Publications

Data from Baseline Circulating Tumor Cell Counts Significantly Enhance a Prognostic Score for Patients Participating in Phase I Oncology Trials

<div>Abstract<p><b>Background:</b> High circulating tumor cell (CTC) counts are associated with poor prognosis in several cancers. Enrollment of patients on phase I oncology trials requires a careful assessment of the potential risks and benefits. Many patients enrolled on such trials using established eligibility criteria have a short life expectancy and are less likely to benefit from trial participation. We hypothesized that the incorporation of CTC counts might improve patient selection for phase I trials.</p><p><b>Methods:</b> This retrospective analysis evaluated patients who had baseline CTCs enumerated prior to their starting on a phase I trial. CTCs were enumerated using the CellSearch System.</p><p><b>Results:</b> Between January 2006 and December 2009 a total of 128 patients enrolled in phase I trials had CTC counts evaluated. Higher CTC counts as a continuous variable independently correlated with risk of death in this patient population (<i>P</i> = 0.006). A multivariate point-based risk model was generated using CTCs as a dichotomous variable (≥3 or <3), and incorporated other established prognostic factors, including albumin <35 g/L, lactate dehydrogenase greater than upper limit of normal, and >2 metastatic sites. Comparison of receiver operating characteristic curves demonstrated that the addition of baseline CTC counts improved the performance of the prospectively validated Royal Marsden Hospital phase I prognostic score, which now identifies three risk groups (<i>P</i> < 0.0001): good prognosis [score 0–1, median overall survival (OS) 63.7 weeks], intermediate prognosis (score 2–3, median OS 37.3 weeks), and poor prognosis (score 4, median OS 13.4 weeks).</p><p><b>Conclusion:</b> CTC enumeration improved the performance of a validated prognostic score to help select patients for phase I oncology trials. <i>Clin Cancer Res; 17(15); 5188–96. ©2011 AACR</i>.</p></div>

Early Post-treatment Prostate-specific Antigen at 4 Weeks and Abiraterone and Enzalutamide Treatment for Advanced Prostate Cancer: An International Collaborative Analysis

Declines in prostate-specific antigen (PSA) levels at 12 wk are used to evaluate treatment response in metastatic castration-resistant prostate cancer (mCRPC). PSA fall by ≥30% at 4 wk (PSA4w30) has been reported to be associated with better outcome in a single-centre cohort study. To evaluate clinical relevance of early PSA decline in mCRPC patients treated with next-generation hormonal treatments (NGHTs) such as abiraterone and enzalutamide. This was a retrospective multicentre analysis. Eligible patients received NGHT for mCRPC between 6 January 2006 and 31 December 2017 in 13 cancer centres worldwide, and had PSA levels assessed at baseline and at 4 and/or 12 wk after treatment. PSA response was defined as a ≥30% decline (progression as a ≥25% increase) from baseline. Association with overall survival (OS) was analysed using landmark multivariable Cox regression adjusting for previous chemotherapy, including cancer centre as a shared frailty term. We identified 1358 mCRPC patients treated with first-line NGHT (1133 had PSA available at 4 wk, and 948 at both 4 and 12 wk). Overall, 583 (52%) had a PSA4w30; it was associated with longer OS (median: 23; 95% confidence interval [CI]: 21–25) compared with no change (median: 17; 95% CI: 15–18) and progression (median: 13; 95% CI: 10–15). A PSA12w30 was associated with lower mortality (median OS 22 vs 14; hazard ratio = 0.57; 95% CI = 0.48–0.67; p < 0.001). PSA4w30 strongly correlated with PSA12w30 (ρ = 0.91; 95% CI = 0.90–0.92; p < 0.001). In total, 432/494 (87%) with a PSA4w30 achieved a PSA12w30. Overall, 11/152 (7%) patients progressing at 4 wk had a PSA12w30 (1% of the overall population). PSA changes in the first 4 wk of NGHT therapies are strongly associated with clinical outcome from mCRPC and can help guide early treatment switch decisions. Prostate-specific antigen changes at 4 wk after abiraterone/enzalutamide treatment are important to determine patients' outcome and should be taken into consideration in clinical practice.

