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A novel Cu-IOPC sensor was developed by combining the SiO2-based inverse opals with imidazolyl. Such mechanism is based on the specific binding of imidazole with copper ions, then the copper ions can be detected with high accuracy and efficiency.

Suppl Figures 1-3, Suppl Table 1 Supplemental Figure 1. Study schema. Supplemental Figure 2. Overall survival in patients treated with ENTO + 7+3. OS is censored on the date the patient was last known to be alive (if it was not known the patient had died by the end of study follow-up). Supplemental Figure 3. Heat map showing single patients (each column) by HOXA9 and MEIS1 categorization, cytogenetic or molecular risk and outcomes.

Purpose:Spleen tyrosine kinase (SYK) signaling is a proposed target in acute myeloid leukemia (AML). Sensitivity to SYK inhibition has been linked to HOXA9 and MEIS1 overexpression in preclinical studies. This trial evaluated the safety and efficacy of entospletinib, a selective inhibitor of SYK, in combination with chemotherapy in untreated AML.Patients and Methods:This was an international multicenter phase Ib/II study, entospletinib dose escalation (standard 3+3 design between 200 and 400 mg twice daily) + 7+3 (cytarabine + daunorubicin) in phase Ib and entospletinib dose expansion (400 mg twice daily) + 7+3 in phase II.Results:Fifty-three patients (n = 12, phase Ib and n = 41, phase II) with previously untreated de novo (n = 39) or secondary (n = 14) AML were enrolled (58% male; median age, 60 years) in this study. The composite complete response with entospletinib + 7+3 was 70%. Patients with baseline HOXA9 and MEIS1 expression higher than the median had improved overall survival compared with patients with below median HOXA9 and MEIS1 expression. Common adverse events were cytopenias, febrile neutropenia, and infection. There were no dose-limiting toxicities. Entospletinib-related skin rash and hyperbilirubinemia were also observed.Conclusions:Entospletinib with intensive chemotherapy was well-tolerated in patients with AML. Improved survival was observed in patients with HOXA9/MEIS1 overexpression, contrasting published data demonstrating poor survival in such patients. A randomized study will be necessary to determine whether entospletinib was a mediator this observation.

Ligustri Lucidi Fructus is dried and mature fruit of Ligubtrum lucidum Ait., which has the effects of nourishing liver and kidney. Herein, an accurate and sensitive method was established for separation and identification of the absorbed constituents and metabolites of Ligustri Lucidi Fructus in rat plasma based on ultra-high-performance liquid chromatography-Q-Exactive Orbitrap tandem mass spectrometry. A total of 73 prototype constituents and 148 metabolites were identified or characterized in administered plasma, and the possible metabolic pathways of constituents mainly involved hydroxylation, sulfation, demethylation, and glucuronidation. Besides, the network pharmacology was further investigated to illuminate its potential mechanism of treatment for liver injury by the biological targets regulating related pathways. Network pharmacological analysis showed that target components through 399 targets regulating 220 pathways. The docking results showed that 36 key target components were closely related to liver injury. Overall, the study clearly presented the metabolic processes of Ligustri Lucidi Fructus and gave a comprehensive metabolic profile of Ligustri Lucidi Fructus in vivo firstly. Combining with network pharmacology and molecular docking discovered potential drug targets and disclose the biological processes of Ligustri Lucidi Fructus, which will be a viable step toward uncovering the secret mask of study for traditional Chinese medicine. This article is protected by copyright. All rights reserved.

Purpose: To compare the efficacy and safety profiles of epidural analgesia (EA) and opioid analgesia (OA) in Chinese patients with thoracic trauma (TT). Methods: Patients with confirmed diagnosis of thoracic trauma were given either EA (via a catheter) or slow-release OA. The following efficacy variables were assessed in the two treatment groups: pain score, and changes in cytokine and catecholamine levels from baseline after treatment. Moreover, respiratory parameters were determined before and after treatment. The safety associated with each anesthesia was also evaluated. Quantitative data were analyzed either with Student’s t-test or MannWhitney test, while categorical data were analyzed using Fisher exact or Chi-square test, based on data size. Results: A total of 200 patients completed the study (100 patients in each group). Pain, as assessed by verbal rating scale (VRS), was slightly lower in patients after treatment with EA, when compared to the patients treated with OA. However, the difference was not statistically significant (p < 0.05). Maximum inspiratory force (cmH2O) and tidal volume (liters) were slightly improved in patients treated with EA, when compared to OA-treated patients, although the difference was not statistically significant (p < 0.05). Moreover, the two treatments produced comparable levels of cytokines and catecholamines. Conclusion: The efficacy and safety data for EA and OA in Chinese non-obese patients with TT indicate numerically favorable outcome for EA, when compared to OA. Keywords: Epidural analgesia, Opioid analgesia, Chinese patients, Thoracic trauma

The Caulerpa taxifolia is excellent marine green algae, which produced enormous bioactive compounds with more biological activities. Also, it is an excellent source for synthesis of Ag NPs with increased bioactivity against various infections. In our study, the marine algae marine algae Caulerpa taxifolia mediated Ag NPs was synthesized effectively. The synthesized Ag NPs was characterized well using UV-spectrometer and X-ray powder diffraction (XRD) and confirmed as synthesized particle was Ag NPs. The available structure of the Ag NPs was morphologically identified by scanning electron microscope (SEM), and exact minimum size, polydispersive spherical shape of the entire Ag NPs structure was confirmed by Transmission electron microscope (TEM). Further, the anti-cancer efficiency of biosynthesized Ag NPs against A549 lung cancer cells was found at 40 µg/mL concentration by cytotoxicity experiment. In addition, the phase contrast images of the result were supported the Ag NPs, which damaged the A549 morphologically clearly. Finally, florescence microscopic images were effectively proved the anti-cancerous effect against A549 lung cancer cells due to the condensed morphology of increased death cells. All the confirmed in-vitro results were clearly stated that the Caulerpa taxifolia mediated Ag NPs has superior anti-cancer agent against A549 lung cancer cells.

Purpose: Spleen tyrosine kinase (SYK) signaling is a proposed target in acute myeloid leukemia (AML). Sensitivity to SYK inhibition has been linked to HOXA9 and MEIS1 overexpression in preclinical studies. This trial evaluated the safety and efficacy of entospletinib, a selective inhibitor of SYK, in combination with chemotherapy in untreated AML. Patients and Methods: This was an international multicenter phase Ib/II study, entospletinib dose escalation (standard 3+3 design between 200 and 400 mg twice daily) + 7+3 (cytarabine + daunorubicin) in phase Ib and entospletinib dose expansion (400 mg twice daily) + 7+3 in phase II. Results: Fifty-three patients (n = 12, phase Ib and n = 41, phase II) with previously untreated de novo (n = 39) or secondary (n = 14) AML were enrolled (58% male; median age, 60 years) in this study. The composite complete response with entospletinib + 7+3 was 70%. Patients with baseline HOXA9 and MEIS1 expression higher than the median had improved overall survival compared with patients with below median HOXA9 and MEIS1 expression. Common adverse events were cytopenias, febrile neutropenia, and infection. There were no dose-limiting toxicities. Entospletinib-related skin rash and hyperbilirubinemia were also observed. Conclusions: Entospletinib with intensive chemotherapy was well-tolerated in patients with AML. Improved survival was observed in patients with HOXA9/MEIS1 overexpression, contrasting published data demonstrating poor survival in such patients. A randomized study will be necessary to determine whether entospletinib was a mediator this observation.

