Evaluation of the impact of renal impairment on the pharmacokinetics of glasdegib in otherwise healthy volunteers

Cancer shared this article with you from Inoreader Evaluation of the impact of renal impairment on the pharmacokinetics of glasdegib in otherwise healthy volunteers Via Latest Results for Cancer Chemotherapy and Pharmacology Abstract Purpose Glasdegib is being developed for indications in myeloid malignancies. The effect of renal impairment on the pharmacokinetics (PK) of a single, oral, 100-mg glasdegib dose under fasted conditions was assessed. Methods Open-label, parallel-group study (NCT03596567). Participants of good general health were selected and categorized, based on their estimated glomerular filtration rate, into normal (≥ 90 mL/min), moderate (≥ 30 to < 60 mL/min), or severe (< 30 mL/min) renal impairment groups. Blood samples were collected up to 120 h post-dose. PK exposure parameters were calculated using non-compartmental analysis. Results All 18 participants completed the study. Respectively, ratios of adjusted geometric means (90% confidence interval) for glasdegib area under the curve from time 0 to infinity and peak plasma concentration versus normal participants were 205% (142–295%) and 137% (97–193%) in the moderate group, and 202% (146–281%) and 120% (77–188%) in the severe group. Glasdegib median time to peak plasma concentration was 2.0 h in both impairment groups and 1.5 h in the normal group. Mean oral clearance was decreased by approximately 50% in both renal impairment groups compared with the normal group. The plasma-free fraction of glasdegib was not altered by renal impairment. Five all-causality adverse events were reported in three participants; two were considered treatment-related. Conclusion The similar changes in exposure observed for participants with renal impairment, coupled with the known safety data from clinical experience, suggest that a lower starting dose of glasdegib may not be required for moderate or severe renal impairment. Trial registration: ClinicalTrials.gov: NCT03596567 (started May 17, 2018). View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Pingyangmycin enhances the antitumor efficacy of anti-PD-1 therapy associated with tumor-infiltrating CD8 + T cell augmentation

Cancer shared this article with you from Inoreader Pingyangmycin enhances the antitumor efficacy of anti-PD-1 therapy associated with tumor-infiltrating CD8 + T cell augmentation Via Latest Results for Cancer Chemotherapy and Pharmacology Abstract Purpose To investigate the antitumor efficacy of pingyangmycin (PYM) in combination with anti-PD-1 antibody and determine the capability of PYM to induce immunogenic cell death (ICD) in cancer cells. Methods The murine 4T1 breast cancer and B16 melanoma models were used for evaluation of therapeutic efficacy of the combination of PYM with anti-PD-1 antibody. The ELISA kits were used to quantify the ICD related ATP and HMGB1 levels. The Transwell assay was conducted to determine the chemotaxis ability of THP-1 cell in vitro. The flow cytometry was used to measure reactive oxygen species level and analyze the ratio of immune cell subsets. Results PYM induced ICD in murine 4T1 breast cancer and B16 melanoma cells and increased the release of nucleic acid fragments that may further promote the monocytic chemotaxis. In the 4T1 murine breast cancer model, PYM alone, anti-PD-1 antibody alone, and their combination suppressed tumor growth by 66.3%, 16.1% and 77.6%, respectively. PYM markedly enhanced the therapeutic efficacy of anti-PD-1 antibody against 4T1 breast cancer. The calculated CDI (coefficient of drug interaction) indicated synergistic effect. Evaluated by graphic analysis, the nucleated cells intensity in the femur bone marrow remained unchanged. Histopathological observations revealed no noticeable toxico-pathological changes in the lung and various organs, indicating that the PYM and anti-PD-1 antibody combination exerted enhanced efficacy at well-tolerated dosage level. By the combination treatment, a panel of immunological changes emerged. The ratio of CD3+ cells, NK cells and NKT c ells increased and Tregs decreased in peripheral blood. The DCs increased in the spleen. Prominent changes occurred in tumor infiltrating lymphocytes. The ratio of CD8+ cells increased, while that of CD4+ cells decreased; however, the ratio of CD3+ cells remained unchanged, implying that certain immunological responses emerged in the tumor microenvironment. PYM alone could also increase CD8+ cells and reduce CD4+ cells in tumor infiltrating lymphocytes. Conclusions The studies indicate that PYM, as an ICD inducer with mild myelosuppression effect, may enhance the therapeutic efficacy of anti-PD-1 antibody in association with tumor infiltrating CD8+ T cell augmentation. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Genetic variants in NKG2D axis and susceptibility to Epstein–Barr virus-induced nasopharyngeal carcinoma