Experimental and numerical behaviour of blind bolted flush endplate composite connections

Size-dependent vibration of bi-directional functionally graded microbeams with arbitrary boundary conditions

An efficient shear deformation theory for vibration of functionally graded plates

Abstract CT097: A first-in-human phase I dose escalation study of the OX40 agonist MOXR0916 in patients with refractory solid tumors

Abstract Background: OX40 is a co-stimulatory receptor that is transiently expressed by T cells upon antigen recognition. In murine models, OX40 engagement by an agonist anti-OX40 antibody can promote durable tumor regression associated with co-stimulation of effector T cells and reduction of regulatory T cells. MOXR0916 is a humanized effector-competent agonist IgG1 monoclonal antibody that targets OX40. Methods: A Phase I, open-label, multicenter study was conducted to evaluate the safety and pharmacokinetics (PK) of MOXR0916 in patients (pts) with locally advanced or metastatic refractory solid tumors that have progressed after available standard therapy. MOXR0916 was administered at fixed doses every 3 weeks (q3w), and treatment beyond RECIST progression was permitted in the absence of clinical deterioration. A 3+3 dose-escalation was conducted in immunotherapy-naïve pts with a 21-day window to evaluate dose-limiting toxicity (DLT). A dedicated expansion cohort enrolled pts who consented to serial tumor biopsies, enabling immune profiling by immunohistochemistry and gene expression methods. In the biopsy cohort, prior immunotherapy with adequate washout was permitted, provided there was no history of Grade (G) ?3 immune-mediated adverse events (AEs). Results: Enrollment in the dose-finding phase of the trial is complete, with 34 pts treated across 10 dose escalation cohorts (dose levels 0.2-1200 mg) and 36 pts treated in the serial biopsy cohort (dose levels 3.2-600 mg). While NSCLC (n = 8), clear cell RCC (n = 6), melanoma (n = 2), and bladder (n = 2) were represented, less immunogenic tumor types predominated. The median number of prior regimens for metastatic disease was 2 (range 0-9); 4 pts had received prior checkpoint inhibitors. As of 11 Jan 2016, no DLTs, G4/5 AEs attributed to study treatment, or AEs leading to treatment discontinuation were reported. The majority of treatment-related AEs were G1 in severity; 4 related G3 events (autoimmune hepatitis responsive to steroids, worsening dyspnea in a pt with malignant pleural effusions, hypertension, and fatigue) were reported. At doses ?40 mg q3w, PK was linear and sustained peripheral blood OX40 receptor saturation was achieved. Tumor pharmacodynamic (PD) biomarker modulation supportive of the mechanism of action was observed in a subset of pts. Eleven of 70 pts (16%) have been treated with MOXR0916 for &amp;gt; 6 months (?9 cycles) with a best response of stable disease per RECIST v1.1. Updated clinical data will be presented. Conclusions: In a heterogeneous, refractory population, MOXR0916 was well-tolerated at all doses evaluated. The recommended dose and schedule based on PK and OX40 receptor saturation is 300 mg q3w. Tumor PD modulation and evidence of prolonged stable disease support the ongoing expansion phase to evaluate anti-tumor activity in select indications and Phase Ib trial in combination with atezolizumab (anti-PD-L1). Citation Format: Aaron R. Hansen, Jeffrey R. Infante, Grant McArthur, Michael S. Gordon, Alexander M. Lesokhin, Ann-Lee Stayner, Todd M. Bauer, Shahneen Sandhu, Frank Tsai, Alexandra Snyder, Deepa S. Subramaniam, Jeong Kim, Eric Stefanich, Chi-Chung Li, Jane Ruppel, Maria Anderson, Houston Gilbert, Bruce McCall, Mahrukh A. Huseni, Ina Rhee, Michael Pishvaian. A first-in-human phase I dose escalation study of the OX40 agonist MOXR0916 in patients with refractory solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT097.

