•Bevacizumab (Avastin®), a VEGF-A targeting monoclonal antibody, was the first approved angiogenesis inhibitor.•Approved in a range of solid tumor indications, bevacizumab is an important part of the ...standard of care in oncology.•The recently identified immune modulatory roles of VEGF provide a powerful rationale for combination therapies.•First clinical studies of the combination of bevacizumab with immune checkpoint inhibitors have shown efficacy.
When the VEGF-A-targeting monoclonal antibody bevacizumab (Avastin®) entered clinical practice more than 15 years ago, it was one of the first targeted therapies and the first approved angiogenesis inhibitor. Marking the beginning for a new line of anti-cancer treatments, bevacizumab remains the most extensively characterized anti-angiogenetic treatment. Initially approved for treatment of metastatic colorectal cancer in combination with chemotherapy, its indications now include metastatic breast cancer, non-small-cell lung cancer, glioblastoma, renal cell carcinoma, ovarian cancer and cervical cancer. This review provides an overview of the clinical experience and lessons learned since bevacizumab’s initial approval, and highlights how this knowledge has led to the investigation of novel combination therapies.
In the past 15 years, our understanding of VEGF’s role in the tumor microenvironment has evolved. We now know that VEGF not only plays a major role in controlling blood vessel formation, but also modulates tumor-induced immunosuppression. These immunomodulatory properties of bevacizumab have opened up new perspectives for combination therapy approaches, which are being investigated in clinical trials. Specifically, the combination of bevacizumab with cancer immunotherapy has recently been approved in non-small-cell lung cancer and clinical benefit was also demonstrated for treatment of hepatocellular carcinoma. However, despite intense investigation, reliable and validated biomarkers that would enable a more personalized use of bevacizumab remain elusive.
Overall, bevacizumab is expected to remain a key agent in cancer therapy, both due to its established efficacy in approved indications and its promise as a partner in novel targeted combination treatments.
Previous studies have demonstrated the efficacy and safety of bevacizumab in the treatment of non-small-cell lung cancer (NSCLC).
Summary data from randomised trials comparing first-line bevacizumab ...plus platinum-based chemotherapy with chemotherapy alone for inoperable locally advanced, recurrent or metastatic NSCLC were meta-analysed. Pooled hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and pooled odds ratio (OR) for adverse events were calculated. The chi-squared tests evaluated interactions between treatment effects, and prognostic factors and patient characteristics.
Data of 2194 patients (1313 bevacizumab; 881 controls) from four phase II and III trials: AVF-0757g, JO19907, ECOG 4599 and AVAiL, were analysed. Compared with chemotherapy alone, bevacizumab significantly prolonged OS (HR 0.90; 95% confidence interval CI 0.81, 0.99; P=0.03), and PFS (0.72; 95% CI 0.66, 0.79; P<0.001). Bevacizumab showed a significantly greater effect on OS in patients with adenocarcinoma versus other histologies (P=0.02), and patients with body weight loss ≤5% versus >5% (P=0.03). Bevacizumab significantly increased the risk of grade ≥3 proteinuria, hypertension, haemorrhagic events, neutropenia, and febrile neutropenia.
Bevacizumab significantly prolonged OS and PFS when added to first-line platinum-based chemotherapy in patients with advanced NSCLC; no unexpected toxicity was evident.
A better understanding of the pathophysiology and evolution of non‐small cell lung cancer (NSCLC) has identified a number of molecular targets and spurred development of novel targeted therapeutic ...agents. The MET receptor tyrosine kinase and its ligand hepatocyte growth factor (HGF) are implicated in tumor cell proliferation, migration, invasion, and angiogenesis in a broad spectrum of human cancers, including NSCLC. Amplification of MET has been reported in approximately 5%–22% of lung tumors with acquired resistance to small‐molecule inhibitors of the epidermal growth factor receptor (EGFR). Resistance to EGFR inhibitors is likely mediated through downstream activation of the phosphoinositide 3‐kinase /AKT pathway. Simultaneous treatment of resistant tumors with a MET inhibitor plus an EGFR inhibitor can abrogate activation of downstream effectors of cell growth, proliferation, and survival, thereby overcoming acquired resistance to EGFR inhibitors. Development and preclinical testing of multiple agents targeting the HGF–MET pathway, including monoclonal antibodies targeting HGF or the MET receptor and small‐molecule inhibitors of the MET tyrosine kinase, have confirmed the crucial role of this pathway in NSCLC. Several agents are now in phase III clinical development for the treatment of NSCLC. This review summarizes the role of MET in the pathophysiology of NSCLC and in acquired resistance to EGFR inhibitors and provides an update on progress in the clinical development of inhibitors of MET for treatment of NSCLC.