We evaluated the ability of different fluorescent indicators by various analytical instruments, including a laser scanning confocal microscope (LSCM), fluorescence plate reader, and flow cytometer (FCM), to measure the mitochondrial membrane potential (ΔΨm) of cardiac H9c2 cells during oxidative stress-induced mitochondrial injury. The mitochondrial oxygen consumption rate and a transmission electron microscope were used to detect changes in mitochondrial functions and morphology, respectively. Cardiac H9c2 cells were exposed to H2O2 (500, 750, 1000, and 1250 μM) to induce mitochondrial oxidative stress injury, and fluorescent indicators including tetramethyl rhodamine ethyl ester (TMRE), 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolocarbocyanine iodide (JC-1), and rhodamine 123 (R123) were used to detect changes in ΔΨm using an LSCM, fluorescence plate reader, and FCM. The decrease in ΔΨm caused by H2O2 was determined by endpoint and dynamic analyses after staining with JC-1 or TMRE. With the R123 probe, the LSCM could only detect the change in ΔΨm caused by 1000 μM H2O2. Moreover, R123 was less effective than JC-1 and TMRE for measurement of ΔΨm by the LSCM. Our data indicated that an LSCM is the most suitable instrument to detect dynamic changes in ΔΨm, whereas all three instruments can detect ΔΨm at the endpoint.

Ligustri Lucidi Fructus (LLF) is the dried and mature fruit of Ligubtrum lucidum Ait., which has the effect of nourishing the liver and kidney, brightening the eyes and promoting the growth of black hair. Wine-processed LLF is commonly used in traditional Chinese medicine; however, the processing mechanisms are still unclear. Herein, a system data acquisition and mining strategy was designed to investigate the chemical profile differences between the raw and wine-processed LLF, based on high-performance liquid chromatography-Orbitrap high resolution mass spectrometry coupled with multivariate statistical analysis including principal component analysis and partial least square analysis. Afterwars, a total of 55 components were found to be the main contributors to the significant difference between raw and wine-processed LLF by comparison with chromatographic behaviors, intact precursor ions, and characteristic MS fragmentation patterns. In addition, 10 main constituents of raw and wine-processed LLF were simultaneously determined by UHPLC-MS/MS for analyzing the content variations. Some structural transformation mechanisms during wine processing were deduced from the results. The results may provide a scientific foundation for deeply elucidating the wine-processing mechanism of LLF.

An accurate and sensitive ultra-high-performance liquid chromatography coupled with triple quadrupole mass spectrometry method was established and validated for the determination of nine bioactive compounds of Ligustri Lucidi Fructus in rat plasma. Separation was performed on Halo® C18 column with a mobile phase of acetonitrile and 0.1% formic acid in water. The eluate was detected by multiple reaction monitoring scanning operating in the negative ionization mode. This assay method was validated for selectivity, linearity, intra- and interday precision, accuracy, recovery, matrix effect, and stability, and all methodological parameters fulfilled the Food and Drug Administration criteria for bioanalytical validation. The established method was successfully applied to a comparative pharmacokinetic study of raw and wine-processed Ligustri Lucidi Fructus in rats for the first time. It was found that the AUC0-24 and Cmax value of salidroside, hydroxytyrosol, and nuezhenidic acid were increased significantly after processing, while the AUC0-24 and Cmax value of oleoside 11-methyl ester, 1'''-O-β-d-glucosylformoside, specnuezhenide, G13, oleonuezhenide, and oleanolic acid were decreased, which suggested that processing affects the absorption and bioavailability of Ligustri Lucidi Fructus. The results might be valuable for the clinical reasonable application and understanding the processing mechanism of Ligustri Lucidi Fructus.

Spleen tyrosine kinase (SYK) signaling is a proposed target in acute myeloid leukemia (AML). Sensitivity to SYK inhibition has been linked toThis was an international multicenter phase Ib/II study, entospletinib dose escalation (standard 3+3 design between 200 and 400 mg twice daily) + 7+3 (cytarabine + daunorubicin) in phase Ib and entospletinib dose expansion (400 mg twice daily) + 7+3 in phase II.Fifty-three patients (Entospletinib with intensive chemotherapy was well-tolerated in patients with AML. Improved survival was observed in patients with

Transmembrane emp24 protein transport domain containing 3 (TMED3) is a newly identified cancer-related protein in several malignancies. However, its role in carcinogenesis is still controversial. The project was performed to explore the possible function of TMED3 in the carcinogenesis of non-small cell lung cancer (NSCLC). TMED3 were abundantly expressed in NSCLC tissue, and high TMED3 levels predicted reduced survival in NSCLC patients. NSCLC cells with TMED3 silencing proliferated and invaded more slowly, and were more sensitive to the chemotherapy drug cisplatin than control NSCLC cells. TMED3 silencing reduced the activity of Wnt/β-catenin pathway, associated with the repression of AKT. Restraint of AKT blocked TMED3-overexpression-evoked enhancing effects on Wnt/β-catenin pathway. Moreover, down-regulating Wnt/β-catenin activity reversed TMED3-overexpression-evoked enhancing effects on the proliferation and invasion of NSCLC cells. Additionally, inhibition of TMED3 also displayed antitumor effects in vivo in nude mice. Taken together, our data demonstrate that TMED3 exerts a protumor function in NSCLC by enhancing Wnt/β-catenin signaling by modulating AKT. Our findings demonstrate that TMED3 inhibition displayed outstanding antitumor effects in vitro and in vivo, and may be a candidate target for future exploiting targeted therapies for NSCLC management.

Ubiquitin-specific protease 14 (USP14), one of three proteasome-associated deubiquitinating enzymes (DUBs), plays an essential role in the development of human carcinoma. However, to the best of our knowledge, the role of USP14 in esophageal squamous cell carcinoma (ESCC) is unknown. In the current study, we investigated the expression and role of USP14 in ESCC. Our results showed that the level of USP14 was significantly increased in ESCC tissues and cell lines. Downregulation of USP14 significantly inhibited ESCC cell proliferation and ESCC tumor growth in nude mice. Downregulation of USP14 also suppressed the migration/invasion in ESCC cells. Mechanically, downregulation of USP14 decreased the protein expression levels of β-catenin, cyclin D1, and c-Myc in ESCC cells. In conclusion, our study shows that USP14 plays an important role in the progression and metastasis of ESCC. Therefore, these data suggest that USP14 may be a potentially useful therapeutic strategy for the treatment of ESCC.

Circular RNAs (circRNAs) have good stability and long half-life in blood and other body fluid, and possess regulatory effects on various biological processes as miRNA/RNA-binding protein sponges, or by competing endogenous RNA, indicating their great potential as biomarkers or targets of cancer therapy. In this study, we mainly explored the role and mechanism of circular RNA SMARCA5 (circsSMARCA5) in non-small cell lung cancer (NSCLC). Quantitative RT-PCR was applied to measure the expression levels of genes, and then, the relationships among circsSMARCA5, microRNA-670-5p (miR-670-5p), and RBM24 were further analyzed. Animal and cell experiments were performed to explore the functions of circsSMARCA5 in NSCLC cells. The results showed that circsSMARCA5 was expressed at low level in NSCLC tissues and cells, while miR-670-5p had high level in NSCLC tissues. Dual luciferase reporter assay verified that miR-670-5p was the target of circsSMARCA5, and RBM24 has the binding site of miR-670-5p. Further analysis showed that circsSMARCA5 could negatively regulate miR-670-5p and had positive relationship with RBM24. Moreover, circsSMARCA5 obviously inhibited tumor growth in vivo, reduced cell proliferation and increased cell apoptosis in vitro, while miR-670-5p mimic or RBM24 knockdown could reverse these effects. Thus, circsSMARCA5 may serve as an NSCLC suppressor by regulating the miR-670-5p/RBM24 axis, and it may have the potential to be a biomarker or therapeutic target for NSCLC.

