Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGF-β and PD-L1, in Patients with Non-Small Cell Lung Cancer Resistant or Refractory to Immune Checkpoint Inhibitors

Bintrafusp alfa; Bifunctional; Non-small cell lung cancerBintrafusp alfa; Bifuncional; Càncer de pulmó de cèl·lules no petitesBintrafusp alfa; Bifuncional; Cáncer de pulmón de células no pequeñasBackground Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of transforming growth factor beta receptor II (a TGF-β “trap”) fused to a human immunoglobulin G1 monoclonal antibody blocking programmed cell death 1 ligand 1 (PD-L1). We report the efficacy and safety in patients with non-small cell lung cancer (NSCLC) that progressed following anti-PD-(L)1 therapy. Materials and Methods In this expansion cohort of NCT02517398—a global, open-label, phase I trial—adults with advanced NSCLC that progressed following chemotherapy and was primary refractory or had acquired resistance to anti-PD-(L)1 treatment received intravenous bintrafusp alfa 1200 mg every 2 weeks until confirmed progression, unacceptable toxicity, or trial withdrawal. The primary endpoint was best overall response (by Response Evaluation Criteria in Solid Tumors version 1.1 adjudicated by independent review committee); secondary endpoints included safety. Results Eighty-three eligible patients (62 [74.7%] treated with ≥3 prior therapies) received bintrafusp alfa. Four patients (3 primary refractory, 1 acquired resistant) had confirmed partial responses (objective response rate, 4.8%; 95% CI, 1.3%-11.9%), and 9 had stable disease. Tumor cell PD-L1 expression was not associated with response. Nineteen patients (22.9%) experienced grade ≥3 treatment-related adverse events, most commonly asthenia (3 [3.6%]) and fatigue, eczema, and pruritus (2 each [2.4%]). One patient had grade 4 amylase increased. One patient died during treatment for pneumonia before initiation of bintrafusp alfa. Conclusion Although the primary endpoint was not met, bintrafusp alfa showed some clinical activity and a manageable safety profile in patients with heavily pretreated NSCLC, including prior anti-PD-(L)1 therapy. Tumor responses occurred irrespective of whether disease was primary refractory or had acquired resistance to prior anti-PD-(L)1 therapy.This study was funded by Merck (CrossRef Funder ID: 10.13039/100009945) and was previously part of an alliance between Merck and GlaxoSmithKline, in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3)

Diosgenin Induces Apoptosis in HepG2 Cells through Generation of Reactive Oxygen Species and Mitochondrial Pathway

Diosgenin, a naturally occurring steroid saponin found abundantly in legumes and yams, is a precursor of various synthetic steroidal drugs. Diosgenin is studied for the mechanism of its action in apoptotic pathway in human hepatocellular carcinoma cells. Based on DAPI staining, diosgenin-treated cells manifested nuclear shrinkage, condensation, and fragmentation. Treatment of HepG2 cells with 40 μM diosgenin resulted in activation of the caspase-3, -8, -9 and cleavage of poly-ADP-ribose polymerase (PARP) and the release of cytochrome c. In the upstream, diosgenin increased the expression of Bax, decreased the expression of Bid and Bcl-2, and augmented the Bax/Bcl-2 ratio. Diosgenin-induced, dose-dependent induction of apoptosis was accompanied by sustained phosphorylation of JNK, p38 MAPK and apoptosis signal-regulating kinase (ASK)-1, as well as generation of the ROS. NAC administration, a scavenger of ROS, reversed diosgene-induced cell death. These results suggest that diosgenin-induced apoptosis in HepG2 cells through Bcl-2 protein family-mediated mitochndria/caspase-3-dependent pathway. Also, diosgenin strongly generated ROS and this oxidative stress might induce apoptosis through activation of ASK1, which are critical upstream signals for JNK/p38 MAPK activation in HepG2 cancer cells

The prognostic factors of resected non-small cell lung cancer with chest wall invasion

