Targeting the hypoxic fraction of tumours using hypoxia activated prodrugs

The presence of a microenvironment within most tumours containing regions of low oxygen tension or hypoxia has profound biological and therapeutic implications. Tumour hypoxia is known to promote the development of an aggressive phenotype, resistance to both chemotherapy and radiotherapy and is strongly associated with poor clinical outcome. Paradoxically, it is recognised as a high priority target and one therapeutic strategies designed to eradicate hypoxic cells in tumours are a group of compounds known collectively as hypoxia activated prodrugs (HAPs) or bioreductive drugs. These drugs are inactive prodrugs that require enzymatic activation (typically by 1 or 2 electron oxidoreductases) to generate cytotoxic species with selectivity for hypoxic cells being determined by (i) the ability of oxygen to either reverse or inhibit the activation process and (ii) the presence of elevated expression of oxidoreductases in tumours. The concepts underpinning HAP development were established over 40 years ago and have been refined over the years to produce a new generation of HAPs that are under preclinical and clinical development. The purpose of this article is to describe current progress in the development of HAPs focusing on the mechanisms of action, preclinical properties and clinical progress of leading examples

Risk-Reducing Salpingo-Oophorectomy and Breast Cancer Risk Reduction in the Gynecologic Oncology Group Protocol-0199 (GOG-0199)

Background: Risk-reducing salpingo-oophorectomy (RRSO) has been associated with approximately 50% breast cancer risk reduction among women with a pathogenic variant in BRCA1 or BRCA2 (BRCA1/2), a finding that has recently been questioned. Methods: We estimated incidence rates of breast cancer and all cancers combined during 5 years of follow-up among participants selecting RRSO or ovarian cancer screening (OCS) among women with a BRCA1/2 pathogenic variant or strong breast and/or ovarian cancer family history. Ovarian or fallopian tube or peritoneal cancer incidence rates were estimated for the OCS group. Breast cancer hazard ratios (HRs) for time-dependent RRSO were estimated using Cox regression with age time-scale (4943 and 4990 women-years in RRSO and OCS cohorts, respectively). All statistical tests were two-sided. Results: The RRSO cohort included 925 participants, and 1453 participants were in the OCS cohort (381 underwent RRSO during follow-up), with 88 incident breast cancers diagnosed. Among BRCA1/2 pathogenic variant carriers, a non-statistically significant lower breast cancer incidence was observed in the RRSO compared with the OCS cohort (HR = 0.86, 95% confidence interval  = 0.45 to 1.67; P = .67). No difference was observed in the overall population or among subgroups stratified by prior breast cancer history or menopausal status. Seven fallopian tube and four ovarian cancers were prospectively diagnosed in the OCS cohort, and one primary peritoneal carcinoma occurred in the RRSO cohort. Conclusions: These data suggest that RRSO might be associated with reduced breast cancer incidence among women with a BRCA1/2 pathogenic variant, although the effect, if present, is small. This evolving evidence warrants a thorough discussion regarding the impact of RRSO on breast cancer risk with women considering this intervention

Prognostic Value of Lordosis Decrease in Radiographic Adjacent Segment Pathology After Anterior Cervical Corpectomy and Fusion

Abstract While cervical lordosis alteration is not uncommon after anterior cervical arthrodesis, its influence on radiological adjacent segment pathology (RASP) is still unclear. Biomechanical changes induced by arthrodesis may contribute to ASP onset. To investigate the correlation between cervical lordosis decrease and RASP onset after anterior cervical corpectomy and fusion (ACCF) and to determine its biomechanical effect on adjacent segments after surgery, 80 CSM patients treated with ACCF were retrospectively studied, and a baseline finite element model of the cervical spine as well as post-operation models with normal and decreased lordosis were established and validated. We found that post-operative lordosis decrease was prognostic in predicting RASP onset, with the hazard ratio of 0.45. In the FE models, ROM at the adjacent segment increased after surgery, and the increase was greater in the model with decreased lordosis. Thus, post-operative cervical lordosis change significantly correlated with RASP occurrence, and it may be of prognostic value. The biomechanical changes induced by lordosis change at the adjacent segments after corpectomy may be one of the mechanisms for this phenomenon. Restoring a well lordotic cervical spine after corpectomy may reduce RASP occurrence and be beneficial to long-term surgical outcomes