Laparoscopic Excision of Endometriosis May Require Unilateral Parametrectomy

Nerve-sparing complete excision of endometriosis may not be possible. In these patients, unilateral parametrectomy may be a reasonable alternative management strategy

vandetanib improves anti tumor effects of l19mtnfα in xenograft models of esophageal cancer

Purpose: Targeting the tumor vasculature by vascular disrupting agents (VDAs) has shown therapeutic activity in mouse models. In most cases, however, VDA efficacy is substantially compromised by the inability of these drugs to completely kill tumor cells located at the periphery of the tumor mass. In this study, we investigated anti-tumor effects of L19mTNFα, a fusion protein composed of L19 (scFv), specific for the angiogenesis-associated ED-B containing fibronectin isoform, and murine TNFα, in xenograft models of esophageal cancer. Experimental design: We evaluated ED-B expression in esophageal cancer samples. Subsequently, we generated subcutaneous xenografts from primary tumors, treated them with the L19mTNFα scFv, and determined effects on tumor vasculature, viability and proliferation, and VEGF expression and infiltration by hematopoietic cells. To overcome tumor resistance, L19mTNFα scFv was combined with vandetanib, a tyrosine kinase inhibitor of VEGF receptor, epidermal growth factor receptor, and RET signaling. Results: ED-B was broadly expressed by esophageal cancer cell lines, as well as xenografts and primary surgical samples of esophageal cancer. Administration of L19mTNFα acutely damaged tumor vasculature and increased necrosis, indicating a VDA-like activity of this immunoconjugate. This event was followed, however, by rapid tumor growth recovery associated with increased expression of VEGF and recruitment of CD11b+Gr1+ myeloid cells into tumors. Combination of L19mTNFα with vandetanib severely impaired vascular functions in tumors, leading to a reduction of cell proliferation and increased necrosis, without apparent signs of toxicity. Conclusion: These findings indicate that a combination of vascular damaging agents with anti-angiogenic drugs could represent a promising therapeutic strategy for esophageal cancer. Clin Cancer Res; 17(3); 447–58. ©2010 AACR

A multi-center, real-life experience on liquid biopsy practice for EGFR testing in non-small cell lung cancer (NSCLC) patients

Background: circulating tumor DNA (ctDNA) is a source of tumor genetic material for EGFR testing in NSCLC. Real-word data about liquid biopsy (LB) clinical practice are lacking. The aim of the study was to describe the LB practice for EGFR detection in North Eastern Italy. Methods: we conducted a multi-regional survey on ctDNA testing practices in lung cancer patients. Results: Median time from blood collection to plasma separation was 50 min (20\u2013120 min), median time from plasma extraction to ctDNA analysis was 24 h (30 min\u20135 days) and median turnaround time was 24 h (6 h\u20135 days). Four hundred and seventy five patients and 654 samples were tested. One hundred and ninety-two patients were tested at diagnosis, with 16% EGFR mutation rate. Among the 283 patients tested at disease progression, 35% were T790M+. Main differences in LB results between 2017 and 2018 were the number of LBs performed for each patient at disease progression (2.88 vs. 1.2, respectively) and the percentage of T790M+ patients (61% vs. 26%)

liquid biopsy as tool to monitor and predict clinical benefit from chemotherapy ct and immunotherapy it in advanced non small cell lung cancer ansclc a prospective study

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Real-world data on treatment outcomes in EGFR-mutant non-small-cell lung cancer patients receiving osimertinib in second or further lines

Aims: This study describes real-world outcomes of pretreated EGFR T790M-positive (T790M+) advanced non-small-cell lung cancer patients progressing after first- or second-generation tyrosine kinase inhibitors and receiving osimertinib, compared with T790M-negative (T790M-) patients. We have also described progression patterns and treatment sequences. Patients & methods: This is a retrospective multicenter Italian observational study including consecutive Caucasian patients referred between 2014 and 2018. Results: 167 patients were included. Median progression-free survival was 9.8 months (95% CI: 8.3-13.3) for T790M+ and 6.0 months (95% CI: 4.9-7.2) for T790M- patients, respectively. Median overall survival was 20.7 months (95% CI: 18.9-28.4) for T790M+ and 10.6 months (95% CI: 8.6-23.6) for T790M- patients, respectively. The T790M mutation correlated with absence of new sites of disease. After progression, most T790M+ patients continued osimertinib, whereas most T790M- patients received a different treatment line. Conclusion: Better outcomes were shown in patients receiving osimertinib. A more limited progression pattern for T790M+ was suggested

PO-338 Recurrent glioblastoma: a complex scenario dominated by loss of MMR proteins

