Study on the Performance of a Surface with Coupled Wettability Difference and Convex-Stripe Array for Improved Air Layer Stability.

The existence of an air layer reduces friction drag on superhydrophobic surfaces. Therefore, improving the air layer stability of superhydrophobic surfaces holds immense significance in reducing both energy consumption and environmental pollution caused by friction drag. Based on the properties of mathematical discretization and the contact angle hysteresis generated by the wettability difference, a surface coupled with a wettability difference treatment and a convex-stripe array is developed by laser engraving and fluorine modification, and its performance in improving the air layer stability is experimentally studied in a von Kármán swirling flow field. The results show that the destabilization of the air layer is mainly caused by the Kelvin-Helmholtz instability, which is triggered by the density difference between gas and liquid, as well as the tangential velocity difference between gas and liquid. When the air layer is relatively thin, tangential wave destabilization occurs, whereas for larger thicknesses, the destabilization mode is coupled wave destabilization. The maximum Reynolds number that keeps the air layer fully covering the surface of the rotating disk (with drag reduction performance) during the disk rotation process is defined as the critical Reynolds number (Rec), which is 1.62 × 105 for the uniform superhydrophobic surface and 3.24 × 105 for the superhydrophobic surface with a convex stripe on the outermost ring (SCSSP). Individual treatments of wettability difference and a convex-stripe array on the SCSSP further improve the air layer stability, but Rec remains at 3.24 × 105. Finally, the coupling of the wettability difference treatment with a convex-stripe array significantly improves the air layer stability, resulting in an increase of Rec to 4.05 × 105, and the drag reduction rate stably maintained around 30%.

Phase-locked µPIV analysis of flow dynamics in a simulated root canal with different laser-activated irrigations.

PURPOSE: To measure the dynamic characteristics of the flow field in a complex root canal model activated by two laser-activated irrigation (LAI) modalities at different activation energy outputs: photon-induced photoacoustic streaming (PIPS) and microshort pulse (MSP). METHODS: A phase-locked micro-scale Particle Image Velocimetry (µPIV) system was employed to characterise the temporal variations of LAI-induced velocity fields in the root canal following a single laser pulse. The wall shear stress (WSS) in the lateral root canal was subsequently estimated from the phase-averaged velocity fields. RESULTS: Both PIPS and MSP were able to generate the 'breath mode' of the irrigant current under all tested conditions. The transient irrigation flush in the root canal peaked at speeds close to 6 m/s. However, this intense flushing effect persisted for only about 2000 µs (or 3% of a single laser-pulse activation cycle). For MSP, the maximum WSS magnitude was approximately 3.08 Pa at an activation energy of E = 20 mJ/pulse, rising to 9.01 Pa at E = 50 mJ/pulse. In comparison, PIPS elevated the WSS to 10.63 Pa at E = 20 mJ/pulse. CONCLUSION: Elevating the activation energy can boost the peak flushing velocity and the maximum WSS, thereby enhancing irrigation efficiency. Given the same activation energy, PIPS outperforms MSP. Additionally, increasing the activation frequency may be an effective strategy to improve irrigation performance further.

Transient apical peak pressure measurement of Er:YAG laser-activated irrigation in different in vitro tooth models using a high-frequency sensor system.

The transient apical pressure side effect is an important safety consideration for Er:YAG laser-activated irrigation (LAI). Therefore, this study aimed to measure the transient apical peak pressure (TAPP) of LAI under different laser settings in various tooth models using a high-frequency sensor system. Tooth models with different pulp chamber structures, apical diameters, and curvatures were prepared using transparent resin and filled with deionised water. The Er:YAG laser fibre was placed 3 mm from the root canal orifice. Irrigation was performed at 10-40 mJ and 20-50 Hz using the super short pulse mode. The TAPP was measured using a 50,000-sample/second pressure sensor connected to the models' apices. The TAPP of LAI was significantly higher than that of other chemical preparation methods. Among all investigated factors, pulp chamber anatomy and apical diameters had the greatest effects and were highly related to the apical peak pressure. Root canal curvature showed no direct correlation with TAPP. The larger the final prepared working width, the greater the TAPP. Furthermore, both pulse energy and frequency had positive correlations with TAPP. In conclusion, tooth anatomy factors and laser parameter settings influenced TAPP during Er:YAG LAI. Therefore, proper settings of laser parameters are important to improve the safety of Er:YAG LAI.