Aims Circular RNA PRKCI (circPRKCI) and poly ADP-ribose polymerase 9 (PARP9) are related to the development of cancers. In this study, we aimed to explore the regulatory mechanisms between circPRKCI and PARP9 in EC progression and radioresistance. Materials and methods The levels of circPRKCI, PARP9 mRNA, and miR-186-5p were assessed by quantitative real time polymerase chain reaction (qRT-PCR). Western blot analysis was employed to examine the levels of several proteins. The viability, colony formation, cell cycle progression, and apoptosis of EC cells were determined with CCK-8, colony formation, or flow cytometry assays. The relationship between circPRKCI or PARP9 and miR-186-5p was verified with the dual-luciferase reporter and RIP assays. Key findings We observed that circPRKCI and PARP9 were upregulated while miR-186-5p was downregulated in EC tissues and cells. Furthermore, circPRKCI knockdown decreased tumor growth in vivo and constrained cell viability, colony formation, cell cycle progression, elevated cell radiosensitivity in EC cells in vitro. Importantly, circPRKCI modulated PARP9 expression through sponging miR-186-5p. Besides, PARP9 overexpression overturned circPRKCI silencing-mediated effects on the viability, colony formation, cell cycle progression, and radiosensitivity of EC cells. Significance CircPRKCI regulated cell malignancy and radioresistance through modulating the miR-186-5p /PARP9 axis in EC, which provided a might target for EC treatment.

The incidence of non-small cell lung cancer (NSCLC) has significantly increased in China, while the prognosis of affected patients is poor. The pathogenesis of NSCLC is thought to be regulated by microRNAs (miRs). The present study used a miR array in order to determine the expression of miR-361-5p, which was significantly lower in NSCLC tissues compared with that in adjacent tissues, indicating a crucial role of miR-361-5p during the progression of NSCLC. Furthermore, the effects of transfection-induced upregulation of miR-361-5p on the NSCLC cell line H23 were assessed. Overexpression of miR-361-5p inhibited the proliferation and colony formation ability of H23 cells. In addition, apoptosis of H23 cells was induced by upregulation of miR-361-5p. Furthermore, signal transducer and activator of transcription 6 (STAT6) was confirmed as a direct target of miR-361-5p by a dual-luciferase reporter assay. Moreover, inhibition of STAT6 by small interfering RNA or miR-361-5p also decreased the expression of B-cell lymphoma extra large (Bcl-xL). In vivo, miR-361-5p significantly reduced tumor growth in a nude mouse xenograft model, and suppressed STAT6 and Bcl-xL expression. In conclusion, the present study indicated that miR-361-5p may represent a novel molecular tool for therapeutic and diagnostic strategies in NSCLC.

Radical prostatectomy (RP) can cure men with unfavorable intermediate- or high-risk prostate cancer (PC). However, some will experience short prostate-specific antigen (PSA) doubling time (PSADT) failure that requires additional treatment with increased toxicity. The present study investigated whether the greatest percentage of involved biopsy core length (GPC) can preoperatively identify men at risk of short PSADT failure.A total of 503 men with biopsy-proven PC underwent RP at an academic institution from January 2005 to December 2008. Men with incomplete pathologic information, those who had received neoadjuvant or adjuvant hormonal therapy or chemotherapy, and those who had undergone adjuvant radiation therapy were excluded. The median follow-up period was 4.89 years (interquartile range, 1.97-5.68 years). A competing risk regression was used to assess whether an increasing GPC value was associated with an increased PSADT at 10-month failure risk, adjusting for age, percentage of positive biopsy results, and risk group.Of the 402 men, 34 (8.46%) developed PSA failure, 17 (50.0%) of whom had a PSADT of 10 months. An increasing GPC value was significantly associated with an increased PSADT of 10-month failure risk (adjusted hazard ratio, 1.03; 95% confidence interval, 1.01-1.06; P = .015). Men with a GPC30% (median) versus ≤ 30% and unfavorable intermediate- or high-risk PC (P = .011), but not low or favorable intermediate-risk PC (P = .57), had a significantly greater incidence of PSADT 10-month failure estimates (30% vs. 0% at 5 years).Men planning to undergo RP for unfavorable intermediate- or high-risk PC with a GPC of30% should be considered for randomized trials evaluating the effect on survival of the neoadjuvant use of treatment that extends survival in those with castrate-resistant metastatic PC.

Background Some men with biopsy Gleason score (GS) 7 prostate cancer (PC) harbor occult GS 8 to 10 PC and might be undertreated with short-term androgen deprivation therapy (ADT) and radiation therapy (RT). With advancing age associated with occult high-grade PC, we evaluated PC-specific mortality (PCSM) risk after RT and short-term ADT for older men with GS 4+3 PC and men of any age with GS 8 to 10 PC. Patients and Methods The study cohort comprised 206 men with unfavorable-risk PC treated with RT or RT and 6 months of ADT on a randomized trial between 1995 and 2001. Competing risks regression was used to compare PCSM risk for men with GS 8 to 10 PC to men with GS ≤ 3+4, GS 4+3 and age ≤ 73 years (median age), and GS 4+3 and age > 73 years, adjusting for PC risk factors, comorbidity, and treatment. Results After a median follow-up of 14.3 years, 135 men died (65.53%), 24 (17.78%) of PC. Men age > 73 years with GS 4+3 PC did not have significantly lower PCSM risk compared with men with GS 8 to 10 (adjusted hazard ratio [AHR], 1.08; 95% confidence interval [CI], 0.29-4.06; P = .91); whereas unhealthy men (AHR, 0.20; 95% CI, 0.04-0.93; P = .04) and men age ≤ 73 years with GS 4+3 (AHR, 0.09; 95% CI, 0.01-1.03; P = .05) fared better. Conclusion Men age > 73 years with biopsy GS 4+3 did not have a significant difference in PCSM risk than men with GS 8 to 10, supporting further study of multiparametric magnetic resonance imaging in such men with no or minimal comorbidity before determining ADT duration.

Joint models for longitudinal and survival data are routinely used in clinical trials or other studies to assess a treatment effect while accounting for longitudinal measures such as patient-reported outcomes (PROs). In the Bayesian framework, the deviance information criterion (DIC) and the logarithm of the pseudo marginal likelihood (LPML) are two well-known Bayesian criteria for comparing joint models. However, these criteria do not provide separate assessments of each component of the joint model. In this paper, we develop a novel decomposition of DIC and LPML to assess the fit of the longitudinal and survival components of the joint model, separately. Based on this decomposition, we then propose new Bayesian model assessment criteria, namely, ΔDIC and ΔLPML, to determine the importance and contribution of the longitudinal (survival) data to the model fit of the survival (longitudinal) data. Moreover, we develop an efficient Monte Carlo method for computing the Conditional Predictive Ordinate (CPO) statistics in the joint modeling setting. A simulation study is conducted to examine the empirical performance of the proposed criteria and the proposed methodology is further applied to a case study in mesothelioma.

Objectives To determine if androgen-deprivation therapy (ADT) is associated with excess cardiac-specific mortality (CSM) in men with prostate cancer and no cardiovascular comorbidity, coronary artery disease risk factors, or congestive heart failure (CHF) or past myocardial infarction (MI). Patients and Methods In all, 5077 men (median age 69.5 years) with cT1c-T3N0M0 prostate cancer were treated with brachytherapy with or without neoadjuvant ADT (median duration 4 months) between 1997 and 2006. Fine and Gray competing risks analysis evaluated the association of ADT with CSM, adjusting for age, year of brachytherapy, and ADT treatment propensity score among men in groups defined by cardiac comorbidity. Results After a median follow-up of 4.8 years, no association was detected between ADT and CSM in men with no cardiac risk factors (1.08% at 5 years for ADT vs 1.27% at 5 years for no ADT, adjusted hazard ratio (AHR) 0.83; 95% confidence interval (CI), 0.39–1.78; P = 0.64; n = 2653) or in men with diabetes mellitus, hypertension, or hypercholesterolaemia (2.09% vs 1.97%, AHR 1.33; 95% CI 0.70–2.53; P = 0.39; n = 2168). However, ADT was associated with significantly increased CSM in men with CHF or MI (AHR 3.28; 95% CI 1.01–10.64; P = 0.048; n = 256). In this subgroup, the 5-year cumulative incidence of CSM was 7.01% (95% CI 2.82–13.82%) for ADT vs 2.01% (95% CI 0.38–6.45%) for no ADT. Conclusion ADT was associated with a 5% absolute excess risk of CSM at 5 years in men with CHF or prior MI, suggesting that administering ADT to 20 men in this potentially vulnerable subgroup could result in one cardiac death.

