Nuclear IGF-1R predicts chemotherapy and targeted therapy resistance in metastatic colorectal cancer.

BACKGROUND: Although chemotherapy is the cornerstone treatment for patients with metastatic colorectal cancer (mCRC), acquired chemoresistance is common and constitutes the main reason for treatment failure. Monoclonal antibodies against insulin-like growth factor-1 receptor (IGF-1R) have been tested in pre-treated mCRC patients, but results have been largely deceiving. METHODS: We analysed time to progression, overall survival, and the mutational status of RAS, BRAF and nuclear p-IGF-1R expression by immunohistochemistry, in 470 metastatic CRC patients. The effect of IGF-1R activation and distribution was also assessed using cellular models of CRC and RNAi for functional validation. RESULTS: Nuclear IGF-1R increased in metastatic tumours compared to paired untreated primary tumours, and significantly correlated with poor overall survival in mCRC patients. In vitro, chemo-resistant cell lines presented significantly higher levels of IGF-1R expression within the nuclear compartment, and PIAS3, a protein implicated also in the sumoylation process of intranuclear proteins, contributed to IGF-1R nuclear sequestration, highlighting the essential role of PIAS3 in this process. Intriguingly, we observed that ganitumab, an IGF-1R blocking-antibody used in several clinical trials, and dasatinib, an SRC inhibitor, increased the nuclear localisation of IGF-1R. CONCLUSIONS: Our study demonstrates that IGF-1R nuclear location might lead to chemotherapy and targeted agent resistance.

Enhancing the First-Pass Effect in Acute Stroke: The Impact of Stent Retriever Characteristics.

Introduction: Although stentrievers (SRs) have been a mainstay of mechanical thrombectomy (MT), and current guidelines recommend the use of SRs in the treatment of large vessel occlusion stroke (LVO), there is a paucity of studies in the literature comparing SRs directly against each other in terms of mechanical and functional properties. Timely access to endovascular therapy and the ability to restore intracranial flow in a safe, efficient, and efficacious manner have been critical to the success of MT. This study aimed to investigate the impact of contemporary SR characteristics, including model, brand, size, and length, on the first-pass effect (FPE) in patients with acute ischemic stroke. Methods: Consecutive patients with M1 occlusion treated with a single SR+BGC were recruited from the ROSSETTI registry. The primary outcome was the FPE that was defined as modified (mFPE) or true (tFPE) for the achievement of modified thrombolysis in cerebral infarction (mTICI) grades 2b-3 or 3 after a single device pass, respectively. We compared patients who achieved mFPE with those who achieved tFPE according to SR characteristics. Results: We included 610 patients (52.3% female and 47.7% male, mean age 75.1 ± 13.62 years). mFPE was achieved in 357 patients (58.5%), whereas tFPE was achieved in 264 (43.3%). There was no significant association between SR characteristics and mFPE or tFPE. Specifically, the SR size did not show a statistically significant relationship with improvement in FPE. Similarly, the length of the SR did not yield significant differences in the mFPE and tFPE, even when the data were grouped. Conclusions: Our data indicate that contemporary SR-mediated thrombectomy characteristics, including model, brand, size, and length, do not significantly affect the FPE.

Endovascular thrombectomy first-pass reperfusion and ancillary device placement.

BACKGROUND: Recent randomized trials have demonstrated the efficacy of mechanical thrombectomy in treating acute ischemic stroke, however, further research is required to optimize this technique. We aimed to evaluate the impact of guide catheter position and clot crossing on revascularization rates using A Direct Aspiration First Pass Technique (ADAPT). METHODS: Data were collected between January 2018 and August 2019 as part of the Spanish ADAPT Registry on ACE catheters (SARA), a multicenter observational study assessing real-world thrombectomy outcomes. Demographic, clinical, and angiographic data were collected. Subgroup analyses assessed the relationship between guide catheter/microguidewire position and modified Trombolysis in Cerebral Infarction (mTICI) scores. First pass effect (FPE) was defined as mTICI 3 after single pass of the device. RESULTS: From a total of 589 patients, 80.8% underwent frontline aspiration thrombectomy. The median score on the National Institutes of Health Stroke Scale (NIHSS) was 16.0. After adjusting for confounders, the likelihood of achieving FPE (adjusted Odds Ratio (aOR), 0.587; 95% confidence interval (CI), 0.38 to 0.92; p=0.0194) were higher among patients with more distal petrocavernous placement of guide catheter. The likelihood of achieving FPE (aOR, 0.592; 95% CI, 0.39 to 0.90; p=0.0138) and final angiogram complete reperfusion (aOR, 0.465; 95% CI, 0.30 to 0.73; p=0.0008) were higher among patients without microguidewire crossing the clot. No difference was noted for time from arterial puncture to reperfusion in any study group. At the 90-day follow-up, the mortality rate was 9.2% and 65.8% of patients across the entire study cohort were functionally independent (modified Rankin Scale (mRS) 0-2). CONCLUSIONS: Petrocavernous guide catheter placement improved first-pass revascularization. Crossing the occlusion with a microguidewire lowered the likelihood of achieving FPE and complete reperfusion after final angiogram.