<p>Abstract</p> <p>Background</p> <p>We retrospectively reviewed the clinical features and surgical outcomes of patients with a surgically resected NSCLC invading chest wall in order to identify prognostic factors that impact long term survival.</p> <p>Methods</p> <p>Between January 1990 and December 2009, 107 patients who underwent surgical resection for chest wall invading NSCLC were reviewed. Tumors invading only the parietal pleura were defined as superficial invasions, and those involving the soft tissue or ribs were defined as deep invasions.</p> <p>Results</p> <p>There were 91 men and 16 women; median age was 64 years (range 30 to 80 years). Overall 5 year survival rate was 26.3%. The univariate prognostic factors for survival included gender, extent of resection (pneumonectomy vs lobectomy), tumor size(> 5 cm vs ≤ 5 cm), nodal status (N0 or N1 vs N2), completeness of resection (complete vs incomplete) and completeness of adjuvant chemotherapy. At multivariate analysis, five independent prognostic factors were shown; depth of invasion (superficial vs deep), tumor size, nodal status, completeness of resection, and completeness of adjuvant chemotherapy. In patients with completely resected T3N0 NSCLC, completion of chemotherapy is the only prognostic factor for long term survival.</p> <p>Conclusions</p> <p>Completeness of resection, nodal status, depth of invasion, tumor size, and adjuvant chemotherapy were prognostic factors for long-term survival in NSCLC patients with chest wall invasion. Because of poor prognosis in cases with chest wall invasion that have N2 positive LN, that is difficult to achieve complete resection and that need pneumonectomy, definite chemoradiotherapy or neoadjuvant chemoradiotherapy should be considered first in these cases.</p

Profiling age-related epigenetic markers of stomach adenocarcinoma in young and old subjects

The purpose of our study is to identify epigenetic markers that are differently expressed in the stomach adenocarcinoma (STAD) condition. Based on data from The Cancer Genome Atlas (TCGA), we were able to detect an age-related difference in methylation patterns and changes in gene and miRNA expression levels in young (n = 14) and old (n = 70) STAD subjects. Our analysis identified 323 upregulated and 653 downregulated genes in old STAD subjects. We also found 76 miRNAs with age-related expression patterns and 113 differentially methylated genes (DMGs), respectively. Our further analysis revealed that significant upregulated genes (n = 35) were assigned to the cell cycle, while the muscle system process (n = 27) and cell adhesion-related genes (n = 57) were downregulated. In addition, by comparing gene and miRNA expression with methylation change, we identified that three upregulated genes (ELF3, IL1??, and MMP13) known to be involved in inflammatory responses and cell growth were significantly hypomethylated in the promoter region. We further detected target candidates for age-related, downregulated miRNAs (hsa-mir-124-3, hsa-mir-204, and hsa-mir-125b-2) in old STAD subjects. This is the first report of the results from a study exploring age-related epigenetic biomarkers of STAD using high-throughput data and provides evidence for a complex clinicopathological condition expressed by the age-related STAD progression. &amp;copy; the authors, publisher and licensee Libertas Academica Limitedopen

A randomized, phase II study of gefitinib alone versus nimotuzumab plus gefitinib after platinum-based chemotherapy in advanced non-small cell lung cancer (KCSG LU12-01)

We aimed to evaluate the efficacy of dual inhibition of epidermal growth factor receptor (EGFR) with nimotuzumab (EGFR monoclonal antibody) plus gefitinib (EGFR-tyrosine kinase inhibitor) in advanced non-small cell lung cancer (NSCLC) after platinum-based chemotherapy. An open label, randomized, phase II trial was conducted at 6 centers; 160 patients were randomized (1:1) to either gefitinib alone or nimotuzumab (200 mg, i. v. weekly) plus gefitinib (250 mg p. o. daily) until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS) at 3 months. Of the total 160 enrolled patients, 155 (77: gefitinib, 78: nimotuzumab plus gefitinib) received at least one dose and could be evaluated for efficacy and toxicity. The majority had adenocarcinoma (65.2%) and ECOG performance status of 0 to 1 (83.5%). The median follow-up was 22.1 months, and the PFS rate at 3 months was 48.1% in gefitinib and 37.2% in nimotuzumab plus gefitinib (P = not significant, NS). The median PFS and OS were 2.8 and 13.2 months in gefitinib and 2.0 and 14.0 months in nimotuzumab plus gefitinib. Combined treatment was not associated with superior PFS to gefitinib alone in patients with EGFR mutation (13.5 vs. 10.2 months in gefitinib alone, P=NS) or those with wild-type EGFR (0.9 vs. 2.0 months in gefitinib alone, P=NS). Combined treatment did not increase EGFR inhibition-related adverse events with manageable toxicities. The dual inhibition of EGFR with nimotuzumab plus gefitinib was not associated with better outcomes than gefitinib alone as a second-line treatment of advanced NSCLC (NCT01498562).