Cancer shared this article with you from Inoreader Genetic variants in NKG2D axis and susceptibility to Epstein–Barr virus-induced nasopharyngeal carcinoma Via Cancer Abstract Background Nasopharyngeal carcinoma (NPC) is a rare epithelial carcinoma arising from the nasopharyngeal region. The pathogenesis of NPC is linked to Epstein–Barr virus (EBV) infection, although genetics and lifestyle factors appears to be also implicated. NKG2D is an immunoreceptor expressed by NK and T-cell subsets that recognizes MICA protein and other ligands on tumor cells. NKG2D interaction with MICA plays a role in the immunosurveillance to viruses and cancer. Methods We investigated potential associations between functional polymorphisms in NKG2D and MICA genes with NPC susceptibility. We conducted a case–control study including 255 Vietnamese patients with EBV + non-differentiated NPC and 220 healthy controls. Results We observed a significant association between the LNK/LNK genotype of rs1049174 (a variant associated with lower NKG2D receptor expression and reduced NK cell cytotoxicity) and increased susceptibility to NPC (adjusted OR = 1.66, 95% CI 1.07–2.59; p = 0.024). Similarly, the AA genotype of MICA rs2596542 was significantly associated with NPC (adjusted OR = 2.12; 95% CI 1.22–3.81; p = 0.009). In addition, tumor specimens of NPC patients with the AA genotype displayed a higher expression level of MICA proteins and showed higher EBV titers compared with tumor tissues from patients with the GG or GA genotypes. Higher EBV copy numbers were also observed in tumors with the A allele of MICA rs1051792 (also known as MICA-129 Met/Val) compared with those with the G allele; however, MICA rs1051792 variants were not associated with NPC susceptibility. These results suggest that genetic variants in components of the NKG2D axis may influence the individual susceptibility to EBV-induced NPC. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Colorectal anastomosis during cytoreductive radical surgery in patients with peritoneal surface malignancies. Validation of a new technique (without stoma) to prevent anastomosis leakage in more than 1000 procedures

Cancer shared this article with you from Inoreader Colorectal anastomosis during cytoreductive radical surgery in patients with peritoneal surface malignancies. Validation of a new technique (without stoma) to prevent anastomosis leakage in more than 1000 procedures Via Clinical and translational oncology Abstract Objective To describe a novel end-to-end "true" reinforced stapling colorectal anastomosis and to assess surgical outcomes in a large case series of advanced cancer patients undergoing this procedure. Summary background data Anastomotic leakage (AL) remains the main concern following surgery for colorectal cancer. Methods Between September 2006 and May 2018, in the context of the Catalonian Program of Peritoneal Carcinomatosis, 1193 consecutive patients with advanced abdominal and/or pelvic tumors were included in a prospective single-center study. They underwent cytoreductive radical surgery (CRS) in most cases combined with hyperthermic intraperitoneal chemotherapy (HIPEC). Among other surgical procedures, 374 patients underwent rectal resection and colorectal/ileorectal anastomosis, whether alone or associated to other digestive anastomosis. Key aspects of colorectal anastomosis technique were: (1) complete dissection and mobilization of the distal third of the rectum, (2) placement of a stitch that included both ends of the linear stapling of the rectal stump that was knotted on the anvil of the circular stapler, (3) "cleaning" the fatty tissue of the intestinal ends, (4) adjustment of the height of staples to the thickness of the intestinal wall, and (5) a second layer of interrupted nonperforating sutures placed circumferentially to reinforce the stapled anastomoses. A diverting stoma was not performed. Results According to clinical criteria, of the 1193 patients included, 296 cases underwent CRS (group 1) and 897 cases CRS + HIPEC (group 2). In group 1, 332 surgical procedures were performed, with 248 digestive anastomoses, of which 98 (39.5%) were colorectal anastomoses, associated to other digestive anastomosis in 37 cases. In group 2, 972 surgical procedures were performed, with 707 digestive anastomoses, of which 263 were colorectal (37.2%), 116 were associated with other digestive anastomosis. Ileocolic anastomosis was the most frequently associated digestive anastomosis. 71 major urinary reconstructions, 283 radical hysterectomies and no diverting stoma were performed. Globally, there was only three colo-ileorectal AL (3/374 = 0.8%). The overall 90-day mortality rate was 0.25%. Conclusions A technical modification to create a "true" end-to-end and completely circular reinforced anastomosis effectively prevents anastomotic leakage in patients with advanced tumors undergoing radical resection of the rectum, with no need of diverting stoma. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Significance of boost dose for T4 nasopharyngeal carcinoma with residual primary lesion after intensity-modulated radiotherapy