Acute 1,2-Dichloropropane Poisoning due to Ingestion of Rubber Cement: An Autopsy Case Report and Review.

ABSTRACT: 1,2-Dichloropropane (1,2-DCP) is a common industrial solvent and chemical intermediate that can cause acute poisoning to humans through exposure during its production and industrial use. The target organs of 1,2-DCP include the eyes, respiratory system, liver, kidney, central nervous system, and skin. Forensic identification of 1,2-DCP poisoning is difficult because of the lack of characteristic pathological changes. This article reports an autopsy case of acute 1,2-DCP poisoning caused by self-ingestion of rubber cement. A woman developed seizures and coagulation dysfunction after ingesting approximately 10 mL of rubber cement and died 43 hours later. Autopsy revealed generalized subcutaneous hemorrhage, cardiopulmonary multifocal hemorrhage, bronchopneumonia, severe cerebral edema, focal hepatic necrosis, granular deposition in the glomerular capsule and renal tubules, and delipidation of the adrenal cortex. These findings indicate that 1,2-DCP poisoning can induce central nervous system dysfunction, respiratory system damage, liver and kidney function damage, hemolytic anemia, disseminated intravascular coagulation, and adrenal damage. This case may provide useful perspectives for forensic identification of 1,2-DCP poisoning in the future.

Longitudinal Evaluation of Circulating Tumor DNA Using Sensitive Amplicon-Based Next-Generation Sequencing to Identify Resistance Mechanisms to Immune Checkpoint Inhibitors for Advanced Urothelial Carcinoma.

Serial evaluation of circulating tumor DNA may allow noninvasive assessment of drivers of resistance to immune checkpoint inhibitors (ICIs) in advanced urothelial cancer (aUC). We used a novel, amplicon-based next-generation sequencing assay to identify genomic alterations (GAs) pre- and post-therapy in 39 patients with aUC receiving ICI and 6 receiving platinum-based chemotherapy (PBC). One or more GA was seen in 95% and 100% of pre- and post-ICI samples, respectively, commonly in TP53 (54% and 54%), TERT (49% and 59%), and BRCA1/BRCA2 (33% and 33%). Clearance of ≥1 GA was seen in 7 of 9 patients responding to ICI, commonly in TP53 (n = 4), PIK3CA (n = 2), and BRCA1/BRCA2 (n = 2). A new GA was seen in 17 of 20 patients progressing on ICI, frequently in BRCA1/BRCA2 (n = 6), PIK3CA (n = 3), and TP53 (n = 3), which seldom emerged in patients receiving PBC. These findings highlight the potential for longitudinal circulating tumor DNA evaluation in tracking response and resistance to therapy.

Robustness of neural network calibration model for accurate spatial positioning.

The present study devotes to a systematical exploration for the robustness of neural network-based camera calibration method in the circumstance of three-dimensional (3D) spatial positioning via machine vision technique. By analyzing the error propagation route in the calibration-reconstruction process, a dimensionless error attenuation coefficient is proposed to measure the robustness of a calibration model with respect to input calibration error. Using this metric, the robustness of the neural network (NN) model under different optical configurations, i.e., input noise level, optical distortion and camera viewing angle, are analyzed in detail via synthetic simulation. Due to its generalized fitting capacity, the NN model is found to be superior to conventional pinhole model and polynomial model in terms of model robustness. To take full advantage of this feature, the NN model is further deployed to the scenarios of asymmetric camera layout and multiple camera joint calibration. Both synthetic simulation and experiment test demonstrate that the NN model can significantly improve the robustness and the accuracy of 3D spatial positioning in these non-normal scenarios.

Combination of cyclin-dependent kinase and immune checkpoint inhibitors for the treatment of bladder cancer.

