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Background: The antifibrotic drugs, nintedanib and pirfenidone, inhibit the decline in forced vital capacity in patients with idiopathic pulmonary fibrosis (IPF). Nintedanib also inhibits the onset of acute exacerbation and reduces the risk of all-cause mortality. However, their effectiveness in real-world practice remains unclear. Our study aimed to investigate the changes in forced vital capacity, survival period, causes of death, and risk factors for mortality in patients with IPF receiving antifibrotic drugs. Methods: This retrospective study enrolled Japanese patients who visited Toho University Sakura Medical Center who were diagnosed with IPF and received antifibrotic drugs. Results: We included 102 patients [mean age ± standard deviation (SD): 71.8 ± 7.5 years], of whom 76 were males. The decline in forced vital capacity (mean ± SD) during the antifibrotic therapy period was − 154 ± 259 mL/year, which was significantly lower than before the antifibrotic therapy period (− 484 ± 589 mL/year; n = 80, p = 0.003). Altogether, 52 deaths were confirmed, and the median survival time from antifibrotic therapy initiation was 38.0 months (95% confidence interval: 25.9–50.1 months). Acute exacerbation accounted for 9.6% of all deaths (95% confidence interval: 1.6–17.6). The decline in forced vital capacity during antifibrotic therapy was a risk factor for mortality. Conclusions: In actual clinical practice in Japan, antifibrotic drugs suppressed the gradual decline in forced vital capacity, which is a risk factor for mortality. However, the median survival period remained poor at 38 months. [ABSTRACT FROM AUTHOR]

Both lung carcinoma and idiopathic pulmonary fibrosis (IPF) have an adverse prognosis, and the co-existence of both diseases is not uncommon. We introduce a clinical case involving a patient diagnosed with concurrent occurrences of lung adenocarcinoma and IPF. The patient underwent a therapeutic regimen comprising the administration of docetaxel in conjunction with nintedanib. This treatment approach was followed by the sustained utilization of maintenance nintedanib over an extended duration, leading to substantial enhancements in the patient’s quality of life. Furthermore, we discuss the few therapeutic options concerning this clinical challenge and possible future therapeutic options. [ABSTRACT FROM AUTHOR]

Although anti-angiogenic agents have been of limited use in the treatment of non-small cell lung cancer (NSCLC) until recently, further roles for the use of angiogenesis inhibition have emerged in the era of targeted therapy and immune checkpoint blockade. Given the shared common downstream signals of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) with their complementary roles in tumorigenesis and tumor angiogenesis, the dual inhibition of EGFR and VEGF pathways represents a rational strategy to maximize clinical efficacy and overcome resistance in the treatment of EGFR-mutant NSCLC. VEGF-driven angiogenesis is a potent driver of immunosuppressive tumor microenvironment (TME), with the recruited immunosuppressive cells driving angiogenesis, highlighting the interplay between the tumor vasculature and the anticancer immunity. Anti-angiogenic therapy can normalize the tumor vasculature and reprogram the TME from immunosuppressive into immunosupportive. Intensive research is under way to utilize the anti-angiogenic combination therapy to its full potential in diverse clinical settings in urgent unmet needs for the treatment of NSCLC. In this review, we present an overview of tumor angiogenesis and summarize the scientific background and preclinical and clinical evidence of anti-angiogenic therapy in combination with target therapy and immunotherapy for the treatment of NSCLC. [ABSTRACT FROM AUTHOR]

Background: Idiopathic pulmonary fibrosis (IPF) is the most common type of interstitial pneumonia. Lung cancer, mainly non-small cell lung cancer (NSCLC), is a complication of idiopathic pulmonary fibrosis. IPF is also an independent risk factor of lung cancer. Some studies have shown that the complement system can promote the progression of interstitial pulmonary fibrosis. In addition, C1q has also demonstrated to exert a tumor-promoting effect in many tumors. However, the role of C1q in idiopathic pulmonary fibrosis and lung cancer still remain unclear. Methods: We selected common differentially expressed genes in IPF and non-small cell lung cancer using datasets from GEO, and investigated common hub gene. The hub genes were validated in IPF by establishing mouse model of IPF and using another four datasets from the GEO. Multiple databases were analyzed including those of Kaplan–Meier Plotter, Tumor Immune Estimation Resource (TIMER2.0) and the Human Protein Atlas (HPA) for NSCLC. Results: In this study, 37 common DEGs were identified in IPF and NSCLC including 32 up-regulated genes and 5 down-regulated genes, and C1q was identified as common hub gene. The methylation status of C1q decreased and the expression levels of C1q increased in both lung cancer and idiopathic pulmonary fibrosis. The prognosis of non-small cell lung cancer and IPF patients with high levels of C1q is poor. Conclusions: These results show that C1q participates in pulmonary fibrosis and non-small cell lung cancer, and may be a potential diagnostic / prognostic biomarker or a therapeutic target. [ABSTRACT FROM AUTHOR]

