ovid MEDLINE.ResultsThirteen published controlled trials were identified by our search criteria. Ten trials were placebo controlled, and 9 of the 10 were conducted in a rigorous double-blind design. The selected clinical trials demonstrated substantial heterogeneity in baseline patient demographics, sample size, and vitamin D intervention strategies. Serious adverse events attributable to vitamin D supplementation were rare across all studies. On the basis of studies reviewed to date, the strongest evidence supports further research into adjunctive vitamin D therapy for tuberculosis, influenza, and viral upper respiratory tract illnesses. In the selected studies, certain aspects of study design are highlighted to help guide future clinical research in the field.ConclusionMore rigorously designed clinical trials are needed for further evaluation of the relationship between vitamin D status and the immune response to infection as well as for delineation of necessary changes in clinical practice and medical care of patients with vitamin D deficiency in infectious disease settings. (Endocr Pract. 2009;15:438-449)     

Solid Scintillators for Receptor Assays: An Environmentally Safe Alternative to Liquid Scintillation Cocktails

Abstract

Scintillation counting of tritiated ligands is widespread in receptor assays and has necessitated the use of scintillation cocktails containing environmentally damaging solvents that pose health hazards to their users. A safer mode of dry scintillation counting, based on the solid scintillator Xtalscint, was evaluated in whole-cell and membrane receptor assays. The results compared favorably with those obtained with glass-fiber filters and conventional liquid counting methods. It is concluded that solid scintillators may be used as an environmentally safer alternative to liquid scintillation in these assays.     

AZT toxicity and AIDS prophylaxis: Is AZT beneficial for HIV+ asymptomatic persons with 500 or more T4 cells per cubic millimeter?

Analyses of the effects of prophylactic use of zidovudine (AZT) on progression to acquired immune deficiency syndrome (AIDS) in human immunodeficiency virus seropositive (HIV+) asymptomatic persons with T4 lymphocyte (CD4+) cell counts 500 mm³ is reported for data obtained from two studies, the Australian European Group Collaborative Study, a multi-centered double-blind placebo-controlled clinical trial of the effects of AZT on progression to AIDS and other clinical endpoints, and the San Francisco Men's Health Study, an observational cohort. The analyses of the data of both studies demonstrate no benefit from AZT treatment in terms of progression to AIDS for those who are asymptomatic with CD4+ cell counts 500 mm³. The analysis of the San Francisco study, performed with Kaplan-Meier survivorship estimates, indicates a heterogeneity in the efficacy of AZT between baseline CD4+ cell count strata, 200–499 mm³ and 500–800 mm³. Within the 200–499 stratum, 47% of those receiving AZT therapy and 62% of those not receiving AZT therapy progressed to AIDS during the study period. By contrast, within the 500–800 stratum 41% of those receiving AZT therapy and 27% of those not receiving AZT therapy progressed to AIDS during the same period. Application of the Cox proportional hazards survivorship regression model for the relative risk of progression to AIDS to these same data accounts for this heterogeneity. The model includes an interaction between AZT treatment and baseline CD4+ cell counts. The hematological toxicity of AZT, demonstrated in clinical studies and laboratory investigations, indicates a biological correlate for this interaction: the toxic effects of AZT on the more intact immune system of those with CD4+ cell counts in the 500–800 mm³ range.Abbreviations ACTG AIDS Clinical Trials Group - AIDS Acquired immune deficiency syndrome - AMT 3-amino-3-deoxythymidine - ARC AIDS-related-complex - AZT 3-azido-3-deoxythymidine, zidovudine - BFU-E Erythrocyte burst-forming units - CD4+ T4 lymphocyte - CFU-GM Granulocyte macrophage colony-forming units - EAGCS European-Australian Group Collaborative Study - HIV Human immunodeficiency virus - SFMHS San Francisco Men's Health Study     

Colorectal cancer and country of birth in New South Wales,Australia: All-of-population data for prioritising health service delivery and research

IntroductionCancer care and outcomes differ across cultural groups in Australia. Quantifying these differences facilitates prioritisation and targeting of services and research. All-of-population data are needed by health agencies to understand and fulfil their cancer-control responsibilities. Compiling these data can be challenging while maintaining privacy. We have used data linkage to gain population-wide colorectal cancer data on stage (degree of spread), treatment, and survival in New South Wales (NSW), Australia, by country of birth (COB), and consider service implications.MethodsWe studied colon and rectal cancers diagnosed in 2003–2016 and recorded on the NSW Cancer Registry (n = 41,575), plus linked hospital data and data from Australian Medical and Pharmaceutical Benefits payments, other treatment data and death records. Outcomes for 12 COB categories were analysed using multiple logistic and proportional hazards regression, with Australia as the reference category.ResultsCompared with Australian born, the adjusted odds ratio for distant spread of colon cancer was higher for people born in Lebanon and the United Kingdom. Treatment was less common for people born in China (surgery), Germany (systemic), Italy (surgery), New Zealand (any treatment) and Vietnam (all treatments), while treatment for rectal cancer was more common for people born in Italy (surgery), United Kingdom (radiotherapy, systemic therapy), and Vietnam (surgery), and less frequent for people born in China (radiotherapy). Adjusted 5-year survival was higher for people born in China, Italy, Vietnam, Greece (colon), Lebanon (colon) and other non-English speaking countries. More advanced stage was negatively related to having surgery and survival.ConclusionsThis study illustrates how linked data can enable comparisons of multiple outcomes for colorectal cancer by country of birth across an entire population. Results disclose “big picture” variations in population characteristics, stage, treatment and survival. This will enable better targeting and prioritisation of services and inform research priorities to address disparities.     