Efficacy and safety of FOLFIRI/aflibercept (FA) in an elderly population with metastatic colorectal cancer (mCRC) after failure of an oxaliplatin-based regimen.

BACKGROUND: The VELOUR study showed the benefit of FOLFIRI-Aflibercept (FA) versus FOLFIRI in patients with metastatic colorectal cancer (mCRC) in second-line treatment. However, only 36% of the included patients were ≥65 years. Thus, we seek to evaluate the efficacy and safety of FA in the elderly population in the context of routine practice. MATERIALS AND METHODS: We conducted an observational, retrospective, multicenter, observational study of patients ≥70 years with mCRC treated with FA after progression to oxaliplatin chemotherapy in routine clinical practice in 9 hospitals of the GITuD group. RESULTS: Of 388 patients treated with FA between June 2013 and November 2018, 75 patients ≥70 years were included. The median number of cycles was 10 and the objective response (ORR) and disease control rates (DCR) were 33.8% and 72.0%, respectively. With a median follow-up of 27.1 months, median Progression-free survival (PFS) was 6.6 months and median Overall Survival (OS) was 15.1 months. One third fewer metastasectomies were performed in the ≥75 years' subgroup (24 vs. 52%, p = 0.024) and more initial FOLFIRI dose reductions (68 vs. 36%, p = 0.014). ORR (23.8% vs. 38.3%), DCR (42.8% vs. 85.1%), and PFS (4 vs. 7.8 months; p = 0.017) were significantly less, without difference in OS (9.9 vs. 17.1 months; p = 0.129). The presence of prior hypertension (HT) (PFS 7.9 vs. 5.7 months, p = 0.049) and HT ≥ grade 3 during treatment (PFS 7.6 vs. 6.6 months, p = 0.024) were associated with longer PFS. The most frequent grade 3/4 adverse events were: asthenia (21.3%), neutropenia (14.7%), and diarrhea (14.7%). 57.3% required FOLFIRI dose reduction; 34.7% of aflibercept, including discontinuation (5.3% and 18.7%, respectively). CONCLUSIONS: FA combination is effective in patients ≥70 years. The occurrence of HT is predictive of efficacy. Close monitoring of toxicity and initial dose adjustment is recommended.

Addition of intracranial aspiration to balloon guide catheter does not improve outcomes in large vessel occlusion anterior circulation stent retriever based thrombectomy for acute stroke.

BACKGROUND: Balloon guide catheter (BGC) in stent retriever based thrombectomy (BGC+SR) for patients with large vessel occlusion strokes (LVOS) improves outcomes. It is conceivable that the addition of a large bore distal access catheter (DAC) to BGC+SR leads to higher efficacy. We aimed to investigate whether the combined BGC+DAC+SR approach improves angiographic and clinical outcomes compared with BGC+SR alone for thrombectomy in anterior circulation LVOS. METHODS: Consecutive patients with anterior circulation LVOS from June 2019 to November 2020 were recruited from the ROSSETTI registry. Demographic, clinical, angiographic, and outcome data were compared between patients treated with BGC+SR alone versus BGC+DAC+SR. The primary outcome was first pass effect (FPE) rate, defined as near complete/complete revascularization (modified Thrombolysis in Cerebral Infarction (mTICI) 2c-3) after single device pass. RESULTS: We included 401 patients (BGC+SR alone, 273 (66.6%) patients). Patients treated with BGC+SR alone were older (median age 79 (IQR 68-85) vs 73.5 (65-82) years; p=0.033) and had shorter procedural times (puncture to revascularization 24 (14-46) vs 37 (24.5-63.5) min, p<0.001) than the BGC+DAC+SR group. Both approaches had a similar FPE rate (52% in BGC+SR alone vs 46.9% in BGC+DAC+SR, p=0.337). Although the BGC+SR alone group showed higher rates for final successful reperfusion (mTICI ≥2b (86.8% vs 74.2%, p=0.002) and excellent reperfusion, mTICI ≥2 c (76.2% vs 55.5%, p<0.001)), there were no significant differences in 24 hour National Institutes of Health Stroke Scale score or rates of good functional outcome (modified Rankin Scale score of 0-2) at 3 months across these techniques. CONCLUSIONS: Our data showed that addition of distal intracranial aspiration catheters to BGC+SR based thrombectomy in patients with acute anterior circulation LVO did not provide higher rates of FPE or improved clinical outcomes.