Rapid and Sensitive Detection of Lung Cancer Biomarker Using Nanoporous Biosensor Based on Localized Surface Plasmon Resonance Coupled with Interferometry

We propose a nanobiosensor to evaluate a lung cancer-specific biomarker. The nanobiosensor is based on an anodic aluminum oxide (AAO) chip and functions on the principles of localized surface plasmon resonance (LSPR) and interferometry. The pore-depth of the fabricated nanoporous AAO chip was 1 µm and was obtained using a two-step electrochemical anodization process. The sensor chip is sensitive to the refractive index (RI) changes of the surrounding medium and also provides simple and label-free detection when specific antibodies are immobilized on the gold-deposited surface of the AAO chip. In order to confirm the effectiveness of the sensor, the antibodies were immobilized on the surface of the AAO chip, and the lung cancer-specific biomarker was applied atop of the immobilized-antibody layer using the self-assembled monolayer method. The nanoporous AAO chip was used as a sensor system to detect serum amyloid A1, which is a lung cancer-specific biomarker. The specific reaction of the antigen-antibody contributes to the change in the RI. This in turn causes a shift in the resonance spectrum in the refractive interference pattern. The limit of detection (LOD) was found to be 100 ag/mL and the biosensor had high sensitivity over a wide concentration range

Safety and Efficacy of Dacomitinib in Korean Patients with KRAS Wild-Type Advanced Non–Small-Cell Lung Cancer Refractory to Chemotherapy and Erlotinib or Gefitinib: A Phase I/II Trial

IntroductionDacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor ([HER]-1/EGFR, HER-2, and HER-4) tyrosine kinase inhibitor, demonstrated antitumor activity in Western patients with non–small-cell lung cancer (NSCLC) at a dose of 45 mg once daily. We report data from a phase I/II, multicenter, open-label study of Korean patients with refractory KRAS wild-type adenocarcinoma NSCLC (defined as patients with evidence of disease progression during or within 6 months of treatment with chemotherapy and gefitinib or erlotinib).MethodsThe phase I dose-finding portion identified the recommended phase II dose (RP2D) in Korean patients, evaluated safety, and characterized the pharmacokinetics of dacomitinib. In the phase II portion, patients received dacomitinib at the RP2D. The primary end point was progression-free survival at 4 months (PFS4m).ResultsTwelve patients enrolled in phase I, and 43 patients enrolled in phase II at the RP2D of 45 mg once daily. In phase II, PFS4m was 47.2% (95% confidence interval [CI], 31.6–61.3; one-sided p-value = 0.0007). Median PFS was 15.4 weeks (95% CI, 9.7–17.6); median overall survival was 46.3 weeks (95% CI, 32.7–not reached); and the objective response rate was 17.1% (95% CI, 7.2–32.1). Common treatment-related adverse events were dermatitis acneiform, diarrhea, and paronychia; there were no treatment-related grade 4 or 5 adverse events. Pharmacokinetic parameters of dacomitinib in Korean patients were similar to those reported in Western patients. By patient report, NSCLC symptoms “cough” and “pain” showed improvement within 3 weeks of initiating treatment.ConclusionsDacomitinib was well tolerated and had antitumor activity in Korean patients with NSCLC who had previously progressed on chemotherapy and an epidermal growth factor receptor tyrosine kinase inhibitor