Association between use of Qingfei Paidu Tang and mortality in hospitalized patients with COVID-19: A national retrospective registry study

BackgroundQingfei Paidu Tang (QPT), a formula of traditional Chinese medicine, which was suggested to be able to ease symptoms in patients with Coronavirus Disease 2019 (COVID-19), has been recommended by clinical guidelines and widely used to treat COVID-19 in China. However, whether it decreases mortality remains unknown.PurposeWe aimed to explore the association between QPT use and in-hospital mortality among patients hospitalized for COVID-19.Study designA retrospective study based on a real-world database was conducted.MethodsWe identified patients consecutively hospitalized with COVID-19 in 15 hospitals from a national retrospective registry in China, from January through May 2020. Data on patients’ characteristics, treatments, and outcomes were extracted from the electronic medical records. The association of QPT use with COVID-19 related mortality was evaluated using Cox proportional hazards models based on propensity score analysis.ResultsOf the 8939 patients included, 28.7% received QPT. The COVID-19 related mortality was 1.2% (95% confidence interval [CI] 0.8% to 1.7%) among the patients receiving QPT and 4.8% (95% CI 4.3% to 5.3%) among those not receiving QPT. After adjustment for patient characteristics and concomitant treatments, QPT use was associated with a relative reduction of 50% in-hospital COVID-19 related mortality (hazard ratio, 0.50; 95% CI, 0.37 to 0.66 p < 0.001). This association was consistent across subgroups by sex and age. Meanwhile, the incidences of acute liver injury (8.9% [95% CI, 7.8% to 10.1%] vs. 9.9% [95% CI, 9.2% to 10.7%]; odds ratio, 0.96 [95% CI, 0.81% to 1.14%], p = 0.658) and acute kidney injury (1.6% [95% CI, 1.2% to 2.2%] vs. 3.0% [95% CI, 2.6% to 3.5%]; odds ratio, 0.85 [95% CI, 0.62 to 1.17], p = 0.318) were comparable between patients receiving QPT and those not receiving QPT. The major study limitations included that the study was an observational study based on real-world data rather than a randomized control trial, and the quality of data could be affected by the accuracy and completeness of medical records.ConclusionsQPT was associated with a substantially lower risk of in-hospital mortality, without extra risk of acute liver injury or acute kidney injury among patients hospitalized with COVID-19.     

A marginal likelihood approach for estimating penetrance from kin-cohort designs

The kin-cohort design is a promising alternative to traditional cohort or case-control designs for estimating penetrance of an identified rare autosomal mutation. In this design, a suitably selected sample of participants provides genotype and detailed family history information on the disease of interest. To estimate penetrance of the mutation, we consider a marginal likelihood approach that is computationally simple to implement, more flexible than the original analytic approach proposed by Wacholder et al. (1998, American Journal of Epidemiology 148, 623-629), and more robust than the likelihood approach considered by Gail et al. (1999, Genetic Epidemiology 16, 15-39) to presence of residual familial correlation. We study the trade-off between robustness and efficiency using simulation experiments. The method is illustrated by analysis of the data from the Washington Ashkenazi Study.     

Propensity score matching with time-dependent covariates

In observational studies with a time-dependent treatment and time-dependent covariates, it is desirable to balance the distribution of the covariates at every time point. A time-dependent propensity score based on the Cox proportional hazards model is proposed and used in risk set matching. Matching on this propensity score is shown to achieve a balanced distribution of the covariates in both treated and control groups. Optimal matching with various designs is conducted and compared in a study of a surgical treatment, cystoscopy and hydrodistention, given in response to a chronic bladder disease, interstitial cystitis. Simulation studies also suggest that the statistical analysis after matching outperforms the analysis without matching in terms of both point and interval estimations.     