Introduction Glioblastoma (GBM) is the most common primary brain tumour in adults and the Stupp protocol represents the standard of care. However, the tumour invariably relapses suggesting marked intra-tumour genetic heterogeneity enabling rapid adaptation to therapy. In-depth characterisation of recurrent GBM (rGBM) might contribute to better understand mechanisms behind tumour progression and enable rGBM treatment with targeted drugs. Material and methods Matched GBM samples have been collected at diagnosis and recurrence from adult patients (n=57) treated with the Stupp protocol. Expression of mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, MSH6) was evaluated by IHC, followed by exome sequencing of 3 pairs showing loss of MSH6 reactivity as well as of 3 MSH6 positive pairs. In addition, established genetic and epigenetic markers of GBM were investigated along with their correlation with loss of MMR proteins and patients' survival. Results and discussions According to IHC results, 13 out of 52 rGBM samples (25%) lacked expression of MMR proteins. In particular, 11 among the 13 samples (85%) showed partial or total reduction of MSH6 expression. Conversely, almost all GBM samples at diagnosis (96.4%) stained positive for the 4 MMR markers. Consistent with IHC data, exome sequencing disclosed lack of variants in MMR genes in primary samples whereas rGBM samples lacking MSH6 expression were mutated in the abovementioned genes and shared a c.3438+1G>A* splicing variant in MSH6 with a potential loss of function effect. Moreover, MSH6 negative relapsed specimens were characterised by 30 to 100-fold more variants compared to the matched primary ones and lacked microsatellite instability. Notably, MMR deficiency was associated with significant telomere shortening. Conversely, the tumour pairs expressing MMR proteins showed an almost comparable number of mutations in primary versus relapsed samples and absence of variants in MMR genes both in the initial tumours and in their recurrent counterpart. Conclusion Our study shows that IHC staining is a valuable tool to identify a subset of rGBM patients with alterations in MMR genes linked to high mutational burden and, hence, potentially eligible for drugs targeting immune checkpoint inhibitors

Endostatin inhibits VEGF-A induced osteoclastic bone resorption in vitro

BACKGROUND: Endostatin is a C-terminal fragment of collagen XVIII which is a component of basement membranes with the structural properties of both collagens and proteoglycans. Endostatin has a major role in angiogenesis which is intimately associated with bone development and remodeling. Signaling between the endothelial cells and the bone cells, for example, may have a role in recruitment of osteoclastic precursor cells. Our study aims at exploring a possibility that endostatin, either as a part of basement membrane or as a soluble molecule, may control osteoclastogenesis and osteoclastic bone resorption in vitro. METHODS: Rat pit formation assay was employed in order to examine the effect of endostatin alone or in combination with vascular endothelial growth factor-A (VEGF-A) on bone resorption in vitro. Effect of these agents on osteoclast differentiation in vitro was also tested. Osteoclastogenesis and the number of osteoclasts were followed by tartrate resistant acid phosphatase (TRACP) staining and resorption was evaluated by measuring the area of excavated pits. RESULTS: Endostatin inhibited the VEGF-A stimulated osteoclastic bone resorption, whereas endostatin alone had no effect on the basal resorption level in the absence of VEGF-A. In addition, endostatin could inhibit osteoclast differentiation in vitro independent of VEGF-A. CONCLUSION: Our in vitro data indicate that collagen XVIII/endostatin can suppress VEGF-A induced osteoclastic bone resorption to the basal level. Osteoclastogenesis is also inhibited by endostatin. The regulatory effect of endostatin, however, is not critical since endostatin alone does not modify the basal bone resorption

Efficacy assessment of interferon-alpha-engineered mesenchymal stromal cells in a mouse plasmacytoma model

Bone marrow mesenchymal stromal cells (BM-MSCs) may survive and proliferate in the presence of cycling neoplastic cells. Exogenously administered MSCs are actively incorporated in the tumor as stromal fibroblasts, thus competing with the local mesenchymal cell precursors. For this reason, MSCs have been suggested as a suitable carrier for gene therapy strategies, as they can be genetically engineered with genes encoding for biologically active molecules, which can inhibit tumor cell proliferation and enhance the anti-tumor immune response. We used BM-MSCs engineered with the murine interferon-alpha (IFN-alpha) gene (BM-MSCs/IFN-alpha) to assess in a mouse plasmacytoma model the efficacy of this approach towards neoplastic plasma cells. We found that IFN-alpha can be efficiently produced and delivered inside the tumor microenvironment. Subcutaneous multiple administration of BM-MSCs/IFN-alpha significantly hampered the tumor growth in vivo and prolonged the overall survival of mice. The anti-tumor effect was associated with enhanced apoptosis of tumor cells, reduction in microvessel density, and ischemic necrosis. By contrast, intravenous administration of BM-MSCs/IFN-alpha did not significantly modify the survival of mice, mainly as a consequence of an excessive entrapment of injected cells in the pulmonary vessels. In conclusion, BM-MSCs/IFN-alpha are effective in inhibiting neoplastic plasma cell growth; however, systemic administration of engineered MSCs still needs to be improved to make this approach potentially suitable for the treatment of multiple myeloma