Metformin: a modulator of bevacizumab activity in cancer? A case report.

Recurrent type I endometrial cancer ((EC)) has poor prognosis and demands novel therapeutic approaches. Bevacizumab, a VEGF-A neutralizing monoclonal antibody, has shown clinical activity in this setting. To our knowledge, however, although some diabetic cancer patients treated with bevacizumab may also take metformin, whether metformin modulates response to anti-VEGF therapy has not yet been investigated. Here, we report the case of a patient with advanced (EC) treated, among other drugs, with bevacizumab in combination with metformin. The patient affected by relapsed (EC) G3 type 1, presented in march 2010 with liver, lungs and mediastinic metastases. After six cycles of paclitaxel and cisplatin she underwent partial response. Later on, she had disease progression notwithstanding administration of multiple lines of chemotherapy. In march 2013, due to brain metastases with coma, she began steroid therapy with development of secondary diabetes. At this time, administration of Bevacizumab plus Metformin improved her performance status. CT scans performed in this time window showed reduced radiologic density of the lung and mediastinic lesions and of liver disease, suggestive of increased tumor necrosis. Strong F-18-FDG uptake by PET imaging along with high levels of monocarboxylate transporter 4 and lack of liver kinase B1 expression in liver metastasis, highlighted metabolic features previously associated with response to anti-VEGF therapy and phenformin in preclinical models. However, clinical benefit was transitory and was followed by rapid and fatal disease progression. These findingsalbeit limited to a single casesuggest that tumors lacking LKB1 expression and/or endowed with an highly glycolytic phenotype might develop large necrotic areas following combined treatment with metformin plus bevacizumab. As metformin is widely used among diabetes patients as well as in ongoing clinical trials in cancer patients, these results deserve further clinical investigation

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

Tumor outgrowth in peripheral blood mononuclear cell-injected SCID mice is not associated with early Epstein–Barr virus reactivation

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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

eStroop: Implementation, Standardization, and Systematic Comparison of a New Voice-Key Version of the Traditional Stroop Task

The Stroop effect is a well-documented phenomenon, demonstrating both interference and facilitation effects. Many versions of the Stroop task were created, according to the purposes of its applications, varying in numerous aspects. While many versions are developed to investigate the mechanisms of the effect itself, the Stroop effect is also considered a general measure of attention, inhibitory control, and executive functions. In this paper, we implement “eStroop”: a new digital version based on verbal responses, measuring the main processes involved in the traditional effect. eStroop features four categories of stimuli in four different colors: (1) geometrical shapes, (2) neutral words, (3) congruent words, and (4) incongruent words. The results of the administration to 307 University students confirm the Stroop effect and offer baseline data for future research and clinical testing. Direct comparisons with other recent versions of the task are discussed, offering insights into differences and similarities between different task variables

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%)

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

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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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