Copyright of Farmacia is the property of Societatea de Stiinte Farmaceutice Romania and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Apatinib is an oral TKI with antiangiogenic properties, and it is currently approved for the treatment of advanced gastric cancer in China. This agent has also been tested in other human solid tumors, including non-small cell lung cancer (NSCLC). Since the combination of chemotherapy and an antiangiogenic agent has been shown to be a feasible strategy in NSCLC, it is conceivable that a similar approach combining apatinib with chemotherapy may yield clinical activity. With this in mind, we investigated the efficiency of apatinib in combination with pemetrexed or docetaxel in advanced NSCLC. We treated a total of 20 patients with metastatic NSCLC adenocarcinoma with apatinib in combination with either pemetrexed or docetaxel from January 2016 to March 2017. The performance status of these patients was 0 or 1. All of these patients had been previously treated with two or more lines of treatment and had experienced disease progression prior to study enrollment. The overall objective response rate (ORR) was 30%, with 6 patients who had partial response (PR), 10 patients who had stable disease (SD), and 4 patients who had progressive disease (PD). The main adverse events were skin rash, hypertension, palmar-plantar erythrodysesthesia syndrome, diarrhea, and fatigue. Nearly 30% of patients required interruption of treatment as a result of toxicity. Our study demonstrated that apatinib combined with systemic cytotoxic chemotherapy has clinical efficacy in patients with disease-refractory metastatic NSCLC and provides evidence for further studies investigating apatinib-based combination regimens. [ABSTRACT FROM AUTHOR]

Summary: Introduction Vatalanib is an oral receptor tyrosine kinase inhibitor that blocks all known VEGF, PDGF, and c-Kit receptors. This phase I study evaluated the safety, tolerability, and biologic activity of the combination of vatalanib with pemetrexed disodium in patients with advanced solid tumors. Methods Patients were administered escalating twice daily doses of vatalanib in combination with pemetrexed disodium in 21-day cycles. A dose expansion cohort was enrolled to further define the maximum tolerated dose (MTD) and further evaluate efficacy. Results A total of 29 patients were enrolled in the study (dose escalation, 9; dose expansion, 20). Dose-limiting toxicities included grade 4 thrombocytopenia (6.9%) and febrile neutropenia, anorexia, constipation, and dehydration. Other common adverse events were fatigue (75%), nausea (66%), vomiting (48%), oral mucositis (31%) and diarrhea (28%). The majority of these toxicities were Grade 1–2. The MTD was reached at vatalanib 250 mg twice daily continuously combined with pemetrexed disodium 500 mg/m2 day 1. Overall, 2 patients (6.9%) had partial responses, 8 (27.6%) had stable disease for at least 4 cycles, 5 had progressive disease (17.2%) and 5 went off study before disease assessment. Conclusion The combination of vatalanib with pemetrexed disodium was feasible, but not well tolerated. The modest efficacy results are consistent with other results obtained from combinations of chemotherapy and a large number of VEGF tyrosine kinase inhibitors. This combination should not be developed further unless predictive biomarkers can be identified. [ABSTRACT FROM AUTHOR]