BACKGROUND: Perturbation of the CDK4/6 pathway is frequently observed in advanced bladder cancer. We investigated the potential of targeting this pathway alone or in combination with chemotherapy or immunotherapy as a therapeutic approach for the treatment of bladder cancer METHODS: The genetic alterations of the CDK4/6 pathway in bladder cancer were first analyzed with The Cancer Genome Atlas database and validated in our bladder cancer patient-derived tumor xenografts (PDXs). Bladder cancer cell lines and mice carrying PDXs with the CDK4/6 pathway perturbations were treated with a CDK4/6 inhibitor palbociclib to determine its anticancer activity and the underlying mechanisms. The combination index method was performed to assess palbociclib and gemcitabine drug-drug interactions. Syngeneic mouse bladder cancer model BBN963 was used to assess whether palbociclib could potentiate anti-PD1 immunotherapy. RESULTS: Of the 413 bladder cancer specimens, 79.2% harbored pertubations along the CDK4/6 pathway. Palbociclib induced G0/G1 cell cycle arrest but with minimal apoptosis in vitro. In mice carrying PDXs, palbociclib treatment reduced tumor growth and prolonged survival from 14 to 32 days compared to vehicle only controls (p = 0.0001). Palbociclib treatment was associated with a decrease in Rb phosphorylation in both cell lines and PDXs. Palbociclib and gemcitabine exhibited antagonistic cytotoxicity in vitro (CI > 3) and in vivo, but palbociclib significantly enhanced the treatment efficacy of anti-PD1 immunotherapy and induced CD8+ T lymphocyte infiltration in syngeneic mouse models. CONCLUSIONS: The CDK4/6 pathway is feasible as a potential target for the treatment of bladder cancer, especially in combination with immunotherapy. A CDK4/6 inhibitor should not be combined with gemcitabine.

Supplemental Nicotinamide Dose-Dependently Regulates Body Phosphorus Excretion via Altering Type II Sodium-Phosphate Co-Transporter Expressions in Laying Hens.

BACKGROUND: Dietary supplemental nicotinamide is used to treat hyperphosphatemia in humans. However, the mechanisms of its impact on body phosphorus homeostasis remain unclear. OBJECTIVE: This study was to determine effects and molecular mechanisms of 3 dietary nicotinamide concentrations on body phosphorus homeostasis in laying hens. METHODS: Hy-Line Brown layers (total = 21; 40 wk old; body weight: 1,876 ± 24 g) were individually housed (n = 7) and fed a corn-soybean meal-based diet supplemented with nicotinamide at 20 (N20), 140 (N140), and 1000 (N1000) mg/kg for 21 d. Serum phosphorus and fibroblast growth factor 23 (FGF23) concentrations, phosphorus and calcium excretion, and mRNA and/or protein of type II sodium-phosphate co-transporters (NPt2a, NPt2ab) and FGF23 and FGF23 receptors were measured in the intestines, calvaria, kidney, and liver. RESULTS: Hens in the N1000 group had a 16% lower serum phosphorus concentration and 22% greater phosphorus excretion than those in the N20 or N140 group (P ≤ 0.05). Compared with hens in the N20 group, hens in the N140 and N1000 groups, which did not differ, had 15-21% lower serum FGF23 concentrations, 19-22% greater calcium excretion, 43-56% lower ileum NPT2b protein production, and 1.5- to 1.6-fold greater kidney NPT2a protein production, respectively (all differences at P ≤ 0.05). CONCLUSIONS: Supplementing high concentrations of nicotinamide in diets for laying hens led to accelerated phosphorus and calcium excretions and decreased serum phosphorus and FGF23 concentrations, which were associated with downregulated intestinal NPt2b protein production. Our findings exclude kidney NPt2a protein production as a primary mechanism for the nicotinamide-induced body phosphorus loss.

Characteristics of the Irrigant Flow in a Simulated Lateral Canal Under Two Typical Laser-Activated Irrigation Regimens.

