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Exploratory analyses indicate an association with the radiation dose to the lungs. At the MTD, olaparib reduced PAR levels by more than 95% and abolished radiation-induced PARylation. Median follow-up of survivors was 4.1 years. Two-year loco-regional control was 84%, median overall survival in patients with locally advanced NSCLC was 28 months.

Combined mildly hypofractionated radiotherapy and low-dose daily cisplatin and olaparib was not tolerable due to esophageal and hematologic toxicity. Severe pulmonary toxicity was observed as well, even without cisplatin. selleck chemicals More conformal radiotherapy schedules with improved pulmonary and esophageal sparing should be explored.

Combined mildly hypofractionated radiotherapy and low-dose daily cisplatin and olaparib was not tolerable due to esophageal and hematologic toxicity. Severe pulmonary toxicity was observed as well, even without cisplatin. More conformal radiotherapy schedules with improved pulmonary and esophageal sparing should be explored.

Prediction models for acute myeloid leukemia (AML) are useful, but have considerable inaccuracy and imprecision. No current model includes covariates related to immune cells in the AML microenvironment. Here, an immune risk score was explored to predict the survival of patients with AML.

We evaluated the predictive accuracy of several

algorithms for immune composition in AML based on a reference of multi-parameter flow cytometry. CIBERSORTx was chosen to enumerate immune cells from public datasets and develop an immune risk score for survival in a training cohort using least absolute shrinkage and selection operator Cox regression model.

Six flow cytometry-validated immune cell features were informative. The model had high predictive accuracy in the training and four external validation cohorts. Subjects in the training cohort with low scores had prolonged survival compared with subjects with high scores, with 5-year survival rates of 46% versus 19% (

< 0.001). Parallel survival rates in validation cohorts-1, -2, -3, and -4 were 46% versus 6% (

< 0.001), 44% versus 18% (

= 0.041), 44% versus 24% (

= 0.004), and 62% versus 32% (

< 0.001). Gene set enrichment analysis indicated significant enrichment of immune relation pathways in the low-score cohort. In multivariable analyses, high-risk score independently predicted shorter survival with HRs of 1.45 (

= 0.005), 2.12 (

= 0.004), 2.02 (

= 0.034), 1.66 (

= 0.019), and 1.59 (

= 0.001) in the training and validation cohorts, respectively.

Our immune risk score complements current AML prediction models.

Our immune risk score complements current AML prediction models.

Recurrent and/or metastatic unresectable cutaneous squamous cell carcinomas (cSCCs) are treated with chemotherapy or radiotherapy, but have poor clinical responses. A limited response (up to 45% of cases) to EGFR-targeted therapies was observed in clinical trials with patients with advanced and metastatic cSCC. Here, we analyze the molecular traits underlying the response to EGFR inhibitors, and the mechanisms responsible for cSCC resistance to EGFR-targeted therapy.

We generated primary cell cultures and patient cSCC-derived xenografts (cSCC-PDXs) that recapitulate the histopathologic and molecular features of patient tumors. Response to gefitinib treatment was tested and gefitinib-resistant (GefR) cSCC-PDXs were developed. RNA sequence analysis was performed in matched untreated and GefR cSCC-PDXs to determine the mechanisms driving gefitinib resistance.

cSCCs conserving epithelial traits exhibited strong activation of EGFR signaling, which promoted tumor cell proliferation, in contrast to mesenchymal.

Human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma (OPSCC) is tumorigenic and has been associated with a favorable prognosis compared with OPSCC caused by tobacco, alcohol, and other carcinogens. Meanwhile, machine learning has evolved as a powerful tool to predict molecular and cellular alterations of medical images of various sources.

We generated a deep learning-based HPV prediction score (HPV-ps) on regular hematoxylin and eosin (H&E) stains and assessed its performance to predict HPV association using 273 patients from two different sites (OPSCC; Giessen,

= 163; Cologne,

= 110). Then, the prognostic relevance in a total of 594 patients (Giessen, Cologne, HNSCC TCGA) was evaluated. In addition, we investigated whether four board-certified pathologists could identify HPV association (

= 152) and compared the results to the classifier.

Although pathologists were able to diagnose HPV association from H&E-stained slides (AUC = 0.74, median of four observers), the interration with p16 status, to identify patients with OPSCC with a favorable prognosis, potentially outperforming combined HPV-DNA/p16 status as a biomarker for patient stratification.

Circulating tumor cells (CTC) are under investigation as a minimally invasive liquid biopsy that may improve risk stratification and treatment selection. CTCs uniquely allow for digital pathology of individual malignant cell morphology and marker expression. We compared CTC features and T-cell counts with survival endpoints in a cohort of patients with metastatic genitourinary cancer treated with combination immunotherapy.

Markers evaluated included pan-CK/CD45/PD-L1/DAPI for CTCs and CD4/CD8/Ki-67/DAPI for T cells. ANOVA was used to compare CTC burden and T-cell populations across timepoints. Differences in survival and disease progression were evaluated using the maximum log-rank test.

From December 2016 to January 2019, 183 samples from 81 patients were tested. CTCs were found in 75% of patients at baseline. CTC burden was associated with shorter overall survival (OS) at baseline (

= 0.022), but not on-therapy. Five morphologic subtypes were detected, and the presence of two specific subtypes with of specific CTC morphologies.