Objectives: Anti-angiogenic agents are reported to exert clinical activity on epidermal growth factor receptor (EGFR) mutant non-small-cell lung cancers. We evaluated the clinical outcomes of nintedanib and docetaxel in refractory NSCLC according to EGFR mutation status during the Korean nintedanib named patient program. Methods: Docetaxel was administered either 75 or 37.5 mg/m2 on D1, D8 q every 3 weeks for 4–6 cycles plus nintedanib 200 mg orally twice daily until disease progression or unacceptable toxicity. Results: Sixty-two patients were enrolled for study. Twenty-eight patients with activating EGFR mutations progressed after EGFR-tyrosine kinase inhibitors (TKI) therapy and 25 out of 28 patients showing progression after platinum doublet chemotherapy were enrolled. The objective response rate was 29% and median PFS and OS were 3.9 months and 11.7 months. Based on the EGFR mutation status, the objective response rate was 39.3 vs. 21.9% (EGFR mut(+) vs. EGFR mut(–), p = 0.142) and median PFS was 6.5 vs. 3.3 months (EGFR mut(+) vs. EGFR mut(–), p = 0.009). No treatment-related deaths were reported. The most frequent drug-related adverse events (AE) were neutropenia (53.2%) and diarrhea (37.1%). Treatment in 12 patients (19.3%) was permanently discontinued due to AEs without disease progression. Conclusions: Our data indicated that nintedanib-docetaxel combination could be considered to be effective treatment in EGFR TKI-resistant EGFR mutant NSCLC. [ABSTRACT FROM AUTHOR]

Background: A sequential approach, synchronizing cell-cycle specific chemotherapy during VEGFR-TKI treatment breaks, may improve the therapeutic index of this combination therapy. In this study we investigate the safety/tolerability and pharmacodynamic effects of docetaxel used in sequential combination with the novel VEGFR-TKI X-82.Methods: Patients with advanced solid malignancies underwent 21-day treatment cycles with X-82 administered daily on days 1-14, a treatment break on days 15-20, and docetaxel administered on day 21. Randomization was 1:1 to either a low-dose X-82 (200 mg) or high-dose X-82 (400 mg) arm. Patients were scheduled to undergo four 3'-deoxy-3'-18F-fluorothymidine (FLT) PET/CT scans to assess changes in tumor cell proliferation. PET standardized uptake values (SUV) were summarized for tumors and changes were assessed using mixed effects models.Results: 14 patients were enrolled and treated with median 3.5 cycles (range 0-12). Three patients in the high-dose cohort (50%) and three patients in the low-dose cohort (38%) experienced at least one grade 3 adverse event during the study (infections, cytopenias, electrolyte abnormalities, and vascular complications). Four patients with 13 metastatic tumors underwent FLT PET/CT scanning. During the cycle 1 X-82 exposure period, tumor SUVmax decreased by - 11% (p = 0.04). After administration of docetaxel and the cycle 2 X-82 exposure period, tumor SUVmax decreased - 44% (p = 0.03).Conclusions: The sequential combination of X-82 and docetaxel was safe and led to diminished FLT uptake. Further, decrease in FLT uptake during cycle 2 (X-82 plus docetaxel) was greater than in cycle 1 (X-82 alone), suggesting sequential chemotherapy enhances the pharmacodynamic effect of therapy. [ABSTRACT FROM AUTHOR]

Copyright of Polish Journal of Thoracic & Cardiovascular Surgery / Kardiochirurgia i Torakochirurgia Polska is the property of Termedia Publishing House and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Angiogenesis, the process leading to the formation of new blood vessels, is one of the hallmarks of cancer. Extensive studies established that i) vascular endothelial growth factor (VEGF) is a key driver of sprouting angiogenesis, ii) VEGF is overexpressed in most solid cancers, and iii) inhibition of VEGF can suppress tumor growth in animal models. This has led to the development of pharmacological agents for anti-angiogenesis to disrupt the vascular supply and starve the tumor of nutrients and oxygen, primarily through the blockade of VEGF/VEGF receptor signaling. This effort has resulted in 11 anti-VEGF drugs approved for certain advanced cancers, either alone or in combination with chemotherapy and other targeted therapies. However, inhibition of VEGF signaling is not effective in all cancers, and anti-angiogenics have often only limited impact on overall survival of cancer patients. This review focuses on the current status of FDA-approved anti-angiogenic antibodies and tyrosine kinase inhibitors and summarizes the progress and future directions of VEGF-targeted therapy. [ABSTRACT FROM AUTHOR]