Dynamic perspective of the neutrophil-to-lymphocyte ratio in metastatic gastric cancer.

PURPOSE: The neutrophil-to-lymphocyte ratio (NLR) is an accessible marker from a routine blood test. This study explored the prognostic and predictive value of a change in NLR (c-NLR) after chemotherapy, baseline NLR (bNLR) and chemotherapy response, in metastatic gastric cancer (mGC) patients. METHODS: A total of 116 mGC patients treated between 2009 to 2019 at seven hospitals from Galician Research Group on Digestive Tumors (GITuD) were reviewed in a multicentre, ambispective and observational study. NLR was calculated and the optimal cut-off was defined as NLR=3.96 based on ROC method. NLR was determined at baseline and after two chemotherapy cycles in first line treatment. Change NLR was calculated as NLR after two chemotherapy cycles minus bNLR. The relation of bNLR and c-NLR to overall survival (OS) was evaluated by Kaplan-Meier method and compared by log-rank test. Dynamic Score (DScore) based on c-NLR and baseline NLR were correlated with OS and radiological response. Univariate, multivariate and chi-square analyses were performed. RESULTS: Median patient age was 68.7 years, and 66% were male. Univariate analysis showed OS correlation for bNLR ≥3.96 (5.97 vs 10.87 months, p=0.001), c-NLR increase (6.63 vs 10.34 months, p=0.021) and DScore (12.74 vs 7.68 vs 2.43 months, p<0.001). High DScore was associated with radiological progression after two cycles (x2=10.26, p=0.006). Multivariate analysis: bNLR ≥3.96 (HR=2.16, p=0.003) and c-NLR increase (HR= 2.36, p=0.003) were prognostic factors of poor OS. CONCLUSION: High bNLR and increased NLR after chemotherapy were associated with worse outcome. Dynamic measurement of NLR provides information for stratifying patients to guide optimal treatment.

Prediction of survival in patients with advanced, refractory colorectal cancer in treatment with trifluridine/tipiracil: real-world vs clinical trial data.

Trifluridine/tipiracil increases overall survival (OS) in patients with refractory, metastatic colorectal cancer (mCRC). A post hoc exploratory analysis of the RECOURSE randomized clinical trial (RCT) established two categories, a good prognosis corresponding to subjects having a low tumor burden and indolent disease. Other models in refractory mCRC are the FAS-CORRECT and Colon Life nomogram. The main objective was to externally validate the prognostic factors of the RECOURSE and FAS-CORRECT trials, and the Colon Life nomogram in a multicenter, real-world series of mCRC treated in 3rd and successive lines with trifluridine/tipiracil. The secondary aim was to develop an OS predictive model, TAS-RECOSMO. Between 2016 and 2019, 244 patients were recruited. Median OS was 8.15 vs 8.12 months for the poor (85% of the subjects) and good (15%) prognosis groups from the RESOURCE trial, respectively, log-rank p = 0.9. The most common grade 3-4 toxicities were neutropenia (17%), asthenia (6%), and anemia (5%). The AFT lognormal model TAS-RECOSMO included six variables: ECOG-PS, KRAS/NRAS/BRAF mutation status, time between diagnosis of metastasis and beginning of trifluridine/tipiracil, NLR, CEA, and alkaline phosphatase. The model's bootstrapped bias-corrected c-index was 0.682 (95% CI, 0.636-0.722). The factors from the Colon Life model, FAS-CORRECT, and RECOURSE displayed a c-index of 0.690, 0.630, and 0.507, respectively. TAS-RECOSMO, FAS-CORRECT, and the Colon Life nomogram appear to predict OS in patients with refractory mCCR who begin trifluridine/tipiracil treatment in the real world. The prognostic groups of the RECOURCE RCT were unable to capture the situation of real-world subjects treated with trifluridine/tipiracil in this series.