Safety of Lutetium-177 prostate-specific membrane antigen-617 (PSMA-617) radioligand therapy in the setting of severe renal impairment: a case report and literature review

Reported here is a case of rapidly progressive metastatic castration-resistant prostate cancer treated with [177Lu]Lu-PSMA-617 in the setting of severe renal impairment and impending ureteric obstruction. PSMA is expressed on renal tubular cells, raising the possibility of radiation-induced nephrotoxicity, and this level of renal impairment would typically exclude the patient from [177Lu]Lu-PSMA-617 therapy. Multidisciplinary input, individualized dosimetry, and patient-specific dose reduction were used to ensure the cumulative dose to the kidneys remained within acceptable limits. He was initially planned for treatment with six cycles of [177Lu]Lu-PSMA-617. However, he had an excellent response to therapy following four cycles of treatment and the last two cycles were omitted. He has been followed for 1-year posttherapy without evidence of disease recurrence. No acute or chronic nephrotoxicity was observed. This case report highlights the utility of [177Lu]Lu-PSMA-617 therapy in severe renal impairment and provides evidence of relative safety in patients who would otherwise not be considered candidates for therapy.This report presents a case of a man with aggressive metastatic prostate cancer who received [177Lu]Lu-PSMA-617 therapy, despite having severely reduced kidney function and worsening ureter obstruction. This treatment could have potential side effects on kidney function, but the medical team used a personalized approach to reduce patient risk. The man was initially planned to have six cycles of therapy, but his excellent response to treatment after four cycles meant the last two cycles were not given. The man has been followed for 1 year after treatment and has not experienced any worsening kidney function. This case shows the safe and effective use of [177Lu]Lu-PSMA-617 therapy in a patient with severely reduced kidney function who would not normally qualify for this treatment.

Concrete-filled steel tubular (CFST) columns database with 3,208 tests

This database is collected for evaluating the reliability of CFST columns designed by modern codes of practice (see Thai H-T, Thai S, Ngo T, Uy B, Kang W-H, Hicks SJ. Reliability considerations of modern codes for CFST columns. Journal of Constructional Steel Research 2021;106482). The database contains 3,208 tests including: - 1,305 tests on circular CFST columns under concentric loading - 1,003 tests on rectangular CFST columns under concentric loading - 499 tests on circular CFST columns under eccentric loading - 401 tests on rectangular CFST columns under eccentric loading

RoboNautilus: a cephalopod-inspired soft robotic siphon for underwater propulsion

Data from Circulating Tumor DNA Predicts Outcome from First-, but not Second-line Treatment and Identifies Melanoma Patients Who May Benefit from Combination Immunotherapy

&lt;div&gt;AbstractPurpose:&lt;p&gt;We evaluated the predictive value of pretreatment ctDNA to inform therapeutic outcomes in patients with metastatic melanoma relative to type and line of treatment.&lt;/p&gt;Experimental Design:&lt;p&gt;Plasma circulating tumor DNA (ctDNA) was quantified in 125 samples collected from 110 patients prior to commencing treatment with immune checkpoint inhibitors (ICIs), as first- (&lt;i&gt;n&lt;/i&gt; = 32) or second-line (&lt;i&gt;n&lt;/i&gt; = 27) regimens, or prior to commencing first-line BRAF/MEK inhibitor therapy (&lt;i&gt;n&lt;/i&gt; = 66). An external validation cohort included 128 patients commencing ICI therapies in the first- (&lt;i&gt;N&lt;/i&gt; = 77) or second-line (&lt;i&gt;N&lt;/i&gt; = 51) settings.&lt;/p&gt;Results:&lt;p&gt;In the discovery cohort, low ctDNA (≤20 copies/mL) prior to commencing therapy predicted longer progression-free survival (PFS) in patients treated with first-line ICIs [HR, 0.20; 95% confidence interval (CI) 0.07–0.53; &lt;i&gt;P&lt;/i&gt; &lt; 0.0001], but not in the second-line setting. An independent cohort validated that ctDNA is predictive of PFS in the first-line setting (HR, 0.42; 95% CI, 0.22–0.83; &lt;i&gt;P&lt;/i&gt; = 0.006), but not in the second-line ICI setting. Moreover, ctDNA prior to commencing ICI treatment was not predictive of PFS for patients pretreated with BRAF/MEK inhibitors in either the discovery or validation cohorts. Reduced PFS and overall survival were observed in patients with high ctDNA receiving anti–PD-1 monotherapy, relative to those treated with combination anti–CTLA-4/anti–PD-1 inhibitors.&lt;/p&gt;Conclusions:&lt;p&gt;Pretreatment ctDNA is a reliable indicator of patient outcome in the first-line ICI treatment setting, but not in the second-line ICI setting, especially in patients pretreated with BRAF/MEK inhibitors. Preliminary evidence indicated that treatment-naïve patients with high ctDNA may preferentially benefit from combined ICIs.&lt;/p&gt;&lt;/div&gt;