Purpose: A population pharmacokinetic model was developed for nintedanib in patients with non-small cell lung cancer (NSCLC) or idiopathic pulmonary fibrosis (IPF). The effects of intrinsic and extrinsic patient factors on exposure of nintedanib and its main metabolite BIBF 1202 were studied.Methods: Data from 1191 patients with NSCLC (n = 849) or IPF (n = 342) treated with oral nintedanib (once- or twice-daily, dose range 50-250 mg) in 4 Phase II or III studies were combined. Plasma concentrations of nintedanib (n = 5611) and BIBF 1202 (n = 5376) were analyzed using non-linear mixed-effects modeling.Results: Pharmacokinetics of nintedanib were described by a one-compartment model with linear elimination, first-order absorption, and absorption lag time. For a typical patient, the absorption rate was 0.0827 h-1, apparent total clearance was 897 L/h, apparent volume of distribution at steady state was 465 L, and lag time was 25 min. Age, weight, smoking, and Asian race were statistically significant covariates influencing nintedanib exposure, but no individual covariate at extreme values (5th and 95th percentiles of baseline values for continuous covariates) resulted in a change of more than 33% relative to a typical patient. Pharmacokinetics and covariate effects for BIBF 1202 were similar to nintedanib. Mild or moderate renal impairment and mild hepatic impairment (classified by transaminase or bilirubin increase above the upper limit of normal) or underlying disease had no significant effects on nintedanib pharmacokinetics.Conclusions: This model adequately described the pharmacokinetic profile of nintedanib in NSCLC and IPF populations and can be used for simulations exploring covariate effects and exposure-response analyses. [ABSTRACT FROM AUTHOR]

Background AZD4547 is a potent, oral, highly selective fibroblast growth factor receptor (FGFR) inhibitor in clinical development for treating tumours with a range of FGFR aberrations, including FGFR mutations, amplifications and fusions. Methods This open-label, Phase I, multicentre study (NCT01213160) evaluated the safety, pharmacokinetics, and preliminary antitumour efficacy (RECIST v1.1) of AZD4547 monotherapy in Japanese patients with advanced solid tumours. Part A was a dose-escalation part; Part B was a dose-expansion part in patients with FGFR-amplified tumours, confirmed by fluorescence in situ hybridization. Results Thirty patients enrolled in Part A (dose range: 40 mg twice daily [bid] to 120 mg bid; 160 mg once daily [qd]), four in Part B (80 mg bid). No dose-limiting toxicities were observed and maximum tolerated dose was not determined. Most common adverse events (AEs; any grade) were: dysgeusia (50% of patients); stomatitis (41%); diarrhoea (38%); hyperphosphataemia (38%); dry mouth (35%). Common grade ≥3 AEs were nausea (12% of patients) and neutropenia (9%). No complete or partial responses were observed: 21/30 patients had stable disease ≥4 weeks in Part A, and 1/4 patients had stable disease ≥10 weeks in Part B. Following single and multiple dosing, absorption rate appeared moderate; peak plasma concentrations generally occurred 3-4 h post-dose, then declined biphasically with terminal half-life ~30 h. Steady state was reached by day 8. Compared with single dosing, plasma concentrations were, on average, 2.4- and 3.3- to 5.4-fold higher after qd and bid dosing, respectively. Conclusions AZD4547 was well tolerated in Japanese patients, with best response of stable disease ≥4 weeks. [ABSTRACT FROM AUTHOR]

Within this retrospective single-center study, we analyzed the survival of 320 multiple myeloma (MM) patients receiving melphalan high-dose chemotherapy (HDCT) and either single (n = 286) or tandem (n = 34) autologous stem cell transplantation (ASCT) from 1996 to 2012. Additionally, the impact of novel induction regimens was assessed. Median follow-up was 67 months, median overall survival (OS) 62 months, median progression-free survival (PFS) 33 months (95% CI 27-39), and treatment-related death (TRD) 3%. Multivariate analysis revealed age ≥ 60 years ( p = 0.03) and stage 3 according to the International Staging System (p = 0.006) as adverse risk factors regarding PFS. Median OS was significantly better in newly diagnosed MM patients receiving induction therapy with novel agents, e.g., bortezomib, thalidomide, or lenalidomide, compared with a traditional regimen (69 vs. 58 months; p = 0.01). More patients achieved at least a very good partial remission in the period from 2005 to 2012 than from 1996 to 2004 (65 vs. 30%; p < 0.001), with a longer median OS in the later period (71 vs. 52 months, p = 0.027). In conclusion, our analysis confirms HDCT-ASCT as an effective therapeutic strategy in an unselected large myeloma patient cohort with a low TRD rate and improved prognosis due to novel induction strategies. [ABSTRACT FROM AUTHOR]