Necessity of Radical Hysterectomy for Endometrial Cancer Patients with Cervical Invasion

To determine whether radical hysterectomy is necessary in the treatment of endometrial cancer patients with cervical involvement, we reviewed the medical records of women who underwent primary surgical treatment for endometrial carcinoma and selected patients with pathologically proven cervical invasion. Among 133 patients, 62 patients underwent extrafascial hysterectomy (EH) and 71 radical or modified radical hysterectomy (RH). The decision regarding EH or RH was made at the discretion of the attending surgeon. The sensitivity of pre-operative magnetic resonance imaging for cervical invasion was 44.7% (38/85). In RH patients, 10/71 (14.1%) patients had frankly histologic parametrial involvement (PMI). All were stage III or over. Eight of 10 patients had pelvic/paraaortic node metastasis and two showed extrauterine spread. In 74 patients with stage II cancer, RH was performed in 41 and PMI was not seen. Sixty-six (89.2%) patients had adjuvant radiation therapy and there were 3 patients who had developed recurrent disease in the RH group and none in the EH group (Mean follow-up: 51 months). Although these findings cannot conclusively refute or support the necessity of radical hysterectomy in patients with cervical extension, it is noteworthy that the risk of PMI seems to be minimal in patients with a tumor confined to the uterus without evidence of extrauterine spread

Yoga Training Improves Metabolic Parameters in Obese Boys

Yoga has been known to have stimulatory or inhibitory effects on the metabolic parameters and to be uncomplicated therapy for obesity. The purpose of the present study was to test the effect of an 8-week of yoga-asana training on body composition, lipid profile, and insulin resistance (IR) in obese adolescent boys. Twenty volunteers with body mass index (BMI) greater than the 95th percentile were randomly assigned to yoga (age 14.7±0.5 years, n=10) and control groups (age 14.6±1.0 years, n=10). The yoga group performed exercises three times per week at 40~60% of heart-rate reserve (HRR) for 8 weeks. IR was determined with the homeostasis model assessment of insulin resistance (HOMA-IR). After yoga training, body weight, BMI, fat mass (FM), and body fat % (BF %) were significantly decreased, and fat-free mass and basal metabolic rate were significantly increased than baseline values. FM and BF % were significantly improved in the yoga group compared with the control group (p\u3c0.05). Total cholesterol (TC) was significantly decreased in the yoga group (p\u3c0.01). HDL-cholesterol was decreased in both groups (p\u3c0.05). No significant changes were observed between or within groups for triglycerides, LDL-cholesterol, glucose, insulin, and HOMA-IR. Our findings show that an 8-week of yoga training improves body composition and TC levels in obese adolescent boys, suggesting that yoga training may be effective in controlling some metabolic syndrome factors in obese adolescent boys

Ribosomal Protein s15 Phosphorylation Mediates LRRK2 Neurodegeneration in Parkinson’s Disease

SummaryMutations in leucine-rich repeat kinase 2 (LRRK2) are a common cause of familial and sporadic Parkinson’s disease (PD). Elevated LRRK2 kinase activity and neurodegeneration are linked, but the phosphosubstrate that connects LRRK2 kinase activity to neurodegeneration is not known. Here, we show that ribosomal protein s15 is a key pathogenic LRRK2 substrate in Drosophila and human neuron PD models. Phosphodeficient s15 carrying a threonine 136 to alanine substitution rescues dopamine neuron degeneration and age-related locomotor deficits in G2019S LRRK2 transgenic Drosophila and substantially reduces G2019S LRRK2-mediated neurite loss and cell death in human dopamine and cortical neurons. Remarkably, pathogenic LRRK2 stimulates both cap-dependent and cap-independent mRNA translation and induces a bulk increase in protein synthesis in Drosophila, which can be prevented by phosphodeficient T136A s15. These results reveal a novel mechanism of PD pathogenesis linked to elevated LRRK2 kinase activity and aberrant protein synthesis in vivo