Cucurbitacin B induces apoptosis of primary effusion lymphoma via disruption of cytoskeletal organization

BackgroundPrimary effusion lymphoma (PEL) is an aggressive B cell non-Hodgkin lymphoma that develops especially in AIDS patients and immunocompromised patients infected with human herpes virus-8 (HHV-8)/Kaposi's sarcoma-associated herpesvirus (KSHV). PEL has a poor prognosis in patients despite conventional chemotherapeutic treatment, and a safe and efficient therapy is required.PurposeTo examine the effects on PEL of cucurbitacin B (CuB), a triterpene found in plants of the Cucurbitaceae family that has several anti-cancer activities.Study designWe evaluated the anti-cancer activities of CuB in vitro and in vivo.MethodsCell proliferation of PEL cell lines was measured by MTT assay. Cleaved caspases and signaling transduction associated proteins were analyzed by western blotting. Wright and Giemsa staining and immunofluorescence staining were carried out to observe cell morphology. Cell cycles were analyzed by flow cytometry. RT-PCR was performed to detect viral gene expressions. A xenograft mouse model was employed to evaluate the anti-cancer activity of CuB in vivo.ResultsCuB inhibited cell proliferation of PEL cell lines (BCBL-1, BC-1, GTO and TY-1) in a dose-dependent manner (0–50 nM) and induced apoptosis of BCBL-1 cells via caspase activation in a dose- and time-dependent manner. In addition, CuB caused cell-shape disruption by inducing actin aggregation and suppressing the p-cofilin level, resulting in BCBL-1 cell arrest at the G2/M phase. In contrast, CuB showed almost no suppression of p-STAT3 and p-Akt activation, which were constitutively activated by KSHV-derived proteins. Furthermore, CuB (0.5 mg/kg) via intraperitoneal injection significantly (p < 0.05) suppressed solid tumor growth in the xenograft mouse model.ConclusionThis study suggests that CuB is a promising agent for PEL treatment.     

Recalibration and Validation of the Charlson Comorbidity Index in Korean Incident Hemodialysis Patients

BackgroundWeights assigned to comorbidities to predict mortality may vary based on the type of index disease and advances in the management of comorbidities. We aimed to develop a modified Charlson comorbidity index (CCI) in incident hemodialysis patients (mCCI-IHD), thereby improving risk stratification for mortality.MethodsData on 24,738 Koreans who received their first hemodialysis treatment between 2005 and 2008 were obtained from the Korean Health Insurance dataset. The mCCI-IHD score were calculated by summing up the weights which were assigned to individual comorbidities according to their relative prognostic significance determined by multivariate Cox proportional hazards model. The modified index was validated in an independent nationwide prospective cohort (n=1,100).ResultsThe Cox proportional hazards model revealed that all comorbidities in the CCI except ulcers significantly predicted mortality. Thus, the mCCI-IHD included 14 comorbidities with re-assigned severity weights. In the validation cohort, both the CCI and the mCCI-IHD were correlated with mortality. However, the mCCI-IHD showed modest but significant increases in c statistics compared with the CCI at 6 months and 1 year. The analyses using continuous net reclassification improvement revealed that the mCCI-IHD improved net mortality risk reclassification by 24.6% (95% CI, 2.5-46.7; P=0.03), 26.2% (95% CI, 1.0-51.4; P=0.04) and 42.8% (95% CI, 4.9-80.8; P=0.03) with respect to the CCI at 6 months and 1 and 2 years, respectively.ConclusionsThe mCCI-IHD facilitates better risk stratification for mortality in incident hemodialysis patients compared with the CCI, suggesting that it may be a preferred index for use in clinical practice and the statistical analysis of epidemiological studies.     

Refining Lipoprotein Assessment in Diabetes: Apolipoprotein B Makes Sense

ObjectiveTo summarize the data that support the measurement of apolipoprotein B as an accurate reflection of low-density lipoprotein (LDL) particle number and an easily adapted parameter in clinical practice.MethodsStudy findings are reviewed and a flow chart is provided to guide lipid assessment in patients with dyslipidemia.ResultsCurrent treatment guidelines for lipid management emphasize LDL cholesterol as the primary treatment target in patients at high risk of cardiovascular events. However, LDL cholesterol is a poor surrogate for LDL particle number, particularly in patients with altered LDL composition, such as those with insulin resistance, metabolic syndrome, and type 2 diabetes. Direct measurement of LDL particle number or size is not practical because of methodology and cost considerations. A suggested alternative target in patients with hypertriglyceridemia is non–high-density lipoprotein (HDL) cholesterol. Abundant evidence suggests that even non-HDL cholesterol is an inadequate approximation of the LDL particle number in such patients. The flow chart emphasizes the need to continue achieving the well-established LDL-cholesterol goal, while also considering apolipoprotein B measurement in those with hypertriglyceridemia, rather than relying on the less accurate surrogate of non-HDL cholesterol, when targeting therapy in such patients.ConclusionPresented evidence supports the measurement of apolipoprotein B as a more accurate reflection of LDL particle number than non-HDL cholesterol, and it is an easily adapted parameter in clinical practice. (Endocr Pract. 2009;15:370-376)     

Analysis of Time to Event Outcomes in Randomized Controlled Trials by Generalized Additive Models

Background

Randomized Controlled Trials almost invariably utilize the hazard ratio calculated with a Cox proportional hazard model as a treatment efficacy measure. Despite the widespread adoption of HRs, these provide a limited understanding of the treatment effect and may even provide a biased estimate when the assumption of proportional hazards in the Cox model is not verified by the trial data. Additional treatment effect measures on the survival probability or the time scale may be used to supplement HRs but a framework for the simultaneous generation of these measures is lacking.