Objectives To determine the recommended dose and efficacy/safety of docetaxel combined with resminostat (DR) in non-small cell lung cancer (NSCLC) patients with previous platinum-based chemotherapy. Materials and Methods A multicenter, open-label, phase I/II study was performed in Japanese patients with stage IIIB/IV or recurrent NSCLC and prior platinum-based chemotherapy. The recommended phase II dose was determined using a standard 3 + 3 dose design in phase I part. Resminostat was escalated from 400 to 600 mg/day and docetaxel fixed at 75 mg/m. In phase II part, the patients were randomly assigned to docetaxel alone (75 mg/m) or DR therapy. Docetaxel was administered on day 1 and resminostat on days 1-5 in the DR group. Treatment was repeated every 21 days until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Results A total of 117 patients (phase I part, 9; phase II part, 108) were enrolled. There was no dose-limiting toxicity in phase I part; the recommended dose for resminostat was 600 mg/day with 75 mg/m of docetaxel. In phase II part, median PFS (95% confidence interval [CI]) was 4.2 (2.8-5.7) months with docetaxel group and 4.1 (1.5-5.4) months with DR group (hazard ratio [HR]: 1.354, 95% CI: 0.835-2.195; p = 0.209). Grade ≥ 3 adverse events significantly more common with DR group than docetaxel group were leukopenia, febrile neutropenia, thrombocytopenia, and anorexia. Conclusion In Japanese NSCLC patients previously treated with platinum-based chemotherapy, DR therapy did not improve PFS compared with docetaxel alone and increased toxicity. [ABSTRACT FROM AUTHOR]

Fibroblast growth factors (FGFs) constitute a large family of polypeptides that are involved in many biological processes, ranging from prenatal cell-fate specification and organogenesis to hormonal and metabolic regulation in postnatal life. During embryonic development, these growth factors are important mediators of the crosstalk among ectoderm-, mesoderm-, and endoderm-derived cells, and they instruct the spatial and temporal growth of organs and tissues such as the brain, bone, lung, gut, and others. The involvement of FGFs in postnatal lung homeostasis is a growing field, and there is emerging literature about their roles in lung pathophysiology. In this review, the involvement of FGF signaling in a wide array of lung diseases will be summarized. Developmental Dynamics 246:235-244, 2017. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Purpose: The clinical features of patients with advanced non-small cell lung cancer (NSCLC) and interstitial lung disease (ILD) have not fully been elucidated. This study aimed to investigate the clinical features of these patients, particularly with idiopathic pulmonary fibrosis (IPF). Methods: Data on 218 patients with pathologically confirmed diagnoses of NSCLC who had been treated with chemotherapy and/or molecular targeted therapy were retrospectively analyzed for progression-free survival (PFS), overall survival (OS), responses to first-line therapy, and incidence of acute exacerbations (AEs). Results: Fifty-three of the 218 patients were diagnosed with ILD, and 34 of them with IPF. The frequency of epidermal growth factor receptor ( EGFR) mutation was significantly lower in ILD and IPF patients than in non-ILD patients (2 or 0 vs. 32 %, respectively). Median PFS and OS were significantly shorter in both ILD and IPF patients than in non-ILD patients (118, 92, and 196 days for PFS, and 267, 223, and 539 days for OS, respectively). Multivariate analysis showed that poor performance status, absence of EGFR mutation, and presence of IPF were poor prognostic factors for PFS and OS. Disease control rate (DCR) was significantly lower in ILD and IPF patients than in non-ILD patients regardless of the presence of EGFR mutation (67 or 53 vs. 85 %, respectively). The incidence of AEs of ILD was significantly higher during chemotherapy with docetaxel-containing regimens (seven of 38; 18.4 %). Conclusions: Both IPF and ILD were associated with lower EGFR positivity, lower DCR, and shorter PFS and OS in advanced NSCLC patients. [ABSTRACT FROM AUTHOR]