Cancer shared this article with you from Inoreader Significance of boost dose for T4 nasopharyngeal carcinoma with residual primary lesion after intensity-modulated radiotherapy Via Cancer Abstract Background Previous studies showed poorer survival in T4 disease with residual lesion. To evaluate the efficacy and toxicity of a boost dose for T4 nasopharyngeal carcinoma (NPC), patients with a residual primary lesion after intensity-modulated radiotherapy (IMRT). Methods 398 T4 NPC patients with residual primary lesions after radical IMRT were retrospectively reviewed. An IMRT boost dose of 4–6.75 Gy was delivered to the residual lesions in 2–3 fractions. Propensity score matching (PSM) was applied to balance potential confounders between groups (ratio, 1:2). The presence of Epstein–Barr virus (EBV) DNA in plasma after IMRT was used for risk stratification. Results Patients who received boost radiation had significantly improved overall survival (OS) and local recurrence-free survival (LRFS) compared with those who did not (all P < 0.05). In the matched cohort, 3-year OS was 86.6% in the boost radiation group and 72.7% in the non-boost group (P = 0.022). Three-year LRFS was 93.4% in the boost radiation group and 83.5% in the non-boost group (P = 0.022). In the subgroup analysis, boost dose was shown to significantly improve 3-year OS (88.0% vs. 74.1%, P = 0.021) in the low-risk group (with undetectable plasma EBV DNA after IMRT). The administration of a boost dose also improved 3-year OS in the high-risk group (with detectable plasma EBV DNA after IMRT) (66.7% vs. 60.0%, P = 0.375). Multivariate analysis demonstrated that boost dose was the only protective prognostic factor. Conclusion The addition of a boost dose for T4 NPC patients with residual primary lesion after radical IMRT provides satisfactory tumor control and clinical benefit. Additional timely and effective strengthening treatments are recommended for patients with detectable levels of plasma EBV DNA after radiotherapy. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Meningiomas and cyproterone acetate

Cancer shared this article with you from Inoreader Meningiomas and cyproterone acetate: a retrospective, monocentric cohort of 388 patients treated by surgery or radiotherapy for intracranial meningioma Via Latest Results for Journal of Neuro-Oncology Abstract Purpose Meningiomas are the most common intracranial tumors, accounting for 20–30% of central nervous system tumors. Recently, the European Medicines Agency issued an alert on cyproterone acetate (CPA) based on the results of a study that found an increased risk of meningioma 7 to 20 times higher when a patient is on CPA. The primary objective of this study was to determine the prevalence of CPA exposure in patients who had one or more intracranial meningiomas treated surgically or with radiation therapy. The secondary objectives were to establish a description of the patients who had intracranial meningioma in Nantes and to establish whether there was a difference in the intrinsic and tumoral characteristics of patients exposed to CPA compared with patients who had no hormonal exposure and patients who had been exposed to other hormones. Methods Monocentric, retrospective study including all patients treated by surgery or radiotherapy for intracranial meningioma from 2014 to 2017 excluding those with a history of exposure to ionizing radiation or neurofibromatosis type 2. Results 388 patients were included, 277 were treated by surgery and 111 by radiotherapy. 3.9% of the patients had a history or current use of CPA, 16.2% were taking other hormonal treatment. Compared with the group without hormonal exposure, the CPA-exposed group had significantly an earlier onset of meningiomas at 48.9 vs. 61.9 years (p = 0.0005) and had more multiple meningiomas, 26.7% vs. 6.1% (p = 0.0115). Conclusions In our study, patients with a history or current use of CPA had significantly more meningiomas and were significantly younger at the onset. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

