Regional chemotherapy by isolated limb perfusion prior to surgery compared with surgery and post-operative radiotherapy for primary, locally advanced extremity sarcoma: a comparison of matched cohorts

Background: Induction chemotherapy by isolated limb perfusion (ILP) with melphalan and tumour necrosis factor-α is an effective strategy to facilitate limb-conserving surgery in locally advanced extremity sarcoma. In a comparison of cohorts matched for grade, size and surgical resectability, we compared the outcome of patients undergoing induction ILP prior to limb-conserving surgery and selective post-operative radiotherapy with patients undergoing limb-conserving surgery and routine post-operative radiotherapy. Methods: Patients with primary, grade 2/3 sarcomas of the lower limbs over 10 cm in size were identified from prospectively maintained databases at 3 centres. Patients treated at a UK centre underwent limb-conserving surgery and post-operative radiotherapy (Standard cohort). Patients at two German centres underwent induction ILP, limb-conserving surgery and selective post-operative radiotherapy (ILP cohort). Results: The Standard cohort comprised 80 patients and the ILP cohort 44 patients. Both cohorts were closely matched in terms of tumour size, grade, histological subtype and surgical resectability. The median age was greater in the Standard vs the ILP cohort (60.5 years vs 56 years, p = 0.033). The median size was 13 cm in both cohorts. 5-year local-recurrence (ILP 12.2%, Standard 20.1%, p = 0.375) and distant metastases-free survival rates (ILP 49.6%, Standard 46.0% p = 0.821) did not differ significantly between cohorts. Fewer patients received post-operative radiotherapy in the ILP cohort compared with the Standard cohort (27% vs 82%, p < 0.001). Conclusion: In comparative cohorts, the outcomes of patients undergoing induction ILP prior to surgery did not differ from those undergoing standard management, although induction ILP was associated with a reduced need for adjuvant radiation

Isolated limb perfusion with biochemotherapy and oncolytic virotherapy combines with radiotherapy and surgery to overcome treatment resistance in an animal model of extremity soft tissue sarcoma.

The management of locally advanced or recurrent extremity sarcoma often necessitates multimodal therapy to preserve a limb, of which isolated limb perfusion (ILP) is a key component. However, with standard chemotherapeutic agents used in ILP, the duration of response is limited. Novel agents or treatment combinations are urgently needed to improve outcomes. Previous work in an animal model has demonstrated the efficacy of oncolytic virotherapy when delivered by ILP and, in this study, we report further improvements from combining ILP-delivered oncolytic virotherapy with radiation and surgical resection. In vitro, the combination of radiation with an oncolytic vaccinia virus (GLV-1h68) and melphalan demonstrated increased cytotoxicity in a panel of sarcoma cell lines. The effects were mediated through activation of the intrinsic apoptotic pathway. In vivo, combinations of radiation, oncolytic virotherapy and standard ILP resulted in delayed tumour growth and prolonged survival when compared with standard ILP alone. However, local disease control could only be secured when such treatment was combined with surgical resection, the timing of which was crucial in determining outcome. Combinations of oncolytic virotherapy with surgical resection and radiation have direct clinical relevance in extremity sarcoma and represent an exciting prospect for improving outcomes in this pathology

Oncolytic vaccinia virus combined with radiotherapy induces apoptotic cell death in sarcoma cells by down-regulating the inhibitors of apoptosis.

Advanced extremity melanoma and sarcoma present a significant therapeutic challenge, requiring multimodality therapy to treat or even palliate disease. These aggressive tumours are relatively chemo-resistant, therefore new treatment approaches are urgently required. We have previously reported on the efficacy of oncolytic virotherapy (OV) delivered by isolated limb perfusion. In this report, we have improved therapeutic outcomes by combining OV with radiotherapy. In vitro, the combination of oncolytic vaccinia virus (GLV-1h68) and radiotherapy demonstrated synergistic cytotoxicity. This effect was not due to increased viral replication, but mediated through induction of intrinsic apoptosis. GLV-1h68 therapy downregulated the anti-apoptotic BCL-2 proteins (MCL-1 and BCL-XL) and the downstream inhibitors of apoptosis, resulting in cleavage of effector caspases 3 and 7. In an in vivo ILP model, the combination of OV and radiotherapy significantly delayed tumour growth and prolonged survival compared to single agent therapy. These data suggest that the virally-mediated down-regulation of anti-apoptotic proteins may increase the sensitivity of tumour cells to the cytotoxic effects of ionizing radiation. Oncolytic virotherapy represents an exciting candidate for clinical development when delivered by ILP. Its ability to overcome anti-apoptotic signals within tumour cells points the way to further development in combination with conventional anti-cancer therapies

Negative Effects of Paternal Age on Children's Neurocognitive Outcomes Can Be Explained by Maternal Education and Number of Siblings

Background: Recent findings suggest advanced paternal age may be associated with impaired child outcomes, in particular, neurocognitive skills. Such patterns are worrisome given relatively universal trends in advanced countries toward delayed nuptiality and fertility. But nature and nurture are both important for child outcomes, and it is important to control for both when drawing inferences about either pathway. Methods and Findings: We examined cross-sectional patterns in six developmental outcome measures among children in the U.S. Collaborative Perinatal Project (n = 31,346). Many of these outcomes at 8 mo, 4 y, and 7 y of age (Bayley scales, Stanford Binet Intelligence Scale, Graham-Ernhart Block Sort Test, Wechsler Intelligence Scale for Children, Wide Range Achievement Test) are negatively correlated with paternal age when important family characteristics such as maternal education and number of siblings are not included as covariates. But controlling for family characteristics in general and mother’s education in particular renders the effect of paternal age statistically insignificant for most developmental measures. Conclusions: Assortative mating produces interesting relationships between maternal and paternal characteristics that can inject spurious correlation into observational studies via omitted variable bias. Controlling for both nature and nurture reveals little residual evidence of a link between child neurocognitive outcomes and paternal age in these data. Result