Background: Multiple myeloma is a plasma cell tumour with an annual incidence in the UK of approximately 40-50 per million i.e. about 4500 new cases per annum. The triple combination cyclophosphamide, bortezomib (Velcade®) and dexamethasone (CVD) is an effective regimen at relapse and has emerged in recent years as the standard therapy at first relapse in the UK. Carfilzomib has good activity as a single agent in the relapsed setting, and it is expected that efficacy will be improved when used in combination with dexamethasone and cyclophosphamide. Methods: MUK Five is a phase II open label, randomised, controlled, parallel group, multi-centre trial that will compare the activity of carfilzomib, cyclophosphamide and dexamethasone (CCD) with that of CVD, given over an equivalent treatment period (24 weeks), in participants with multiple myeloma at first relapse, or refractory to no more than 1 line of treatment. In addition, the study also aims to assess the utility of a maintenance schedule of carfilzomib in these participants. The primary objective of the trial is to assess whether CCD provides non-inferior activity in terms of ⩾ VGPR rates at 24 weeks, and whether the addition of maintenance treatment with carfilzomib to CCD provides superior activity in terms of progression-free survival, as compared to CCD with no maintenance. Secondary objectives include comparing toxicity profiles, further summarizing and comparing the activity of the different treatment arms and analysis of the effect of each treatment arm on minimal residual disease status. Discussion: The development of carfilzomib offers the opportunity to further explore the anti-tumour efficacy of proteasome inhibition and, based on the available evidence, it is important and timely to obtain data on the activity, toxicity and tolerability of this drug. In contrast to ongoing phase III trials, this phase II trial has a unique subset of participants diagnosed with multiple myeloma at first relapse or refractory to no more than 1 line of treatment and will also evaluate the utility of maintenance with carfilzomib for up to 18 months and investigate minimal residual disease status to provide information on depth of response and the prognostic impact thereof. [ABSTRACT FROM AUTHOR]

Background: This exploratory study evaluated the safety/efficacy of nintedanib or sunitinib as first-line therapy in patients with advanced renal cell carcinoma (RCC).Methods: Ninety-six patients were randomised (2:1) to either nintedanib (200 mg twice daily) or sunitinib (50 mg kg(-1) once daily (4 weeks on treatment; 2 weeks off)). Primary endpoint was progression-free survival (PFS) at 9 months. P-values reported are descriptive only; the study was not powered for such comparisons.Results: Progression-free survival at 9 months was comparable between nintedanib and sunitinib (43.1% vs 45.2%, respectively; P=0.85). Median PFS was 8.4 months in each group (hazard ratio (HR), 1.12; 95% confidence interval (CI): 0.70-1.80; P=0.64). Median overall survival was 20.4 and 21.2 months for nintedanib and sunitinib, respectively (HR, 0.92; 95% CI: 0.54-1.56; P=0.76). Overall incidence of any grade adverse events (AEs) was comparable (90.6% vs 93.8%); AEs grade ⩾ 3 were lower with nintedanib than sunitinib (48.4% vs 59.4%). Nintedanib was associated with lower incidences of some AEs typical of antiangiogenic tyrosine kinase inhibitors (TKIs): hypertension, hypothyroidism, hand-foot syndrome, cardiac disorders and haematological abnormalities.Conclusions: In patients with advanced RCC, nintedanib has promising efficacy and similar tolerability to sunitinib, and a manageable safety profile with fewer TKI-associated AEs. [ABSTRACT FROM AUTHOR]

Purpose: The role of second-line chemotherapy in patients with non-small cell lung cancer (NSCLC) and preexisting interstitial pneumonia (IP) previously treated with platinum-based chemotherapy remains uncertain. This study was conducted to elucidate the efficacy and tolerability of second-line docetaxel monotherapy for patients with platinum-refractory advanced (stage IIIB, IV, or relapse) NSCLC and preexisting IP. Methods: A total of 35 patients (median age, 67 years) treated with docetaxel monotherapy in a second-line setting following first-line platinum-based chemotherapy between January 2002 and December 2013 were retrospectively reviewed. Results: The overall response rate and disease control rate were 8.6 % [95 % confidence interval (CI) 0-17.9 %] and 37.1 % (95 % CI 21.1-53.1 %), respectively. The median progression-free survival and median overall survival periods were 1.6 months (95 % CI 1.2-2.0 months) and 5.1 months (95 % CI 3.2-6.7 months), respectively. The incidence of acute exacerbation (AE) of IP following docetaxel monotherapy was 14.3 % (5/35 patients). Of the five patients who developed AE of IP, three patients died. The toxicity of this regimen was substantial, with treatment-related deaths occurring in 5 (14.3 %) patients (AE of IP: 3, sepsis: 2). Conclusions: Docetaxel monotherapy has a poor activity and substantial risks when used for the treatment of platinum-resistant NSCLC with IP. Novel therapeutic approaches should be explored in this setting. [ABSTRACT FROM AUTHOR]