The aim of this study was to investigate whether the MTD could identify men at low risk of PSA recurrence after RP who might not benefit from ART despite other adverse features.The study cohort consisted of 354 men with T1c to T2 prostate cancer diagnosed between September 2001 and December 2008 who underwent RP without adjuvant therapy. Multivariable Cox regression was used to assess the effect of MTD on the risk of PSA recurrence (0.1 ng/mL and verified), adjusting for known predictors.After a median follow-up of 4.0 years, 34 men (9.6%) experienced PSA failure. In multivariable analysis, increasing MTD was significantly associated with an increased PSA recurrence risk (hazard ratio, 2.74; 95% confidence interval, 1.23-6.10; P = .01) within the interaction model. Estimates of PSA recurrence-free survival stratified around the median MTD value (1.2 cm) were significantly different in men with a pre-RP PSA4 ng/mL (P.001; 5-year estimate: 74.5% vs. 99.0%) but not in men with PSA ≤ 4 ng/mL (P = .59; 5-year estimate: 89.6% vs. 92.6%), consistent with the significant interaction (P = .004) between PSA and MTD. Moreover, in men with a pre-RP PSA4 ng/mL these estimates were significantly different if at least 1 adverse feature (pT3, R1, or Gleason score ≥ 8) was present at RP (P = .01; 5-year estimate: 46.6% vs. 100%) versus none (P = .09; 5-year estimate: 93.4% vs. 98.9%).Men with a low MTD (≤ 1.2 cm) appear to be at low risk of PSA recurrence despite adverse features at RP and might not benefit from ART.

The addition of androgen deprivation therapy (ADT) to external beam radiotherapy (RT) decreases prostate cancer-specific mortality (PCSM) in patients with intermediate- and high-risk prostate cancer (PCa); however, whether this is true across the spectrum of percent positive biopsy (PPB) values is unknown and was evaluated in the current study. From 1995 to 2001, 206 men with intermediate- or high-risk PCa were randomized to receive RT alone or RT and 6 months of ADT; 149 men with no or minimal comorbidity comprised the study cohort. Fine and Gray competing risk regression was used to ascertain whether an increasing PPB was associated with an increased risk of PCSM adjusting for age, known PCa prognostic factors, and treatment. After a median follow-up of 14.26 years, 88 men died in total (59 %), 20 of prostate cancer (23 %). RT as compared to RT + ADT [adjusted hazard ratio (AHR) 4.12 (1.10, 15.35), p = 0.04] and an increasing PPB [AHR 1.04 (1.02, 1.06), p 14 years with a PPB of

BACKGROUND Recently, men with intermediate-risk prostate cancer (PC) were classified into favorable and unfavorable categories; however, whether the risk of PC-specific mortality (PCSM) among men with high-risk PC versus unfavorable intermediate-risk PC is increased is unknown. METHODS In a prospective, randomized trial conducted between 1995 and 2001, 206 men with intermediate-risk or high-risk PC were randomized to receive 70 Gy with or without 6 months of androgen-suppression therapy (AST). The subgroup of 197 patients with information available on the percentage of positive biopsies formed the cohort. Fine and Gray regression analysis was used to assess whether men with high-risk PC versus unfavorable intermediate-risk PC had an increased risk of PCSM. RESULTS After a median follow-up of 14.3 years, there were 127 deaths (64.5%), including 22 deaths (17.3%) from PC. There were no PC deaths in the favorable intermediate-risk group. There was an increase in the risk of PCSM among men with high-risk PC versus unfavorable intermediate-risk PC, but the difference was not significant (adjusted hazard ratio, 1.59; 95% confidence interval, 0.66-3.83; P = .30) after adjusting for age, randomized treatment arm, and comorbidity. CONCLUSIONS The lack of PC deaths among men with favorable intermediate-risk PC suggests that adding AST may not reduce their risk of PCSM; whereas many men with unfavorable intermediate-risk PC are at risk for harboring occult PC with Gleason scores from 8 to 10 and, if proven, would benefit from long-term AST. Multiparametric magnetic resonance imaging and targeted biopsy of suspicious lesions should be considered to identify PC with Gleason scores from 8 to 10 in these men. Cancer 2014;120:1787–1793. © 2014 American Cancer Society.

Purpose. Increasing body mass index (BMI) is associated with higher risk prostate cancer (PC) at presentation. Whether increasing BMI also prompts earlier salvage androgen suppression therapy (sAST) is unknown.Materials and Methods. Between 1995 and 2001, 206 men with unfavorable risk PC were treated with radiation therapy (RT) or RT and six months of androgen suppression therapy in a randomized controlled trial (RCT). 108 sustained PSA failure; 51 received sAST for PSA approaching 10 ng/mL; 49 with BMI data comprised the study cohort. A multivariable Cox regression analysis identified pretreatment factors associated with earlier sAST receipt.Results. Increasing BMI prompted earlier sAST (median years: 3.7 for overweight/obese, 6.9 for normal weight; adjusted hazard ratio (AHR): 1.11; 95% CI: 1.04, 1.18;P=0.002) as did high versus other risk PC (median: 3.2 versus 5.2 years; AHR: 2.01; 95% CI: 1.05, 3.83;P=0.03). Increasing median time to sAST was observed for overweight/obese men with high versus other risk PC and for normal-weight men with any risk PC being 2.3, 4.6, and 6.9 years, respectively (P<0.001for trend).Conclusion. Increasing BMI was associated with earlier sAST. A RCT evaluating whether BMI reduction delays or eliminates need for sAST is warranted.