LDLRAD2 promotes pancreatic cancer progression through Akt/mTOR signaling pathway

Cancer shared this article with you from Inoreader LDLRAD2 promotes pancreatic cancer progression through Akt/mTOR signaling pathway Via Latest Results for Medical Oncology Abstract Low-density lipoprotein receptor class A domain containing 2 (LDLRAD2) acts as a protein-coding gene in a large number of human diseases. However, the potential roles and underlying mechanism in pancreatic cancer remains unclear. Therefore, this study was conducted to address this question. Herein, we found that the expression of LDLRAD2 was elevated in pancreatic cancer tissues and cell lines. LDLRAD2 knockdown inhibited pancreatic cancer cell proliferation, migration, and invasion in vitro. Besides, silencing LDLRAD2 impaired tumor growth and metastasis in vivo and up-regulated the E-Cadherin level, whereas down-regulated the expression of N-Cadherin and Vimentin levels, which indicating that LDLRAD2 knockdown suppresses EMT. Additionally, LDLRAD2 knockdown decreased the Warburg effect and glycolytic enzymes expression. Pathway scan assay and western blotting assay indicated that LDLRAD2 knockdown significantly down-regulated the expression of phosphorylation of Akt and phosphorylation of mTOR, which suggested that knockdown of LDLRAD2 inhibits Akt/mTOR signaling pathway. Taken together, these findings suggested that LDLRAD2 may be an oncogene in pancreatic cancer via modulating Akt/mTOR signaling pathway. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Influence of VEGFR2 gene polymorphism on the clinical outcomes of apatinib for patients with chemotherapy – refractory extensive-stage SCLC: a real-world retrospective study

Cancer shared this article with you from Inoreader Influence of VEGFR2 gene polymorphism on the clinical outcomes of apatinib for patients with chemotherapy – refractory extensive-stage SCLC: a real-world retrospective study Via Int J Clin Oncol Abstract Purpose Great individual differences were observed regarding the efficacy of apatinib clinically. The aim of present study was to investigate the influence of vascular endothelial growth factor receptor2 (VEGFR2) gene polymorphism on the clinical outcomes of apatinib for patients with chemotherapy–refractory extensive-stage small cell lung cancer (ES-SCLC). Methods A total of 128 patients with chemotherapy–refractory ES-SCLC who were treated with apatinib at an initial dosage of 250 or 500 mg were included in this study. The change of target lesions was assessed. Overall response rate (ORR) was evaluated. Prognosis was carried out and safety profile was documented. Additionally, peripheral blood and biopsy cancer tissue specimens of the patients with SCLC were collected for the analysis of polymorphism and VEGFR2 gene mRNA expression, respectively. The association between genotype status and baseline characteristics was performed. Univariate analysis of genotype status and prognosis was carried out using Kaplan–Meier survival analysis and multivariate analysis were adjusted by Cox regression analysis. Results Efficacy of apatinib included partial response (PR) in 15 patients, stable disease (SD) in 86 patients, progressive disease (PD) in 27 patients. Therefore, ORR of the 128 patients with ES-SCLC was 11.7%, and disease control rate (DCR) was 78.9%. Prognosis suggested that the median progression-free survival (PFS) and overall survival (OS) of the 128 patients with ES-SCLC was 4.2 months and 8.2 months, respectively. The polymorphism analysis focusing on VEGFR2 gene indicated that one single nucleotide polymorphism 889C>T was of clinical significance. Prevalence of 889C>T among the 128 patients with SCLC were as follows: CC genotype 87 cases (68.0%), CT genotype 38 cases (29.7%) and TT genotype 3 cases (2.3%), the minor allele frequency of 889C>T was 0.17, which was in accordance with Hardy–Weinberg Equilibrium (P = 0.628). Patients with CT and TT genotypes were merged in the subsequent analysis. Prognosis analysis exhibi ted that the median PFS of patients with CT/TT genotype and CC genotype was 3.3 and 5.0 months, respectively (P = 0.02). Furthermore, the median OS of patients was 5.5 and 9.0 months, respectively (P = 0.008). Additionally, multivariate Cox regression analysis of OS demonstrated that CT/TT genotype was an independent factor for OS [Hazard ratio (HR) = 0.64, P = 0.019]. However, the safety profile according to genotype status of 889C>T failed to show significant difference. Interestingly, mRNA expression analysis suggested that the mRNA expression of VEGFR2 in cancer tissues were significantly different according to CC and CT/TT genotypes (P < 0.001). Conclusion The administration with apatinib for patients with chemotherapy–refractory ES-SCLC was of potential clinical significance. The clinical outcomes of patients with ES-SCLC who were treated with apatinib could be impacted by VEGFR2 889C>T polymorphism through mediating the VEGFR2 mRNA expression. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Combination of CD47 and CD68 expression predicts survival in eastern-Asian patients with non-small cell lung cancer