Although abundant myeloid cell populations in the pancreatic ductal adenocarcinoma (PDAC) microenvironment have been postulated to suppress antitumor immunity, the composition of these populations, their spatial locations, and how they relate to patient outcomes are poorly understood.

To generate spatially resolved tumor and immune cell data at single-cell resolution, we developed two quantitative multiplex immunofluorescence assays to interrogate myeloid cells (CD15, CD14, ARG1, CD33, HLA-DR) and macrophages [CD68, CD163, CD86, IFN regulatory factor 5, MRC1 (CD206)] in the PDAC tumor microenvironment. link2 Spatial point pattern analyses were conducted to assess the degree of colocalization between tumor cells and immune cells. Multivariable-adjusted Cox proportional hazards regression was used to assess associations with patient outcomes.

In a multi-institutional cohort of 305 primary PDAC resection specimens, myeloid cells were abundant, enriched within stromal regions, highly heterogeneous across tumors, id immune cells are associated with patient outcomes, highlighting the potential role of spatially resolved myeloid cell subtypes as quantitative biomarkers for PDAC prognosis and therapy.

Mesothelin (MSLN) is a glycophosphatidylinositol-linked tumor antigen overexpressed in a variety of malignancies, including ovarian, pancreatic, lung, and triple-negative breast cancer. Early signs of clinical efficacy with MSLN-targeting agents have validated MSLN as a promising target for therapeutic intervention, but therapies with improved efficacy are still needed to address the significant unmet medical need posed by MSLN-expressing cancers.

We designed HPN536, a 53-kDa, trispecific, T-cell-activating protein-based construct, which binds to MSLN-expressing tumor cells, CD3ε on T cells, and to serum albumin. Experiments were conducted to assess the potency, activity, and half-life of HPN536 in

assays, rodent models, and in nonhuman primates (NHP).

HPN536 binds to MSLN-expressing tumor cells and to CD3ε on T cells, leading to T-cell activation and potent redirected target cell lysis. A third domain of HPN536 binds to serum albumin for extension of plasma half-life. In cynomolgus monkeys, HPN536 at doses ranging from 0.1 to 10 mg/kg demonstrated MSLN-dependent pharmacologic activity, was well tolerated, and showed pharmacokinetics in support of weekly dosing in humans.

HPN536 is potent, is well tolerated, and exhibits extended half-life in NHPs. It is currently in phase I clinical testing in patients with MSLN-expressing malignancies (NCT03872206).

HPN536 is potent, is well tolerated, and exhibits extended half-life in NHPs. It is currently in phase I clinical testing in patients with MSLN-expressing malignancies (NCT03872206).

We conducted a phase I/II study to investigate the safety and efficacy of nivolumab with paclitaxel plus ramucirumab.

Patients with advanced gastric cancer (AGC) refractory to first-line chemotherapy were included. Patients received nivolumab (3 mg/kg on days 1 and 15) combined with paclitaxel (80 mg/m

on days 1, 8, and 15) and ramucirumab (8 mg/kg on days 1 and 15) every 4 weeks. After feasibility evaluation in six patients (phase I), 37 additional patients were enrolled in the phase II part with the primary endpoint of 6-month progression-free survival (PFS) rate with two-sided 80% confidence interval (CI). The combined positive score (CPS) was defined as the number of programmed death-ligand 1-positive cells divided by the total number of viable tumor cells multiplied by 100.

Forty-three patients were enrolled. Of these, 60.5% had CPS ≥ 1. Dose-limiting toxicities were observed in two patients, and the recommended dose was determined as level 1. Thirty-nine (90.7%) patients experienced treatment-related adverse events (AEs) grade ≥3 and 14 (32.6%) patients experienced immune-related AEs grade ≥3. The overall response rate was 37.2% (95% CI, 23.0%-53.5%) and the 6-month PFS rate was 46.5% (80% CI, 36.4%-55.8%;

= 0.067). Median survival time was 13.1 months (95% CI, 8.0-16.6 months) 13.8 months (95% CI, 8.0-19.5 months) in patients with CPS ≥ 1 and 8.0 months (95% CI, 4.8-24.1 months) in patients with CPS < 1.

Nivolumab with paclitaxel plus ramucirumab demonstrated promising antitumor activity with manageable toxicities as second-line treatment for AGC.

Nivolumab with paclitaxel plus ramucirumab demonstrated promising antitumor activity with manageable toxicities as second-line treatment for AGC.

To survey and explore current approaches to deployment of pharmaceutical care prioritisation tools in acute hospitals in the UK.

A national online survey was circulated electronically to chief pharmacists of hospitals to determine if they use a prioritisation tool or process. link3 Where such mechanisms exist, respondents were invited to participate in a semistructured telephone interview to explore the development, evaluation and application of their tool and share relevant documentation. Interviews were transcribed and thematically analysed.

Seventy hospitals (70/130) used a tool or process to prioritise clinical pharmacy services. Thirty-six interviews were conducted, and two were excluded. The majority of tools had been developed in-house. Few hospitals had undertaken formal evaluations of their prioritisation tool. Pharmacy prioritisation tools ranged in complexity and often included a combination of pharmacy service prioritisation, such as medicines reconciliation, and a section to assign an individual patient prioritisation level.