Introduction: In CLL, numerous new therapeutic options have been introduced recently, without establishing a definitive standard therapy or cure for most patients (pts). An advantage of targeted therapies is the avoidance of toxicities associated with chemotherapy. However, all new kinase inhibitors used for treatment of CLL have low rates of complete remission (CR). Combinations of targeted agents have the potential to improve outcomes, shorten treatment duration, and reduce toxicity. Tirabrutinib (a BTK inhibitor), and entospletinib (a SYK inhibitor), both show significant single-agent clinical activity in pts with CLL. In this study, we evaluated tirabrutinib and entospletinib as dual therapy (TE), and as triple therapy in combination with obinutuzumab (TEO). Methods: This is a prospective, open-label, phase 2 protocol (NCT02983617) at 15 clinical centers in Germany that recruited pts with relapsed or refractory CLL between April 2017 and September 2018. As of amendment 3, pts who did not progress while on an inhibitor of BTK, SYK, PI3K, BCL-2 or on obinutuzumab were also included. Pts received the TE regimen with tirabrutinib 80 mg once daily (QD) + entospletinib 400 mg QD for up to 104 weeks, or the TEO regimen adding obinutuzumab at standard dosing for a total of 8 doses of 1000 mg over 21 weeks. After the implementation of protocol amendment 3, randomization was discontinued and all subsequently enrolled pts received the TEO regimen. Response was measured by modified iwCLL 2008 criteria. The primary endpoint was the CR rate at week 25. Results: Thirty-six pts were treated, 6 with TE and 30 with TEO. Median (range) age was 68 (45-82) years, with a median of 1 (1-2) and 2 (1-8) prior anticancer therapies in those assigned to TE and TEO, respectively. As of 16 May 2019, 29 of all 36 pts (81%) continue to receive tirabrutinib and entospletinib on study; 2 (6%) pts completed study drug dosing as specified per protocol at week 104. Twenty-eight of 30 pts (93%) in the TEO arm completed obinutuzumab dosing as specified per protocol. Of the 36 pts, 34 (94%) continued the study and 2 (6%) discontinued the study due to adverse events (AEs) or death, both were in the TEO group. Median duration (range) of exposure to tirabrutinib and entospletinib was 99 (90-105) weeks on TE and 50 (4-104) weeks on TEO, including 20 (2-35) weeks for obinutuzumab. At week 25, CR rate was 0% (90% confidence interval [CI] 0-39.3) with TE and 7% (90% CI 1.2-19.5) with TEO (Table 1). Overall response rates at week 25 were 100% (90% CI 60.7-100) and 90% (90% CI 76.1-97.2) for TE and TEO.One pt on the TEO regimen experienced disease progression (per clinical response assessment) after 3.75 months of therapy. Three (10%) pts on TEO were minimal residual disease (MRD) negative in peripheral blood (PB MRD-) at week 25; one (3%) pt was also MRD negative in bone marrow (BM MRD-).No pts showed MRD negativity with TE therapy. Best rate of CR/PB MRD- was 7% (90% CI 1.2-19.5) and for CR/BM MRD- was 3% (90% CI 0.2-14.9) with TEO. Median time to first PB MRD- was 32 weeks on TEO. Median progression-free survival (PFS) and overall survival have not been reached yet, and 24-month PFS rates were not yet estimable in either treatment group. Treatment-emergent AEs (TEAEs) are listed in Table 2. No pt in the TE and 3 pts (10%) in the TEO group discontinued tirabrutinib and entospletinib due to TEAEs, and no pt discontinued obinutuzumab due to TEAEs. Two (7%) pts in the TEO arm died following a TEAE: an 82-year-old male from subdural hematoma (onset within 30 days of last dosing, and death within 68 days) and a 77-year-old male from syncope (onset on the last dosing date, and death at day 35 after last dosing); both deaths were considered unrelated to study treatment by investigators. Conclusion: A triple combination with tirabrutinib, entospletinib, and obinutuzumab (TEO regimen) was tolerable and demonstrated excellent therapeutic activity in pts with relapsed or refractory CLL, but with limited CR rate. Disclosures Kutsch: Gilead Sciences, Inc.: Research Funding; Mundipharma, AbbVie, Janssen: Other: Travel, accomodation, expenses. Pallasch:Gilead Sciences, Inc.: Honoraria, Research Funding. Tausch:AbbVie: Consultancy, Honoraria, Other: travel support, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. Boehme:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Glenmark Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Helsinn: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; VioPharm: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; InCyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant. Ritgen:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding. Wacker:Celgene: Consultancy; Roche: Consultancy; BMS: Consultancy; Incyte: Consultancy; Amgen: Consultancy. Trappe:Celgene, Janssen, Takeda, TEVA: Other: Congress related travel support ; Atara: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche Pharma: Consultancy, Honoraria, Other: Congress related travel support , Research Funding; AbbVie: Consultancy, Other: Congress related travel support . Dreger:AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau; AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy; Neovii, Riemser: Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia. Stilgenbauer:AbbVie, AstraZeneca, Celgene, Gilead Sciences, Inc., GSK, Hoffmann La-Roche, Janssen, Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Zhang:Gilead Sciences, Inc.: Employment, Other: Shareholder. Jürgensmeier:Gilead Sciences, Inc.: Employment, Other: Shareholder. Bhargava:Gilead Sciences, Inc.: Employment, Other: Shareholder; Tioma Therapeutics: Membership on an entity's Board of Directors or advisory committees; Dicerna Pharmaceuticals: Consultancy; Sanofi, Aveo Pharma: Patents & Royalties. Hallek:Roche, Gilead Sciences, Inc., Mundipharma, Janssen, Celgene, Pharmacyclics, AbbVie: Honoraria, Research Funding, Speakers Bureau. Eichhorst:ArQule: Membership on an entity's Board of Directors or advisory committees; BeiGene: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: GAZYVA (obinutuzumab) is a CD20-directed cytolytic antibody and is indicated in combination with chlorambucil, for the treatment of patients with previously untreated chronic lymphocytic leukemia.

Some men with unfavorable intermediate-risk prostate cancer (PC) have occult disease with a Gleason score of 8 or higher unrecognized on biopsy because of a sampling error that would change management to long from short course androgen-deprivation therapy in conjunction with radiotherapy. Identifying such men could improve outcomes.The study cohort consisted of 136 consecutive men with unfavorable intermediate-risk PC who underwent radical prostatectomy (RP) between 2005 and 2008. We performed logistic regression analysis to identify clinical factors associated with upgrading to a Gleason score of 8 or higher at RP.Fourteen percent of the men were upgraded to a Gleason score of 8 or higher PC at RP. Both increasing prostate-specific antigen (PSA) (adjusted odds ratio, 1.98; 95% confidence interval, 1.19, 3.30; P = .01) and greatest percentage core length (GPC) (adjusted odds ratio, 1.11; 95% confidence interval, 1.03, 1.19; P .01) were significantly associated with upgrading. A significant interaction between PSA and GPC was observed (P = .01). Specifically, men with low PSA (5 ng/mL) and those with larger GPC (70%) were significantly more likely to have a Gleason score of 8 or higher at RP compared to men with low PSA and GPC of 70% or less (35% vs. 0%; P = .01), whereas the same was not true among men with PSA levels ≥ 5 ng/mL (16% vs. 9%; P = .36).In men with unfavorable intermediate-risk PC, a multiparametric magnetic resonance imaging could be considered when the PSA is low and the percentage core length high to identify occult Gleason score 8 or higher disease and change management from short to long course androgen-deprivation therapy and radiotherapy.

Joint models for longitudinal and survival data now have a long history of being used in clinical trials or other studies in which the goal is to assess a treatment effect while accounting for a longitudinal biomarker such as patient-reported outcomes or immune responses. Although software has been developed for fitting the joint model, no software packages are currently available for simultaneously fitting the joint model and assessing the fit of the longitudinal component and the survival component of the model separately as well as the contribution of the longitudinal data to the fit of the survival model. To fulfill this need, we develop a SAS macro, called JMFit. JMFit implements a variety of popular joint models and provides several model assessment measures including the decomposition of AIC and BIC as well as ∆AIC and ∆BIC recently developed in Zhang, Chen, Ibrahim, Boye, Wang, and Shen (2014). Examples with real and simulated data are provided to illustrate the use of JMFit.

Introduction: Targeted therapy for KMT2A (mixed lineage leukemia [MLL]) rearranged acute leukemia (AL) is lacking. KMT2A regulates leukemic stem cell transcription factors HOXA9 and MEIS1. Spleen tyrosine kinase (SYK) signaling induces MEIS1 in conjunction with HOXA9. We hypothesize that this regulatory loop may be sensitive to SYK inhibition with Entospletinib (ENTO) a highly selective, oral SYK inhibitor. In this analysis, we evaluate the efficacy of ENTO in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) with t(v;11q23.3) KMT2A/MLL gene rearrangements. Methods: Patients with KMT2A rearranged AL in two different clinical trials were included. AML patients (NCT02343939) received ENTO 400mg BID monotherapy for up to 14 days prior to and with induction chemotherapy (cytarabine 100 mg/m2 for 7 days plus daunorubicin 60 mg/m2 for 3 days) if previously untreated, or ENTO monotherapy alone if relapsed/refractory (R/R). R/R B-ALL patients received ENTO monotherapy for 7 days prior to and with vincristine and dexamethasone in a phase 1 study (NCT02404220). Results: 18 patients with KMT2A rearranged AL were treated. Untreated AML (n=10) patients had a median age of 49 years. One patient was in a morphologic leukemia-free state after ENTO monotherapy (before chemotherapy). After induction chemotherapy plus ENTO, seven patients had morphologic (CR) and cytogenetic (CRc) remission, but two of them had incomplete count recovery (CRi). The composite CR rate (CR/CRi/CRc) was 90%: 5 CRc, 3 CRi (CR/CRc with incomplete count recovery), and 1 CR. Six patients underwent allogeneic stem cell transplantation (SCT) in CR1. After median follow-up of 9.9 months one patient who achieved CR relapsed, with persistence of t (6;11) and an NRAS mutation. Median overall survival and event-free survival have not been reached. In R/R AML (n=6), patients had a median age of 48 years, with 2 median prior therapies. One had CR and one had CRi (but normal cytogenetics) and both received SCT. In all, 3 AML patients (1 newly diagnosed, 2 R/R) responded to ENTO monotherapy alone. In R/R ALL (n=2), median age was 59 years. Both patients had t (4;11) along with other cytogenetic abnormalities with 2 prior therapies. Both patients achieved CR with loss of KMT2A on cytogenetic testing, and one patient received SCT. Overall, ENTO was safe and well tolerated, even in combination with chemotherapy. Conclusions: KMT2A rearranged AL is sensitive to ENTO with CR observed on monotherapy in AML and high response rates in AL patients treated with combination therapy. This represents the first documentation of CR with small molecule monotherapy (n=3) in this genetic subgroup, which typically portends a poor prognosis. Correlative biomarker studies evaluating HOXA9/MEIS1 in patients with t(v;11q23.3) KMT2A rearranged leukemia treated with ENTO are pending. Citation Format: Alison R. Walker, John C. Byrd, William Blum, Tara Lin, Howland E. Crosswell, Danjie Zhang, Jie Gao, Arati V. Rao, Mark D. Minden, Wendy Stock. High response rates with entospletinib in patients with t(v;11q23.3);KMT2A rearranged acute myeloid leukemia and acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 819.