BACKGROUND AND OBJECTIVES: Photon-induced photoacoustic streaming (PIPS) and shockwave-enhanced emission photoacoustic streaming (SWEEPS) are two promising laser-activated irrigation (LAI) methods for root canal irrigation. Their performance in driving irrigant flush in a complex root canal system will be evaluated by microscale particle image velocimetry (µPIV) measurement and will be compared with that of ultrasonic-activated irrigation (UAI). STUDY DESIGN/MATERIALS AND METHODS: A µPIV system with 7 µm fluorescent tracer particles was adopted to measure two-dimensional (2D) velocity fields around the junction region, with a size of 1.8 mm × 1.5 mm, between one main canal and one lateral canal in an endodontic training block, which was driven by SWEEPS (Er:YAG laser) operating at 15 Hz and 20 mJ. The flow field driven by PIPS (Er:YAG laser) at the same frequency and energy, as well as by UAI (with non-cutting insert) operating at 40% unit power, was also measured for a direct comparison. RESULTS: It was found that both SWEEPS and PIPS can activate a so-called "breath mode" during the irrigation. Namely, the induced irrigant flush presented a back-and-forth oscillation along both the main canal and the lateral one. The maximum flow speed in the lateral canal was observed to be up to 10 m/s in the SWEEPS modality, while reduced to around 7 m/s in the PIPS modality. The penetration length in the lateral canal in both modalities was estimated to be larger than 1 mm. In comparison, the flow field induced by UAI was characterized as irregular vortical structures, the maximum flow speed in the lateral canal was 0.15 m/s and significantly lower than LAI (P < 0.01), and the penetration length was less than 300 µm and lower than LAI (P < 0.05). CONCLUSION: Compared to UAI, PIPS, and SWEEPS are more capable of delivering the irrigant deeper into the lateral canal. Furthermore, the back-and-forth flush in the breath mode is ideal for removing debris during irrigation. Lasers Surg. Med. © 2020 Wiley Periodicals LLC.

Fidelity of a PDX-CR model for bladder cancer.

Patient-derived xenografts (PDXs) are widely recognised as a more physiologically relevant preclinical model than standard cell lines, but are expensive and low throughput, have low engraftment rate and take a long time to develop. Our newly developed conditional reprogramming (CR) technology addresses many PDX drawbacks, but lacks many in vivo factors. Here we determined whether PDXs and CRCs of the same cancer origin maintain the biological fidelity and complement each for translational research and drug development. Four CRC lines were generated from bladder cancer PDXs. Short tandem repeat (STR) analyses revealed that CRCs and their corresponding parental PDXs shared the same STRs, suggesting common cancer origins. CRCs and their corresponding parental PDXs contained the same genetic alterations. Importantly, CRCs retained the same drug sensitivity with the corresponding downstream signalling activity as their corresponding parental PDXs. This suggests that CRCs and PDXs can complement each other, and that CRCs can be used for in vitro fast, high throughput and low cost screening while PDXs can be used for in vivo validation and study of the in vivo factors during translational research and drug development.

Humanized mice in studying efficacy and mechanisms of PD-1-targeted cancer immunotherapy.

Establishment of an in vivo small animal model of human tumor and human immune system interaction would enable preclinical investigations into the mechanisms underlying cancer immunotherapy. To this end, nonobese diabetic (NOD).Cg- PrkdcscidIL2rgtm1Wjl/Sz (null; NSG) mice were transplanted with human (h)CD34+ hematopoietic progenitor and stem cells, which leads to the development of human hematopoietic and immune systems [humanized NSG (HuNSG)]. HuNSG mice received human leukocyte antigen partially matched tumor implants from patient-derived xenografts [PDX; non-small cell lung cancer (NSCLC), sarcoma, bladder cancer, and triple-negative breast cancer (TNBC)] or from a TNBC cell line-derived xenograft (CDX). Tumor growth curves were similar in HuNSG compared with nonhuman immune-engrafted NSG mice. Treatment with pembrolizumab, which targets programmed cell death protein 1, produced significant growth inhibition in both CDX and PDX tumors in HuNSG but not in NSG mice. Finally, inhibition of tumor growth was dependent on hCD8+ T cells, as demonstrated by antibody-mediated depletion. Thus, tumor-bearing HuNSG mice may represent an important, new model for preclinical immunotherapy research.-Wang, M., Yao, L.-C., Cheng, M., Cai, D., Martinek, J., Pan, C.-X., Shi, W., Ma, A.-H., De Vere White, R. W., Airhart, S., Liu, E. T., Banchereau, J., Brehm, M. A., Greiner, D. L., Shultz, L. D., Palucka, K., Keck, J. G. Humanized mice in studying efficacy and mechanisms of PD-1-targeted cancer immunotherapy.

Daunorubicin-containing CLL1-targeting nanomicelles have anti-leukemia stem cell activity in acute myeloid leukemia.