摘要
随着对非小细胞肺癌（NSCLC）病理生理学和演变的深入认识，许多分子靶点得以确定，促进了新型靶向治疗药物的开发。MET受体酪氨酸激酶及其配体肝细胞生长因子（HGF）涉及一系列人类癌症（包括NSCLC）的肿瘤细胞增殖、迁移、浸润和血管生长。据报道，表皮生长因子受体（EGFR）小分子抑制剂获得性耐药的肺肿瘤中，约5%~22%出现MET扩增。EGFR抑制剂耐药可能由磷脂酰肌醇3激酶/AKT通路的下游活化介导。同步应用MET抑制剂联合EGFR抑制剂治疗耐药性肿瘤，可阻断下游激活因子对细胞生长、增殖和生存作用，由此克服EGFR抑制剂的获得性耐药。多种靶向作用于HGF‐MET通路的药物（包括靶向作用于HGF或MET受体的单克隆抗体和MET酪氨酸激酶的小分子抑制剂）的开发和临床前试验已证实，该通路在NSCLC中具有关键作用。目前，已有数种药物进入NSCLC治疗的III期临床开发。本综述总结了MET在NSCLC病理生理学和EGFR抑制剂获得性耐药中的作用，并对MET抑制剂治疗NSCLC临床开发的新进展进行了展望。
The role of MET in the pathophysiology of non‐small cell lung cancer and in acquired resistance to epidermal growth factor receptor inhibitors is summarized. An update on progress in the clinical development of inhibitors of MET for treatment of non‐small cell lung cancer is provided.
Background: E4599 was a phase II/phase III trial, in which 878 patients with advanced non–small cell lung cancer were randomized to carboplatin
+ paclitaxel (PC arm) or PC + bevacizumab (BPC arm). ...Survival and progression-free survival were superior on the BPC arm.
The rationale for markers used in this correlative study was based on elevated vascular endothelial growth factor (VEGF),
basic fibroblast growth factor (bFGF), soluble intercellular adhesion molecule (ICAM) and E-selectin in a variety of malignances
and changes in response to endothelial cell apoptosis.
Materials and Methods: Prospective correlates included measurements of pretreatment plasma VEGF, as well as pretreatment and week 7, bFGF, ICAM,
and E-selectin. Low and high levels were defined as less than or equal to or more than the median.
Results: E-selectin ( P < 0.0001) showed a decrease and bFGF showed an increase ( P = 0.004) from baseline at week 7, which were similar in both arms. Baseline ICAM showed significant associations with response
and survival in both groups. Patients with low baseline ICAM had a higher response rate (32% versus 14%; P = 0.02), better overall survival ( P = 0.00005), and better 1-year survival (65% versus 25%) than those with high ICAM, respectively, regardless of treatment
arm. Patients with high VEGF levels were more likely to respond to BPC compared with PC, but this was not predictive of survival.
The results also suggest a benefit from bevacizumab for patients with low baseline ICAM levels (53% reduction in the progression-free
survival hazard rate).
Conclusions: In this study, baseline ICAM levels were prognostic for survival and predictive of response to chemotherapy with or without
bevacizumab. VEGF levels were predictive of response to bevacizumab but not survival.
PURPOSE Bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor (VEGF) with demonstrated efficacy in combination with carboplatin and paclitaxel (PCB) for the treatment ...of advanced non-small-cell lung cancer (NSCLC). Administration of bevacizumab is postulated to decrease nitric oxide synthesis and lead to hypertension, which may be a physiological sign that the VEGF pathway is more actively being blocked and could result in improved outcomes. PATIENTS AND METHODS Eastern Cooperative Oncology Group (ECOG) 4599 randomly assigned patients with nonsquamous NSCLC to carboplatin and paclitaxel (PC) versus PCB. Hypertensive patients were compared with nonhypertensive patients with respect to overall survival (OS) and progression-free survival (PFS) using blood pressure data and adverse event data separately. High blood pressure (HBP) by the end of cycle 1 was defined as blood pressure > 150/100 at any previous time or at least a 20-mmHg increase in diastolic blood pressure from baseline. Results In a multivariable Cox model adjusting for HBP as a time-varying covariate, comparing those on PCB with HBP with those on PC gave an OS hazard ratio (HR) of 0.60 (95% CI, 0.43 to 0.81; P = .001); comparing those on PCB without HBP with those on PC alone, the OS HR was 0.86 (95% CI, 0.74 to 1.00; P = .05). Comparing the PCB HBP group with PC gave an adjusted PFS HR of 0.54 (95% CI, 0.41 to 0.73; P < .0001) and comparing those on PCB without HBP to those on PC, the HR was 0.72 (95% CI, 0.62 to 0.84; P < .0001). The 6-month cumulative incidence of hypertension was 6.2% (95% CI, 3.9% to 8.6%). CONCLUSION Data from ECOG 4599 suggest that onset of HBP during treatment with PCB may be associated with improved outcomes, and additional studies of the downstream effects of VEGF suppression and hypertension are needed.
Purpose
The objective of this study is to evaluate the safety and long-term outcomes of GORE Synecor™ in ventral hernia repair (VHR).
Methods
This retrospective, single-center case review analyzed ...outcomes in patients who underwent VHR with Synecor from May 2016 to December 2022. Primary outcomes were hernia recurrence and mesh infection rates. Secondary outcomes were 30-day morbidity, 30-day mortality, 30-day readmission, re-operation, surgical-site infection (SSI) and occurrence (SSO) rates, and occurrences requiring intervention (SSOI).
Results
278 patients were identified. Mean follow-up was 24.1 (0.2–87.1) months. Mean hernia defect size was 63.4 (± 77.2) cm
2
. Overall hernia recurrence and mesh infection rates were 5.0% and 1.4% respectively. No mesh infections required full explantation. We report the following overall rates: 13.3% 30-day morbidity, 4.7% 30-day readmission, 2.9% re-operation, 7.2% SSI, 6.1% SSO, and 2.9% SSOI. 30-day morbidity was significantly higher in non-clean (42.1% vs 11.2%,
p
< 0.01), onlay (OL) mesh (37.0% vs preperitoneal (PP) 16.4%,
p
= 0.05 vs retrorectus (RR) 15.0%,
p
< 0.05 vs intraperitoneal (IP) 5.2%,
p
< 0.001), and open cases (23.5% vs 3.1% laparoscopic vs 4.4% robotic,
p
< 0.01). SSI rates were significantly higher in non-clean (31.6% vs 5.4%,
p
< 0.001), OL mesh (29.6% vs RR 11.3%,
p
< 0.05 vs PP 5.5%,
p
< 0.01 vs IP 0.0%,
p
< 0.001), and open cases (15.2% vs 0% laparoscopic vs 0% robotic,
p
< 0.05).
Conclusion
Long-term performance of a novel hybrid mesh in VHR demonstrates a low recurrence rate and favorable safety profile in various defect sizes and mesh placement locations.
Fit elderly patients with advanced non-small-cell lung cancer (NSCLC) benefit from platinum-based, two-drug chemotherapy. Bevacizumab (B) in combination with carboplatin (C) and paclitaxel (P) ...improves survival for advanced, nonsquamous NSCLC, as evidenced in Eastern Cooperative Oncology Group (ECOG) 4599. We conducted a subset analysis of ECOG 4599 to determine the outcome for elderly patients.
ECOG 4599 randomly assigned patients with advanced nonsquamous NSCLC to PC or to PCB. We analyzed outcome in patients who were at least 70 years of age at the time of study entry. Patient characteristics, efficacy, and toxicity data were compared between PC and PCB for the elderly. Outcomes for elderly and younger patients (< 70 years) treated with PCB were also compared.
Among elderly patients (n = 224; 26%), there was a trend towards higher response rate (29% v 17%; P = .067) and progression-free survival (5.9 v 4.9 months; P = .063) with PCB compared with PC, although overall survival (PCB = 11.3 months; PC = 12.1 months; P = .4) was similar. Grade 3 to 5 toxicities occurred in 87% of elderly patients with PCB versus 61% with PC (P < .001), with seven treatment-related deaths in the PCB arm compared with two with PC. Elderly patients had higher incidence of grade 3 to 5 neutropenia, bleeding, and proteinuria with PCB compared with younger patients.
In elderly NSCLC patients, PCB was associated with a higher degree of toxicity, but no obvious improvement in survival compared with PC. Data from this unplanned, retrospective analysis justify prospective evaluation of the therapeutic index of PCB regimen in elderly patients.
Background:
Members of the military are known to experience disproportionately high rates of both glenohumeral instability and superior labrum anterior-posterior (SLAP) tears when compared with ...civilian populations. Although the outcomes after simultaneous repair of Bankart and SLAP lesions have been well described, there is a paucity of literature available regarding the operative management of posterior instability with concomitant superior labral pathology.
Purpose:
To compare outcomes of combined arthroscopic posterior labral and SLAP repair with those of isolated posterior labral repair.
Study Design:
Cohort study; Level of evidence, 3.
Methods:
All consecutive patients younger than 35 years who underwent arthroscopic posterior labral repair from January 2011 to December 2016 with a minimum follow-up of 5 years were identified. From this cohort of eligible patients, all individuals who had undergone combined SLAP and posterior labral repair (SLAP cohort) versus posterior labral repair alone (instability cohort) were then identified. Outcome measures including the visual analog scale score, Single Assessment Numeric Evaluation (SANE), American Shoulder and Elbow Surgeons (ASES) score, Rowe instability score, and range of motion were collected pre- and postoperatively and scores were compared between groups.
Results:
In total, 83 patients met the inclusion criteria for the study. All patients were active-duty military at the time of surgery. The mean follow-up was 93.79 ± 18.06 months in the instability group and 91.24 ± 18.02 months in the SLAP group (P = .5228). Preoperative SANE and ASES scores were significantly worse in the SLAP group. Both groups experienced statistically significant improvements in outcome scores postoperatively (P < .0001 for all), and there were no significant differences in any outcome scores or range of motion between groups. In total, 39 patients in the instability cohort and 37 in the SLAP cohort returned to preinjury levels of work (92.86% vs 90.24%, respectively; P = .7126), and 38 instability patients and 35 SLAP patients returned to preinjury levels of sporting activity (90.48% vs 85.37%, respectively; P = .5195). Two patients in the instability group and 4 patients in the SLAP group were medically discharged from the military (4.76% vs 9.76%; P = .4326), and 2 patients in each cohort had experienced treatment failure at the final follow-up (4.76% vs 4.88%; P > .9999).
Conclusion:
Combined posterior labral and SLAP repair led to statistically and clinically significant increases in outcome scores and high rates of return to active-duty military service that did not differ significantly from the results after isolated posterior labral repair. The results of this study indicate that simultaneous repair is a viable treatment option for the management of combined lesions in active-duty military patients <35 years of age.
A History of Audio Effects Wilmering, Thomas; Moffat, David; Milo, Alessia ...
Applied sciences,
02/2020, Letnik:
10, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Audio effects are an essential tool that the field of music production relies upon. The ability to intentionally manipulate and modify a piece of sound has opened up considerable opportunities for ...music making. The evolution of technology has often driven new audio tools and effects, from early architectural acoustics through electromechanical and electronic devices to the digitisation of music production studios. Throughout time, music has constantly borrowed ideas and technological advancements from all other fields and contributed back to the innovative technology. This is defined as transsectorial innovation and fundamentally underpins the technological developments of audio effects. The development and evolution of audio effect technology is discussed, highlighting major technical breakthroughs and the impact of available audio effects.
PDF