Purpose We estimated the risks of prostate cancer–specific mortality (PCSM) and all-cause mortality (ACM) in men with high-risk prostate cancer (PC) undergoing external beam radiation therapy and brachytherapy with short-course androgen deprivation therapy (ADT) (median 4 months) as compared with men with more favorable-risk PC undergoing standard of care as per the National Comprehensive Cancer Network guidelines. Methods and Materials The prospective study cohort comprised 6595 consecutively treated men with T1-4 N0M0 PC whose treatment included brachytherapy between October 16, 1997, and May 28, 2013. Fine and Gray competing risk regression and Cox regression analyses were used to assess the risks of PCSM and ACM in men with high, unfavorable intermediate, and favorable intermediate risk as compared with low-risk PC. Results After median followup of 7.76 years, 820 men died (12.43%): 72 of PC (8.78%). Men with favorable intermediate–risk PC did not have significantly increased PCSM risk as compared with men with low-risk PC (adjusted hazard ratio [AHR], 1.26; 95% confidence interval [CI] 0.56, 2.88; p-Value 0.58), whereas men with high-risk PC (AHR, 3.74; 95% CI 1.12, 12.53; p-Value 0.032) and unfavorable intermediate–risk PC (AHR, 3.10; 95% CI 1.43, 6.72; p-Value 0.004) did. Based on 10-year adjusted point estimates of PCSM and ACM for men with high-risk PC being 6.01% (95% CI 3.79%, 8.94%) and 21.30% (95% CI 17.45%, 25.42%), respectively, PCSM comprised 28% of ACM. Conclusions In the setting of external beam radiation therapy and brachytherapy, men with high-risk PC have low absolute adjusted estimates of PCSM (∼6%) during the first decade after treatment despite receiving only short-course ADT. Whether long-term ADT can lower PCSM and improve survival in these men requires additional study.

Background and Purpose: The Modified Reminiscence Functions Scale (MRFS) measures the patterns and functions of reminiscence. The purpose of this study was to examine the factor structure of the MRFS in a sample of community-dwelling Black adults. Methods: A convenience sample (N = 335) of Black adults from the Northeast completed the 39-item MRFS. Seven- and 8-factor models were evaluated given the uncertainty regarding the number of factors in previous reminiscence research. Results: Confirmatory factor analysis established validity of the 7-factor model (relative chi-square [Χ^sup 2^/df] = 1.9, Tucker-Lewis index [TLI] = .919, comparative fit index [CFI] = .929, root mean square error of approximation [RMSEA] = .05). Reliability of the subscales ranged from .64 to .90. Conclusions: The MRFS is a reliable and valid measure of reminiscence patterns and functions in Black adults with similar characteristics.Keywords: Modified Reminiscence Functions Scale, confirmatory factor analysis, reminiscence functions, Black adultsReminiscence or a person's recollection of the past serves many vital psychological and social functions. Since Butler's (1963) proposition that reminiscence in older adults was a part of the normal life review process, there has been much research regarding the functions of reminiscence and their positive and negative associations with mental health and well-being. For example, there is evidence demonstrating that certain reminiscence functions are associated with higher quality of life and increased selfesteem (Cappeliez & O'Rourke, 2006; Cappeliez, O'Rourke, & Chaudhury, 2005). In contrast, research has shown other reminiscence functions have associations with negative mental health outcomes such as depression and anxiety (Cappeliez et al., 2005; Watt & Wong, 1991). The adaptive or coping role that reminiscence functions play in later life is another area of interest for reminiscence researchers. Korte, Bohlmeijer, Westerhof, and Pot (2011) in a study that examined the relationship between reminiscence functions and depressive and anxiety symptoms and life satisfaction in Dutch older adults found that reminiscence plays a role in coping with critical life events. Cappeliez and Robitaille (2010) in a cross-sectional, longitudinal study of 1,100 older adults showed that positive reminiscence functions promote psychological well-being through their effects on assimilative and accommodative coping. Although great strides have been made in understanding reminiscence and its functions in the developmental stages of the older adult, much of the empirical foundation for reminiscence is based on Canadian White populations and with populations from Western Europe. There has been some reminiscence research conducted with Black adults. For example, Merriam (1993) showed that Blacks used reminiscence more than Whites for understanding themselves and teaching others about the past. Shellman, Ennis, and Addison (2011) in a contextual examination of reminiscence functions found differences in why and when older Black adults think about the past when compared to other ethnic groups. Flowever, it is essential to use a reliable and valid measure to further investigate reminiscence functions and their relationship with mental health and well-being in older Black adults. The Reminiscence Functions Scale (RFS; Webster, 1993, 1997) is an eight-factor, 43-item measurement developed to assess difference functions or purposes of reminiscence. Although this scale has been widely used in reminiscence research, Shellman et al. (2011) and Washington (2009) found that Black participants had difficulty reading and understanding the directions of the RFS. In addition, some items had little cultural relevance or meaning to the respondents. Washington modified and tested the RFS with a sample of Flispanics, Whites, and Blacks (N = 271). Although the scale was found to be a reliable and valid measure in the diverse sample, no other research studies using the Modified Reminiscence Functions Scale (MRFS) with Black populations were found. …

Radiotherapy (RT), short-course androgen deprivation therapy (ADT), and brachytherapy in various combinations are treatment options for patients with intermediate-risk prostate cancer (PC), but the question of which combination if any is necessary to minimize PC-specific mortality (PCSM) risk in patients with favorable or unfavorable intermediate-risk PC is unknown. The authors assessed PCSM risk after commonly used treatments.The cohort consisted of 2510 men with favorable (1902 men; 75.78%) or unfavorable (608 men; 24.22%) intermediate-risk PC who were treated from 1997 to 2013. Treatment included brachytherapy with or without neoadjuvant ADT among men with favorable disease and brachytherapy with neoadjuvant RT or ADT among men with unfavorable disease. Fine and Gray's competing-risks regression model was used to assess whether ADT among men with favorable disease or RT or ADT among men with unfavorable disease decreased PCSM risk after adjusting for treatment propensity score, year of brachytherapy, and PC prognostic factors.After a median follow-up of 7.78 years, 366 deaths (14.58%) were observed, 29 of which (7.92%) were from PC. There was a significant reduction in PCSM risk in men with unfavorable disease who were treated with ADT versus RT (adjusted hazard ratio, 0.34; 95% confidence interval, 0.13-0.91 [P = .03]), but no significant difference in PCSM risk in men with favorable disease who received ADT and brachytherapy versus brachytherapy (adjusted hazard ratio, 0.67; 95% confidence interval, 0.18-2.57 [P =.56]).Neoadjuvant ADT does not appear to reduce PCSM risk in men undergoing brachytherapy for favorable intermediate-risk PC and should not be considered a standard; however, it appears superior to neoadjuvant RT in men with unfavorable intermediate-risk PC undergoing brachytherapy, making neoadjuvant ADT and brachytherapy a preferred option in these men.