A simple refined theory for bending, buckling, and vibration of thick plates resting on elastic foundation

Second-order Inelastic Dynamic Analysis of Three-dimensional Cable-stayed Bridges

Concrete-filled steel tubular columns: Test database, design and calibration

Supplementary Figure 4 from A Histone Deacetylase Inhibitor, Panobinostat, Enhances Chimeric Antigen Receptor T-cell Antitumor Effect Against Pancreatic Cancer

&lt;p&gt;Supplementary Figure 4. Pano did not enhance the cytotoxicity of CARaMEL cells nor oncolysis of VV-gp100.&lt;/p&gt;

Behaviour and design of composite walls under lateral loading and combined loading

Administering [177Lu]Lu-PSMA-617 Prior to Radical Prostatectomy in Men with High-risk Localised Prostate Cancer (LuTectomy): A Single-centre, Single-arm, Phase 1/2 Study

Prevention of COVID-19 in patients with inflammatory bowel disease in Wuhan, China

Viral screening before initiation of biologics in patients with inflammatory bowel disease during the COVID-19 outbreakWe read with interest the Comment by Ren Mao and colleagues on the implications of coronavirus disease 2019 (COVID-19) in patients with pre-existing digestive diseases, and the strategies implemented in China to restrict the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients with inflammatory bowel disease. 1 We agree with the current evidence that does not support drug suspension and also with the European Crohn's and Colitis Organisation COVID-19We declare no competing interests.

Emodin Alleviates High-Glucose-Induced Pancreatic β-Cell Pyroptosis by Inhibiting NLRP3/GSDMD Signaling

Diabetes mellitus (DM) is a chronic noninfectious disease that is mainly featured by pancreatic β-cell (β-cell) dysfunction and impaired glucose homeostasis. Currently, the pathogenesis of dysfunction of the β-cells in DM remains unclear, and therapeutic approaches to it are limited. Emodin (EMD), a natural anthraquinone derivative, has been preliminarily proven to show antidiabetic effects. However, the underlying mechanism of EMD on β-cells still needs to be elucidated. In this study, we investigated the protective effects of EMD on the high glucose (50 mM)-induced INS-1 cell line and the underlying mechanism. INS-1 cells were treated with EMD (5, 10, and 20 μM) when exposed to high glucose. The effects of EMD were examined by using the inverted phase-contrast microscope, qRT-PCR, ELISA, and western blot. The results showed that EMD could alleviate cellular morphological changes, suppress IL-1β and LDH release, and promote insulin secretion in high-glucose-induced INS-1 cells. Furthermore, EMD inhibits NOD-like receptor protein 3 (NLRP3) activation and gasdermin D (GSDMD) cleavage to alleviate pyroptosis induced by high glucose. Overexpression of NLRP3 reversed the above changes caused by EMD. Collectively, our findings suggest that EMD attenuates high-glucose-induced β-cell pyroptosis by inhibiting NLRP3/GSDMD signaling.