Patients with acute myeloid leukemia have a very poor prognosis related to a high rate of relapse and drug-related toxicity. The ability of leukemia stem cells (LSCs) to survive chemotherapy is primarily responsible for relapse, and eliminating LSCs is ultimately essential for cure. We developed novel disulfide-crosslinked CLL1-targeting micelles (DC-CTM), which can deliver high concentrations of daunorubicin (DNR) into both bulk leukemia cells and LSCs. Compared to free DNR, DC-CTM-DNR had a longer half-life, increased DNR area under the curve concentration by 11-fold, and exhibited a superior toxicity profile. In patient-derived AML xenograft models, DC-CTM-DNR treatment led to significant decreases in AML engraftment and impairment of secondary transplantation compared to control groups. Collectively, we demonstrate superior anti-LSC/AML efficacy, and preferable pharmacokinetic and toxicity profiles of DC-CTM-DNR compared to free DNR. DC-CTM-DNR has the potential to significantly improve treatment outcomes and reduce therapy-related morbidity and mortality for patients with AML.

Methionine Adenosyltransferase 1a (MAT1A) Enhances Cell Survival During Chemotherapy Treatment and is Associated with Drug Resistance in Bladder Cancer PDX Mice.

Bladder cancer is among the top ten most common cancers, with about ~380,000 new cases and ~150,000 deaths per year worldwide. Tumor relapse following chemotherapy treatment has long been a significant challenge towards completely curing cancer. We have utilized a patient-derived bladder cancer xenograft (PDX) platform to characterize molecular mechanisms that contribute to relapse following drug treatment in advanced bladder cancer. Transcriptomic profiling of bladder cancer xenograft tumors by RNA-sequencing analysis, before and after relapse, following a 21-day cisplatin/gemcitabine drug treatment regimen identified methionine adenosyltransferase 1a (MAT1A) as one of the significantly upregulated genes following drug treatment. Survey of patient tumor sections confirmed elevated levels of MAT1A in individuals who received chemotherapy. Overexpression of MAT1A in 5637 bladder cancer cells increased tolerance to gemcitabine and stalled cell proliferation rates, suggesting MAT1A upregulation as a potential mechanism by which bladder cancer cells persist in a quiescent state to evade chemotherapy.

Toward Predicting Acute Myeloid Leukemia Patient Response to 7 + 3 Induction Chemotherapy via Diagnostic Microdosing.

Acute myeloid leukemia (AML) is a rare yet deadly cancer of the blood and bone marrow. Presently, induction chemotherapy with the DNA damaging drugs cytarabine (ARA-C) and idarubicin (IDA), known as 7 + 3, is the standard of care for most AML patients. However, 7 + 3 is a relatively ineffective therapy, particularly in older patients, and has serious therapy-related toxicities. Therefore, a diagnostic test to predict which patients will respond to 7 + 3 is a critical unmet medical need. We hypothesize that a threshold level of therapy-induced 7 + 3 drug-DNA adducts determines cytotoxicity and clinical response. We further hypothesize that in vitro exposure of AML cells to nontoxic diagnostic microdoses enables prediction of the ability of AML cells to achieve that threshold during treatment. Our test involves dosing cells with very low levels of 14C-labeled drug followed by DNA isolation and quantification of drug-DNA adducts via accelerator mass spectrometry. Here, we have shown proof of principle by correlating ARA-C- and DOX-DNA adduct levels with cellular IC50 values of paired sensitive and resistant cancer cell lines and AML cell lines. Moreover, we have completed a pilot retrospective trial of diagnostic microdosing for 10 viably cryopreserved primary AML samples and observed higher ARA-C- and DOX-DNA adducts in the 7 + 3 responders than nonresponders. These initial results suggest that diagnostic microdosing may be a feasible and useful test for predicting patient response to 7 + 3 induction chemotherapy, leading to improved outcomes for AML patients and reduced treatment-related morbidity and mortality.

Correlation of Platinum Cytotoxicity to Drug-DNA Adduct Levels in a Breast Cancer Cell Line Panel.