Joint models for longitudinal and survival data have now become increasingly popular in clinical trials or other studies for assessing a treatment effect while accounting for longitudinal measures such as patient-reported outcomes or tumor response. Most studies in the existing literature primarily focus on reducing the bias and improving efficiency in the estimate of the treatment effect in the joint modeling of survival and longitudinal data. Global fit indices such as Akaike information criterion (AIC) or Bayesian information criterion (BIC) can be used to assess the overall fit of the joint model. However, these indices do not provide separate assessments of each component of the joint model. In this chapter, we develop new model assessment criteria using a novel decomposition of AIC and BIC (i.e., AIC = AIC\(_\textrm{Surv}\) + AIC\(_\textrm{Long} | \textrm{Surv}\) and BIC = BIC\(_\textrm{Surv}\) + BIC\(_\textrm{Long} | \textrm{Surv}\)) to assess the contribution of the survival data to the model fit of the longitudinal data. We apply the proposed methodology to the analysis of a real dataset from a cancer clinical trial in mesothelioma.

To determine if androgen-deprivation therapy (ADT) is associated with excess cardiac-specific mortality (CSM) in men with prostate cancer and no cardiovascular comorbidity, coronary artery disease risk factors, or congestive heart failure (CHF) or past myocardial infarction (MI).In all, 5077 men (median age 69.5 years) with cT1c-T3N0M0 prostate cancer were treated with brachytherapy with or without neoadjuvant ADT (median duration 4 months) between 1997 and 2006. Fine and Gray competing risks analysis evaluated the association of ADT with CSM, adjusting for age, year of brachytherapy, and ADT treatment propensity score among men in groups defined by cardiac comorbidity.After a median follow-up of 4.8 years, no association was detected between ADT and CSM in men with no cardiac risk factors (1.08% at 5 years for ADT vs 1.27% at 5 years for no ADT, adjusted hazard ratio (AHR) 0.83; 95% confidence interval (CI), 0.39-1.78; P = 0.64; n = 2653) or in men with diabetes mellitus, hypertension, or hypercholesterolaemia (2.09% vs 1.97%, AHR 1.33; 95% CI 0.70-2.53; P = 0.39; n = 2168). However, ADT was associated with significantly increased CSM in men with CHF or MI (AHR 3.28; 95% CI 1.01-10.64; P = 0.048; n = 256). In this subgroup, the 5-year cumulative incidence of CSM was 7.01% (95% CI 2.82-13.82%) for ADT vs 2.01% (95% CI 0.38-6.45%) for no ADT.ADT was associated with a 5% absolute excess risk of CSM at 5 years in men with CHF or prior MI, suggesting that administering ADT to 20 men in this potentially vulnerable subgroup could result in one cardiac death.

Joint models for longitudinal and survival data now have a long history of being used in clinical trials or other studies in which the goal is to assess a treatment effect while accounting for longitudinal assessments such as patient-reported outcomes or tumor response. Compared to using survival data alone, the joint modeling of survival and longitudinal data allows for estimation of direct and indirect treatment effects, thereby resulting in improved efficacy assessment. Although global fit indices such as AIC or BIC can be used to rank joint models, these measures do not provide separate assessments of each component of the joint model. In this paper, we develop a novel decomposition of AIC and BIC (i.e., AIC = AICLong + AICSurv|Long and BIC = BICLong + BICSurv|Long) that allows us to assess the fit of each component of the joint model and in particular to assess the fit of the longitudinal component of the model and the survival component separately. Based on this decomposition, we then propose ΔAICSurv and ΔBICSurv to determine the importance and contribution of the longitudinal data to the model fit of the survival data. Moreover, this decomposition, along with ΔAICSurv and ΔBICSurv, is also quite useful in comparing, for example, trajectory-based joint models and shared parameter joint models and deciding which type of model best fits the survival data. We examine a detailed case study in mesothelioma to apply our proposed methodology along with an extensive set of simulation studies.

No deaths from prostate cancer (PC) were observed in men with Gleason score (GS) 7 and a differing, lower GS core (ComboGS), greatest percentage of involved core length < 50%, and favorable intermediate-risk disease despite radiation therapy (RT) alone in 83%. Whether de-escalated therapy with high-dose RT alone is appropriate for these men is being tested prospectively in the Radiation Therapy Oncology Group (RTOG) 0815 clinical trial. Introduction/Background: Men with highest GS � 7 and a differing, lower GS core (ComboGS) have decreased PC-specific mortality (PCSM) risk after RT or RT and androgen deprivation therapy (ADT). Whether the greatest percentage of involved core length (GPC) modulates this risk is unknown. Patients and Methods: Men with GS � 7 PC (n ¼ 333) consecutively treated between December 1989 and July 2000 using RT (n ¼ 268; 80%) or RT and 6 months of ADT (n ¼ 65; 20%) comprised the study cohort. The GPC was calculated using biopsy core and tumor lengths. We used competing risks regression to assess whether increasing GPC was associated with increased PCSM risk in men with or without ComboGS adjusting for risk group, age, and treatment. Results: After a median follow-up of 5.36 years (interquartile range, 3.22-7.61 years), 92 (28%) men died, 28 (30%) of PC. Increasing GPC was significantly associated with increased risk of PCSM (adjusted hazard ratio, 1.02; 95% confidence interval, 1.01-1.03; P ¼ .005). Men with GPC � 50% versus < 50% had significantly greater PCSM estimates when ComboGS was present (P < .001) versus absent (P ¼ .55). Of the 127 men with ComboGS and GPC < 50%, 83% were treated with RT alone and 2 PC deaths were observed; neither in men with GS 7 and favorable intermediate-risk PC. Conclusion: Men treated with RT for ComboGS, GPC < 50%, GS 7, and favorable intermediate-risk PC have a very low risk of early PCSM. The RTOG 0815 trial will establish whether ADT is necessary to optimize curability in these men.

Recently, men with intermediate-risk prostate cancer (PC) were classified into favorable and unfavorable categories; however, whether the risk of PC-specific mortality (PCSM) among men with high-risk PC versus unfavorable intermediate-risk PC is increased is unknown.In a prospective, randomized trial conducted between 1995 and 2001, 206 men with intermediate-risk or high-risk PC were randomized to receive 70 Gy with or without 6 months of androgen-suppression therapy (AST). The subgroup of 197 patients with information available on the percentage of positive biopsies formed the cohort. Fine and Gray regression analysis was used to assess whether men with high-risk PC versus unfavorable intermediate-risk PC had an increased risk of PCSM.After a median follow-up of 14.3 years, there were 127 deaths (64.5%), including 22 deaths (17.3%) from PC. There were no PC deaths in the favorable intermediate-risk group. There was an increase in the risk of PCSM among men with high-risk PC versus unfavorable intermediate-risk PC, but the difference was not significant (adjusted hazard ratio, 1.59; 95% confidence interval, 0.66-3.83; P = .30) after adjusting for age, randomized treatment arm, and comorbidity.The lack of PC deaths among men with favorable intermediate-risk PC suggests that adding AST may not reduce their risk of PCSM; whereas many men with unfavorable intermediate-risk PC are at risk for harboring occult PC with Gleason scores from 8 to 10 and, if proven, would benefit from long-term AST. Multiparametric magnetic resonance imaging and targeted biopsy of suspicious lesions should be considered to identify PC with Gleason scores from 8 to 10 in these men.