Cancer shared this article with you from Inoreader Combination of CD47 and CD68 expression predicts survival in eastern-Asian patients with non-small cell lung cancer Via Cancer Abstract Objective Recent studies have indicated that CD47, interacting with SIRP-α, conveys "don't eat me" signal in evasion of tumor cells and serves as a potential target for cancer immunotherapy. The purpose of this study was to investigate the clinical correlation of CD47 and uncover prognostic implications of CD47 and CD68 in non-small cell lung cancer (NSCLC). Methods The specimens from 384 patients with completely resected NSCLC were collected for immunohistochemical assays of CD47 and CD68. Cox multivariate proportion hazard analyses were conducted to confirm the independent prognostic value of CD47 and CD68. TCGA database and GSE37745 were used to identify the association between CD47 and immune cells. Results In 186 pairs of lung cancer and adjacent tissues, the RNA of CD47 was overexpressed in lung cancer tissues (P < 0.001). High expression of CD47 was associated with worse recurrence-free survival in RNA and protein level (P = 0.032 and P < 0.001, respectively). High expression of CD47 was significantly associated with large tumor size (P = 0.004), advanced pathologic TNM stage (P < 0.001), and histology (P = 0.003). Further analyses demonstrated that CD47 and CD68 predicted outcomes of patients independently. In addition, the expression of CD47 correlated with neutrophils, and did not correlated with B cells and CD4 + T cells in the TCGA database and GSE37745. Conclusion Combined use of CD47 and CD68 exhibited excellent performance in predicting survival of patients with NSCLC. CD47 was a potential therapeutic target for immune therapy of lung cancer. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

The use of zebrafish model in prostate cancer therapeutic development and discovery

Cancer shared this article with you from Inoreader The use of zebrafish model in prostate cancer therapeutic development and discovery Via Latest Results for Cancer Chemotherapy and Pharmacology Abstract Zebrafish is now among the leading in vivo model for cancer research, including prostate cancer. They are an alternative economic model being used to study cancer development, proliferation, and metastasis. They can also be effectively utilized for the development of cancer drugs at all levels, including target validation, and high-throughput screening for possible lead molecules. In this review, we provide a comprehensive overview of the role of zebrafish as an in vivo model in prostate cancer research. Globally, prostate cancer is a leading cause of death in men. Although many molecular mechanisms have been identified as playing a role in the pathogenesis of prostate cancer, there is still a significant need to understand the initial events of the disease. Furthermore, current treatments are limited by the emergence of severe toxicities and multidrug resistance. There is an essential need for economical and relevant research tools to improve our understanding a nd overcome these problems. This review provides a comprehensive summary of studies that utilized zebrafish for different aims in prostate cancer research. We discuss the use of zebrafish in prostate cancer cell proliferation and metastasis, defining signaling pathways, drug discovery and therapeutic development against prostate cancer, and toxicity studies. Finally, this review highlights limitations in this field and future directions to efficiently use zebrafish as a robust model for prostate cancer therapeutics development. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.