Platinum drugs, including carboplatin and oxaliplatin, are commonly used chemotherapy drugs that kill cancer cells by forming toxic drug-DNA adducts. These drugs have a proven, but modest, efficacy against several aggressive subtypes of breast cancer but also cause several side effects that can lead to the cessation of treatment. There is a clinical need to identify patients who will respond to platinum drugs in order to better inform clinical decision making. Diagnostic microdosing involves dosing patients or patient samples with subtherapeutic doses of radiolabeled platinum followed by measurement of platinum-DNA adducts in blood or tumor tissue and may be used to predict patient response. We exposed a panel of six breast cancer cell lines to 14C-labeled carboplatin or oxaliplatin at therapeutic and microdose (1% therapeutic dose) concentrations for a range of exposure lengths and isolated DNA from the cells. The DNA was converted to graphite, and measurement of radiocarbon due to platinum-DNA adduction was quantified via accelerator mass spectrometry (AMS). We observed a linear correlation in adduct levels between the microdose and therapeutic dose, and the level of platinum-DNA adducts corresponded to cell line drug sensitivity for both carboplatin and oxaliplatin. These results showed a clear separation in adduct levels between the sensitive and resistant groups of cell lines that could not be fully explained or predicted by changes in DNA repair rates or mutations in DNA repair genes. Further, we were able to quantitate oxaliplatin-DNA adducts in the blood and tumor tissue of a metastatic breast cancer patient. Together, these data support the use of diagnostic microdosing for predicting patient sensitivity to platinum. Future studies will be aimed at replicating this data in a clinical feasibility trial.

Image-guided photo-therapeutic nanoporphyrin synergized HSP90 inhibitor in patient-derived xenograft bladder cancer model.

Photodynamic therapy is a promising and effective non-invasive therapeutic approach for the treatment of bladder cancers. Therapies targeting HSP90 have the advantage of tumor cell selectivity and have shown great preclinical efficacy. In this study, we evaluated a novel multifunctional nanoporphyrin platform loaded with an HSP90 inhibitor 17AAG (NP-AAG) for use as a multi-modality therapy against bladder cancer. NP-AAG was efficiently accumulated and retained at bladder cancer patient-derived xenograft (PDX) over 7 days. PDX tumors could be synergistically eradicated with a single intravenous injection of NP-AAG followed by multiple light treatments within 7 days. NP-AAG mediated treatment could not only specifically deliver 17AAG and produce heat and reactive oxygen species, but also more effectively inhibit essential bladder cancer essential signaling molecules like Akt, Src, and Erk, as well as HIF-1α induced by photo-therapy. This multifunctional nanoplatform has high clinical relevance and could dramatically improve management for bladder cancers with minimal toxicity.

Wall-Normal Variation of Spanwise Streak Spacing in Turbulent Boundary Layer With Low-to-Moderate Reynolds Number.

Low-speed streaks in wall-bounded turbulence are the dominant structures in the near-wall turbulent self-sustaining cycle. Existing studies have well characterized their spanwise spacing in the buffer layer and below. Recent studies suggested the existence of these small-scale structures in the higher layer where large-scale structures usually receive more attention. The present study is thus devoted to extending the understanding of the streak spacing to the log layer. An analysis is taken on two-dimensional (2D) wall-parallel velocity fields in a smooth-wall turbulent boundary layer with R e τ = 440∼2400, obtained via either 2D Particle Image Velocimetry (PIV) measurement taken here or public Direct Numerical Simulation (DNS). Morphological-based streak identification analysis yields a R e -independent log-normal distribution of the streak spacing till the upper bound of the log layer, based on which an empirical model is proposed to account for its wall-normal growth. The small-scale part of the spanwise spectra of the streamwise fluctuating velocity below y + = 100 is reasonably restored by a synthetic simulation that distributes elementary streak units based on the proposed empirical streak spacing model, which highlights the physical significance of streaks in shaping the small-scale part of the velocity spectra beyond the buffer layer.

A diagnostic microdosing approach to investigate platinum sensitivity in non-small cell lung cancer.

The platinum-based drugs cisplatin, carboplatin and oxaliplatin are often used for chemotherapy, but drug resistance is common. The prediction of resistance to these drugs via genomics is a challenging problem since hundreds of genes are involved. A possible alternative is to use mass spectrometry to determine the propensity for cells to form drug-DNA adducts-the pharmacodynamic drug-target complex for this class of drugs. The feasibility of predictive diagnostic microdosing was assessed in non-small cell lung cancer (NSCLC) cell culture and a pilot clinical trial. Accelerator mass spectrometry (AMS) was used to quantify [14 C]carboplatin-DNA monoadduct levels in the cell lines induced by microdoses and therapeutic doses of carboplatin, followed by correlation with carboplatin IC50 values for each cell line. The adduct levels in cell culture experiments were linearly proportional to dose (R2 = 0.95, p < 0.0001) and correlated with IC50 across all cell lines for microdose and therapeutically relevant carboplatin concentrations (p = 0.02 and p = 0.01, respectively). A pilot microdosing clinical trial was conducted to define protocols and gather preliminary data. Plasma pharmacokinetics (PK) and [14 C]carboplatin-DNA adducts in white blood cells and tumor tissues from six NSCLC patients were quantified via AMS. The blood plasma half-life of [14 C]carboplatin administered as a microdose was consistent with the known PK of therapeutic dosing. The optimal [14 C]carboplatin formulation for the microdose was 107 dpm/kg of body weight and 1% of the therapeutic dose for the total mass of carboplatin. No microdose-associated toxicity was observed in the patients. Additional accruals are required to significantly correlate adduct levels with response.