Introduction: Entospletinib is an orally bioavailable, selective inhibitor of spleen tyrosine kinase. Targeting the B-cell receptor (BCR) signaling pathway with Bruton's tyrosine kinase (BTK) and PI3Kd inhibitors (BTKi and PI3Kdi), approved for treatment of chronic lymphocytic leukemia (CLL), has been a successful therapeutic strategy. Entospletinib is active in CLL and preclinical data suggest that entospletinib may be effective even in the context of resistance to BTKi, including that conferred by activation of PLCγ2 (Liu et. al. Blood 2015). Methods: This is an ongoing phase 2 trial (NCT01799889) of entospletinib in CLL and non-Hodgkin lymphoma. The study protocol includes 2 CLL cohorts for patients who have been previously treated with BTKi or PI3Kdi and 2 additional cohorts for patients with Richter's transformation who have had analogous prior treatment. Patients were treated with entospletinib monotherapy (400 mg BID) and evaluated using modified Hallek/IWG-CLL criteria every 2 to 3 months as previously described (Sharman et. al. Blood 2014). Results: As of June 28, 2016, 34 patients have been enrolled, and 33 have been treated. Of the 28 patients without Richter's transformation, 23 were previously treated with a BTKi (22 ibrutinib, 1 CC-292) and 5 with a PI3Kdi (idelalisib). Median number of prior treatments was 3 (1-7) for patients with prior BTKi and 5 (3-8) for prior PI3Kdi treatment. In total, 35% of the BTKi patients and 60% of the PI3Kdi patients had either a TP53 mutation or del17p; 75% did not have IgHV hypermutation. A median of 2 months (0-14) had elapsed since the prior treatment; 17 patients had progressive disease on prior therapy, while 11 discontinued prior therapy due to intolerance. Thirteen of the 28 patients enrolled without Richter's transformation remain on study with a median PFS of 5.6 months for the prior BTKi cohort and a median PFS of 6.9 months for the prior PI3Kdi cohort. Of the 15 patients who have stopped therapy, 9 discontinued due to disease progression, 5 discontinued due to an AE, and 1 withdrew consent. Overall, 19 patients were evaluable for response (15 BTKi/4 PI3Kdi; Table 1). Of the 6 patients who achieved a PR, all lacked IgHV hypermutation and 3 had either a TP53 mutation or del17p, and 3 had progressed on prior therapy. Following Richter's transformation, 5 patients have been treated with entospletinib (3 with prior BTKi therapy and 2 with prior PI3Ki). The interval since prior treatment was short ( All patients on study experienced a treatment-emergent AE (TEAE) and 49% experienced a serious AE (SAE; Table 2). Only 1 SAE, pancreatitis, was attributed to entospletinib. The most common TEAEs and laboratory abnormalities are listed in Table 2. Additional Grade ≥3 TEAEs reported in more than 1 patient included sepsis (3), atrial fibrillation (2), dehydration (2), neutropenia (2), pneumonia (2), respiratory failure (2), and urinary tract infection (2). The only TEAE attributable to entospletinib that led to discontinuation of treatment was fatigue. Five patients died on study; 2 from progressive disease and 1 each from heart failure, Guillain-Barre syndrome, and cardiac arrest; 3 of these 5 patients died within 30 days of the last dose of study drug [disease progression (2), cardiac arrest (1)]. Conclusion: Early experience from this trial with ongoing enrollment demonstrates that entospletinib has clinical activity following therapy with either BTKi or PI3Kdi. Continued investigation of treatment with entospletinib following progression after therapy with BCR signaling pathway inhibitors is warranted. Disclosures Sharman: Gilead Sciences, Inc.: Honoraria, Research Funding. Shustov:Celgene: Consultancy, Honoraria; SPECTRUM: Consultancy, Research Funding; Seattle Genetics: Research Funding; Novartis: Research Funding; BMS: Consultancy, Honoraria. Smith:Celgene: Honoraria; Spectrum: Honoraria; Abbvie: Research Funding; Genentech: Honoraria. Kolibaba:Cell Therapeutics: Research Funding; Gilead: Consultancy, Research Funding; Genentech: Research Funding; GSK: Research Funding; Janssen: Research Funding; Acerta: Research Funding; Amgen: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Pharmcyclics: Research Funding; Seattle Genetics: Research Funding; TG Therapeutics: Honoraria, Research Funding. Abella-Dominicis:Gilead Sciences: Employment, Equity Ownership. Zhang:Gilead Sciences: Employment, Equity Ownership. Mitra:Gilead Sciences: Employment, Equity Ownership. Yasenchak:Seattle Genetics: Research Funding. Awan:Pharmacyclics: Consultancy; Innate Pharma: Research Funding; Novartis Oncology: Consultancy.

Introduction: Entospletinib (GS-9973) is an orally bioavailable, selective inhibitor of spleen tyrosine kinase (Syk). Syk is a mediator of B-cell receptor signaling in normal and transformed B-cells. Targeting the B-cell receptor (BCR)-signaling pathway has been the focus in many types of B-cell related hematological malignancies including mantle cell lymphoma (MCL). Methods: This reports the MCL cohort in a phase 2 trial that more broadly evaluated the efficacy and safety of entospletinib (800 mg BID) in patients with relapsed and refractory hematological malignancies (NCT01799889). Tumor response was assessed per Cheson 2007 criteria with imaging planned at weeks 8, 16, 24, and then every 12 weeks. The primary endpoint was PFS at week 16. All efficacy data were assessed by an Independent Review Committee. Results: A cohort of 39 patients with MCL was enrolled. The median age was 72 years (range: 49-92), 64% were male, and a median number of prior regimens were 2 (range: 1-6). Prior therapy included anti-CD20 antibodies (95%), alkylating agents (95%; bendamustine 44%), and anthracyclines (77%). Three patients (8%) have received ibrutinib either as investigational drug (n = 1) or as an approved drug (n = 2), and 1 patient (3%) received idelalisib. Median duration of treatment was 21 weeks (range: 1-87), with 1 patient continuing on treatment. Thirty-five (90%) patients were evaluable for tumor response. Four patients (10%) discontinued prior to initial tumor assessment: death (n = 1), disease progression (n = 2) and investigator's discretion (n = 1). The most common TEAEs (any grade/≥gr 3, independent of causality) and common lab abnormalities are summarized in Table 1. There were 4 TEAEs that led to study drug discontinuation (all n = 1): cardiac arrest, pruritus, pyrexia, and maculopapular rash. Six deaths were reported, none of which were related to study drug. The ORR was 15% (90% CI: 6.9%, 28.1%), with 6 (15%) patients achieving a PR and 23 (59%) patients maintaining a stable disease. The PFS rate at week 16 was 66% (95% CI: 46%, 79%). Median PFS was 5.6 months (95% CI: 3.6 months, 8.9 months). These results are based on data analysis of June 28, 2016. Conclusion: Entospletinib was well tolerated and demonstrated modest activity in patients with relapsed or refractory MCL. Further development of entospletinib in MCL will focus on the development of combination therapy. Figure 1 Waterfall Plot of Best % Change from Baseline in SPD. Figure 1. Waterfall Plot of Best % Change from Baseline in SPD. Figure 2 Kaplan-Meier Curve of Progression-Free Survival. Figure 2. Kaplan-Meier Curve of Progression-Free Survival. Disclosures Sharman: Gilead Sciences, Inc.: Honoraria, Research Funding. Kolibaba:Amgen: Research Funding; Celgene: Research Funding; Cell Therapeutics: Research Funding; Genentech: Research Funding; GSK: Research Funding; Janssen: Research Funding; Acerta: Research Funding; Gilead: Consultancy, Research Funding; Novartis: Research Funding; Pharmcyclics: Research Funding; Seattle Genetics: Research Funding; TG Therapeutics: Honoraria, Research Funding. Shustov:Seattle Genetics: Research Funding; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; SPECTRUM: Consultancy, Research Funding; Novartis: Research Funding. Nay:Gilead Sciences, Inc.: Honoraria; Janssen: Honoraria, Other: Advisory board; Celgene: Honoraria, Other: Advisory board; Amgen: Other: Advisory board; Lyndbeck: Honoraria; BMS: Honoraria. Zhang:Gilead Sciences: Employment, Equity Ownership. Shi:Gilead Sciences, Inc.: Employment, Equity Ownership. Forero:University of Alabama at Birmingham: Research Funding. Assouline:BMS: Speakers Bureau; Lundbeck: Consultancy; Janssen: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau.