No abstract

Vascular Endothelial Growth Factor receptors (VEGFRs), the interactions with their ligands and the subsequent signalling pathways are known to play a vital role in tumour angiogenesis. Initial clinical trials of VEGFR inhibitors were disappointing but over the past decade some therapies have been successfully brought to market. At present, VEGFR inhibitors appear to be most promising as adjuvants to conventional chemotherapy. However, several interacting signalling molecules and downstream pathways have recently been shown to interact with VEGFR signalling and provide promising novel targets, such as the platelet-derived growth factor (PDGF), epithelial growth factor (EGF), human epithelial receptor-2, (HER-2) Tie-2 and oestrogen receptors. Elucidation of this web of signalling pathways may identify new therapeutic strategies which may be used in combination with VEGFR inhibitors to augment the efficacy of anti-angiogenic cancer treatments. This review assesses the role of modulating VEGFR activity in cancer and systematically examines current evidence and trials in this area.

Aims The best surgical strategy for the management of displaced bucket-handle (BH) meniscal tears in an anterior cruciate ligament (ACL)-deficient knee is unclear. Combining meniscal repair with ACL reconstruction (ACLR) is thought to improve meniscal healing rates; however, patients with displaced BH meniscal tears may lack extension. This leads some to advocate staged surgery to avoid postoperative stiffness and loss of range of motion (ROM) following ACLR. Methods We reviewed the data for a consecutive series of 88 patients (mean age 27.1 years (15 to 49); 65 male (74%) and 23 female (26%)) who underwent single-stage repair of a displaced BH meniscal tear (67 medial (76%) and 21 lateral (24%)) with concomitant hamstring autograft ACLR. The patient-reported outcome measures (PROMs) EuroQol visual analogue scale (EQ-VAS), EuroQol five-dimension health questionnaire (EQ-5D), Knee injury and Osteoarthritis Outcome Score (KOOS), International Knee Documentation Committee score (IKDC), and Tegner score were recorded at final follow-up. A Kaplan-Meier survival analysis was performed to estimate meniscal repair survivorship. Analyses were performed with different cut-offs for meniscal and ACL injury-to-surgery time (within three weeks, three to ten weeks, and more than ten weeks). Results Meniscal repair survivorship at a median final follow-up of 55 months (interquartile range (IQR) 24 to 91) was 82% (95% confidence interval 70 to 89). A total of 13 meniscus repairs failed (12 requiring meniscectomy and one requiring a further meniscal repair). At final follow-up, median PROMs were: EQ-VAS 85 (IQR 75 to 90), EQ-5D Index 0.84 (IQR 0.74 to 1.00), KOOS Pain 89 (IQR 80 to 94), KOOS Symptoms 82 (IQR 71 to 93), KOOS Activities of Daily Living 97 (IQR 91 to 100), KOOS Sport and Recreation 80 (IQR 65 to 90), KOOS Quality of Life 69 (IQR 53 to 86), IKDC 82.8 (IQR 67.8 to 90.8), and Tegner 6 (IQR 4 to 7). Two patients underwent revision ACLR following further injuries. One patient had an arthroscopic washout for infection at 11 days post-BH meniscal repair/ACLR. Four patients (4.5%) required a further procedure for stiffness, reduced ROM, and pain, and all were operated on within three weeks of meniscal injury. There was no difference in the interval between meniscal injury and surgery between repairs that failed and those that survived. Conclusion These data suggest that concomitant ACLR with repair of displaced BH meniscal tears, even if they have been displaced for some time, appears to afford satisfactory PROMs and good survivorship. Repairs within three weeks of meniscal injury may be associated with higher rates of postoperative reintervention for stiffness. Cite this article: Bone Joint J 2022;104-B(6):680–686.

Many clinical trials are ongoing, but early phase trials show promising results. Recently, there has been a huge explosion of research activity either in the development of new drugs or in the understanding its biology. Many current trials lend support to the rationale behind these therapies, which can function as adjuvants to conventional treatments. It has been argued that normalization of tumor-induced vasculature can promote better drug delivery and prevent resistance to radiotherapy. However, strategies involving the inhibition of the interaction of VEGFRs with ligands and their downstream pathways are not, in general, at a stage where it will be directly useful in clinical cancer treatment. A deeper understanding of these biologic therapies will help to improve the efficacy of conventional treatments and furthermore reduce dose-dependent cytotoxic activity.