A phase 2 clinical trial of everolimus plus bicalutamide for castration-resistant prostate cancer.

BACKGROUND: The mammalian target of rapamycin (mTOR) pathway is up-regulated in castration-resistant prostate cancer (CRPC). Nevertheless, inhibition of mTOR is ineffective in inducing apoptosis in prostate cancer cells, likely because of the compensatory up-regulation of the androgen receptor (AR) pathway. METHODS: Patients who were eligible for this study had to have progressive CRPC with serum testosterone levels <50 ng/dL. No prior bicalutamide (except to prevent flare) or everolimus was allowed. Treatment included oral bicalutamide 50 mg and oral everolimus 10 mg, both once daily, with a cycle defined as 4 weeks. The primary endpoint was the prostate-specific antigen (PSA) response (≥30% reduction) from baseline. A sample size of 23 patients would have power of 0.8 and an α error of .05 (1-sided) if the combination had a PSA response rate of 50% versus a historic rate of 25% with bicalutamide alone. RESULTS: Twenty-four patients were enrolled. The mean age was 71.1 years (range, 53.0-87.0 years), the mean PSA level at study entry was 43.4 ng/dL (range, 2.5-556.9 ng/dL), and the mean length of treatment was 8 cycles (range, 1.0-23.0 cycles). Of 24 patients, 18 had a PSA response (75%; 95% confidence interval [CI], 0.53-0.90), whereas 15 (62.5%; 95% CI, 0.41-0.81) had a PSA decrease ≥50%. The median overall survival was 28 months (95% CI, 14.1-42.7 months). Fourteen patients (54%; 95% CI, 0.37-0.78) developed grade 3 (13 patients) or grade 4 (1 patient with sepsis) adverse events that were attributable to treatment. CONCLUSIONS: The combination of bicalutamide and everolimus has encouraging efficacy in men with bicalutamide-naive CRPC, thus warranting further investigation. A substantial number of patients experienced everolimus-related toxicity. Cancer 2016;122:1897-904. © 2016 American Cancer Society.

Determinants of Survival for Adolescents and Young Adults with Urothelial Bladder Cancer: Results from the California Cancer Registry.

PURPOSE: Bladder cancer is a common malignancy often diagnosed in older adults. Previous studies have reported racial/ethnic disparities in bladder cancer survival outcomes but have not focused on younger patients. We identified whether factors influencing cause specific survival in adolescents and young adults (ages 15 to 39) differed from older adults, and defined prognostic factors specifically in adolescents and young adults using the California Cancer Registry. MATERIALS AND METHODS: Patients diagnosed with bladder cancer between 1988 through 2012 were included in the study. The primary outcome measure was cause specific survival. A multivariable Cox proportional hazards regression model was used to evaluate predictors of cause specific survival in patients of all ages and in adolescents/young adults. Interactions of age and other variables between younger and older adult patients were assessed. RESULTS: Of 104,974 patients with bladder cancer we identified 1,688 adolescent and young adult patients (1.6%). Compared to older patients these patients had a 58% reduced risk of bladder cancer death (HR 0.42, p <0.001). Significant age interactions were identified involving race/ethnicity and histology. Among adolescents and young adults, nonHispanic African-American patients with low socioeconomic status had poor cause specific (HR 7.1, p <0.001) and overall (HR 5.02, p <0.001) survival. CONCLUSIONS: Racial/ethnic and socioeconomic disparities exist in adolescent and young adult patients with bladder cancer in California. Further studies are warranted to identify the underlying causes in order to overcome these disparities.