Methods

By splitting follow-up time at the nodes of a Gauss Lobatto numerical quadrature rule, techniques for Poisson Generalized Additive Models (PGAM) can be adopted for flexible hazard modeling. Straightforward simulation post-estimation transforms PGAM estimates for the log hazard into estimates of the survival function. These in turn were used to calculate relative and absolute risks or even differences in restricted mean survival time between treatment arms. We illustrate our approach with extensive simulations and in two trials: IPASS (in which the proportionality of hazards was violated) and HEMO a long duration study conducted under evolving standards of care on a heterogeneous patient population.

Findings

PGAM can generate estimates of the survival function and the hazard ratio that are essentially identical to those obtained by Kaplan Meier curve analysis and the Cox model. PGAMs can simultaneously provide multiple measures of treatment efficacy after a single data pass. Furthermore, supported unadjusted (overall treatment effect) but also subgroup and adjusted analyses, while incorporating multiple time scales and accounting for non-proportional hazards in survival data.

Conclusions

By augmenting the HR conventionally reported, PGAMs have the potential to support the inferential goals of multiple stakeholders involved in the evaluation and appraisal of clinical trial results under proportional and non-proportional hazards.     

Prospective study of adoptive activated αβT lymphocyte immunotherapy for refractory cancers: development and validation of a response scoring system

Background aimsThis prospective clinical study aimed to determine the efficacy and prognostic factors of adoptive activated αβT lymphocyte immunotherapy for various refractory cancers. The primary endpoint was overall survival (OS), and the secondary endpoint was radiological response.MethodsThe authors treated 96 patients. Activated αβT lymphocytes were infused every 2 weeks for a total of six times. Prognostic factors were identified by analyzing clinical and laboratory data obtained before therapy.ResultsMedian survival time (MST) was 150 days (95% confidence interval, 105–191), and approximately 20% of patients achieved disease control (complete response + partial response + stable disease). According to the multivariate Cox proportional hazards model with Akaike information criterion–best subset selection, sex, concurrent therapy, neutrophil/lymphocyte ratio, albumin, lactate dehydrogenase, CD4:CD8 ratio and T helper (Th)1:Th2 ratio were strong prognostic factors. Using parameter estimates of the Cox analysis, the authors developed a response scoring system. The authors then determined the threshold of the response score between responders and non-responders. This threshold was able to significantly differentiate OS of responders from that of non-responders. MST of responders was longer than that of non-responders (317.5 days versus 74 days). The validity of this response scoring system was then confirmed by internal validation.ConclusionsAdoptive activated αβT lymphocyte immunotherapy has clinical efficacy in certain patients. The authors’ scoring system is the first prognostic model reported for this therapy, and it is useful for selecting patients who might obtain a better prognosis through this modality.     

Multisite studies for validation and improvement of a highly efficient culture assay for detection of undifferentiated human pluripotent stem cells intermingled in cell therapy products

Background aimsThe Multisite Evaluation Study on Analytical Methods for Non-Clinical Safety Assessment of Human-Derived Regenerative Medical Products (MEASURE) is a Japanese experimental public–private partnership initiative, which aims to standardize methodology for tumorigenicity evaluation of human pluripotent stem cell (hPSC)-derived cell therapy products (CTPs). Undifferentiated hPSCs possess tumorigenic potential, and thus residual undifferentiated hPSCs are one of the major hazards for the risk of tumor formation from hPSC-derived CTPs. Among currently available assays, a highly efficient culture (HEC) assay is reported to be one of the most sensitive for the detection of residual undifferentiated hPSCs.MethodsMEASURE first validated the detection sensitivity of HEC assay and then investigated the feasibility of magnetic-activated cell sorting (MACS) to improve sensitivity.ResultsThe multisite experiments confirmed that the lower limit of detection under various conditions to which the human induced pluripotent stem cell lines and culture medium/substrate were subjected was 0.001%. In addition, MACS concentrated cells expressing undifferentiated cell markers and consequently achieved a detection sensitivity of 0.00002%.ConclusionsThese results indicate that HEC assay is highly sensitive and robust and that the application of MACS on this assay is a promising tool for further mitigation of the potential tumorigenicity risk of hPSC-derived CTPs.