To identify predictive biomarkers for clinical responses to bortezomib treatment, 0.06 mL of each whole blood without any cell separation procedures was stimulated ex vivo using five agents, and eight mRNAs were quantified. In six centers, heparinized peripheral blood was prospectively obtained from 80 previously treated or untreated, symptomatic multiple myeloma (MM) patients with measurable levels of M-proteins. The blood sample was procured prior to treatment as well as 2-3 days and 1-3 weeks after the first dose of bortezomib, which was intravenously administered biweekly or weekly, during the first cycle. Six stimulant-mRNA combinations; that is, lipopolysaccharide (LPS)-granulocyte-macrophage colony-stimulating factor (GM-CSF), LPS-CXCL chemokine 10 (CXCL10), LPS-CCL chemokine 4 (CCL4), phytohemagglutinin-CCL4, zymosan A (ZA)-GMCSF and ZA-CCL4 showed significantly higher induction in the complete and very good partial response group than in the stable and progressive disease group, as determined by both parametric (t-test) and non-parametric (unpaired Mann-Whitney test) tests. Moreover, LPS-induced CXCL10 mRNA expression was significantly suppressed 2-3 days after the first dose of bortezomib in all patients, as determined by both parametric (t-test) and non-parametric (paired Wilcoxon test) tests, whereas the complete and very good partial response group showed sustained suppression 1-3 weeks after the first dose. Thus, pretreatment LPS-CXCL10 mRNA and/or the six combinations may serve as potential biomarkers for the response to bortezomib treatment in MM patients. [ABSTRACT FROM AUTHOR]

Bevacizumab is FDA-approved for patients with recurrent GBM. However, the median duration of response is only 4 months. Potential mechanisms of resistance include upregulated FGF signaling and increased PDGF-mediated pericyte coverage. Nintedanib is an oral, small-molecule tyrosine kinase inhibitor of PDGFR α/β, FGFR 1-3, and VEGFR 1-3 that may overcome resistance to anti-VEGF therapy. This was a two-stage phase II trial in adults with first or second recurrence of GBM, stratified by prior bevacizumab therapy (ClinicalTrials.gov number NCT01380782; 1199.94). The primary endpoint was PFS6 in the bevacizumab-naive arm (Arm A) and PFS3 in the post-bevacizumab arm (Arm B). Up to 10 anaplastic glioma (AG) patients were accrued to each arm in exploratory cohorts. Twenty-two patients enrolled in Arm A and 14 in Arm B. Arm A included 12 GBMs (55 %), 13 patients with one prior regimen (59 %), and median age 54 years (range 28-75). Arm B included 10 GBMs (71 %), one patient with one prior regimen (7 %), and median age 52 years (range 32-70). Median KPS overall was 90 (range 60-100). There were no responses. In Arm A (GBM only), PFS6 was 0 %, median PFS 28 days (95 % CI 27-83), and median OS 6.9 months (3.7-8.1). In Arm B (GBM only), PFS3 was 0 %, median PFS 28 days (22-28), and median OS 2.6 months (1.0-6.9). Among AG patients in each arm, PFS6 was 0 %. Treatment was well tolerated. In conclusion, nintedanib is not active against recurrent high-grade glioma, regardless of prior bevacizumab therapy. [ABSTRACT FROM AUTHOR]

Objectives In vitro studies have shown synergistic anti-myeloma effects of bortezomib combined with alkylating agents or anthracycline. We tested safety and efficacy of the combination of bortezomib, doxorubicin cyclophosphamide, and dexamethasone ( ABCD) in the treatment of relapsed/refractory myeloma. Methods ABCD consisted of bortezomib given intravenous ( IV) at dosage 1.3 mg/m2, dexamethasone 40 mg IV on days 1, 4, 8, and 15, pegylated liposomal doxorubicin ( PLD) 20 mg IV on days 1 and 15, plus cyclophosphamide 100 mg/d per os for 15 d. Between January 2008 and February 2009, 24 patients received a median of four 28-d ABCD cycles (range 1-6). All patients had been already treated with a median of two previous lines of treatment (range 1-6): 38% were resistant to previous therapies and 62% were relapsed. Results Clinical response was observed in 12 patients (50%), including 29% of very good partial remissions or better. Side effects included hematological toxicity (31% any grade), grades 3-4 thrombocytopenia (9%), grades 3-4 anemia (17%). Non-hematological toxicity affected 32% of administered cycles and included gastrointestinal disturbances (54%), peripheral neuropathy (8%), and infections (8%). After a median follow-up of 21.5 months (range 2-44 months), median of progression-free survival ( PFS) was 8.7 months and median overall survival was 22.5 months. Achieving at least partial response within the second cycle was associated with a better PFS (19.5 months vs. 3.5 months), P = 0.03, HR 0.35 ( CI 95% 0.13-0.90). Conclusion ABCD is safe and effective for relapsed/refractory MM subjects previously treated with novel agents. [ABSTRACT FROM AUTHOR]

We compared the clinical responses and toxicities between bortezomib-based salvage chemotherapy combined with cyclophosphamide, thalidomide, and dexamethasone (Vel-CTD) and without thalidomide (Vel-CD) in patients with relapsed or refractory MM. Eighty-six patients received at least two cycles of treatment with Vel-CTD (bortezomib 1.3 mg/m i.v. on days 1, 4, 8, and 11; cyclophosphamide 150 mg/m orally on days 1-4; thalidomide 50-100 mg/day orally every day; and dexamethasone 20 mg/m i.v. on days 1, 4, 8, and 11 every 3 weeks), and 67 patients were given at least two cycles of Vel-CD, which is the same regimen as Vel-CTD except without thalidomide. The overall response rates of the Vel-CD and Vel-CTD groups were 88% and 90% ( p > 0.05), respectively. There was no difference in the progression free survival ( p = 0.69) and overall survival rates ( p = 0.49) between the two groups. Grade 3 or more adverse hematologic events occurred in the same proportion of patients in both groups. In terms of non-hematologic toxicities, the Vel-CTD group showed a higher proportion of autonomic neuropathy, motor neuropathy, and sensory neuropathy compared to the Vel-CD group (each, p < 0.05). Only three patients in the Vel-CTD group showed thrombotic events despite aspirin prophylaxis. The Vel-CD regimen in patients with relapsed or refractory MM is an effective and more tolerable salvage therapy compared to Vel-CTD in terms of its comparable response rate and less severe of non-hematologic toxicities. [ABSTRACT FROM AUTHOR]

Targeting intracellular protein turnover by inhibiting the ubiquitin-proteasome pathway as a strategy for cancer therapy is a new addition to our chemotherapeutic armamentarium, and has seen its greatest successes against multiple myeloma. The first-in-class proteasome inhibitor, bortezomib, was initially approved for treatment of patients in the relapsed/refractory setting as a single agent, and was recently shown to induce even greater benefits as part of rationally designed combinations that overcome chemoresistance. Modulation of proteasome function is also a rational approach to achieve chemosensitization to other antimyeloma agents, and bortezomib has now been incorporated into the front-line setting. Bortezomib-based induction regimens are able to achieve higher overall response rates and response qualities than was the case with prior standards of care, and unlike these older approaches, maintain efficacy in patients with clinically and molecularly defined high-risk disease. Second-generation proteasome inhibitors with novel properties, such as NPI-0052 and carfilzomib, are entering the clinical arena, and showing evidence of antimyeloma activity. In this spotlight review, we provide an overview of the current state of the art use of bortezomib and other proteasome inhibitors against multiple myeloma, and highlight areas for future study that will further optimize our ability to benefit patients with this disease. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding the outcomes of patients suffering from multiple myeloma and renal impairment who were treated with bortezomib, cyclophosphamide, and dexamethasone.