Do Clinical Trials Meet Current Care Needs? Views of Digestive Oncology Specialists in Galicia (Spain) Using the Delphi Method.

Background: In recent years, abundant scientific evidence has been generated based on clinical trials (CT) in the field of oncology. The general objective of this paper is to find out the extent to which decision making is based on knowledge of the most recent CT. Its specific objectives are to pinpoint difficulties with decision making based on the CT performed and find out the motivations patients and clinicians have when taking part in a CT. Methodology: Combined, prospective study, based on the Delphi method. A lack of correspondence between the people who take part in CT and patients who come for consultation has been identified. A need for training in analysing and interpreting CT has also been identified and a lack of trust in the results of CT financed by the pharmaceutical industry itself has been perceived. Conclusions: There is a difficulty in selecting oncological treatment due to the lack of correspondence between the patients included in the CT and patients seen in consultation. In this process, real world data studies may be highly useful, as they may provide this group with greater training in interpreting CT and their results.

First-line panitumumab plus capecitabine for the treatment of older patients with wild-type RAS metastatic colorectal cancer. The phase II, PANEL study.

BACKGROUND: Despite the high morbidity and mortality of metastatic colorectal cancer (mCRC) in older patients, they have been underrepresented in clinical trials and their optimal treatment is yet to be determined. This open-label phase II study evaluated the benefits of panitumumab and capecitabine as a first-line chemotherapy regimen in older patients with wild-type [WT] RAS mCRC. PATIENTS AND METHODS: Patients (≥70 years; ECOG≤2) received 3-week cycles of panitumumab (9 mg/kg on day 1) plus capecitabine (850 mg/m2 twice daily on days 1-14) until disease progression or unacceptable toxicity. Response was evaluated every 9 weeks according to RECIST_1.1. Outcome measures were: objective response rate (ORR), duration of response (DoR), time to response (TTR), progression (TTP) and treatment failure (TTF), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Twenty-seven patients (11 women; median age: 78 years; ECOG: 0 [26%], 1 [67%], 2 [7%]) were evaluated. Median follow-up was 17.7 months. Confirmed ORR (95%CI) was 44.4% (25.7-63.2), with 25.9% of patients achieving at least stable disease. Median (95%CI) DoR was 8.7 (5.5-10.4) months, and median TTR was 2.2 (1.9-2.8) months. Median TTP was 9.6 (4.8-11.5) months, with a median TTF of 5.2 (2.8-7.2) months. The median PFS was 7.5 (4.4-10.4) months, and the median OS was 23.7 (7.4-27.5) months. Seventeen (63%) patients reported panitumumab and/or capecitabine-related adverse events grade 3-4, with skin toxicity (18.5%) being the most common. Two (7.4%) deaths were treatment-related. CONCLUSION: This study suggests that panitumumab plus capecitabine is a safe and effective regimen in older patients with WT RAS mCRC.

Paraganglioma of the cauda equina: MR and angiographic findings.

Paragangliomas of the cauda equina are rare benign highly vascular tumors and occur almost exclusively in the cauda equina and filum terminale of the spinal cord. We present a case spinal paraganglioma of the cauda equina in a 75-year-old male with an emphasis on magnetic resonance imaging and conventional angiography findings.

Efficacy and safety of FOLFIRI/aflibercept in second-line treatment of metastatic colorectal cancer in a real-world population: Prognostic and predictive markers.

PURPOSE: The phase III VELOUR trial demonstrated efficacy with combined FOLFIRI-aflibercept in patients with metastatic colorectal cancer previously treated with oxaliplatin with or without bevacizumab versus placebo. The effect of FOLFIRI-aflibercept in routine clinical practice was evaluated. METHODS/PATIENTS: Overall survival (OS), progression-free survival (PFS), response and safety were analysed for 78 patients treated with FOLFIRI-aflibercept at six GITuD institutions. Exploratory analyses of prognostic and predictive markers of efficacy were performed. RESULTS: Patients had good general status (PS 0-1 96.2%), tumours were mostly RAS-mutant (75.6%), synchronous (71.8%), and left-sided (71.8%). Prior therapy included bevacizumab (47.4%) and anti-EGFR agents (12.8%). PFS was longer for metachronous than synchronous tumours (11.0 vs 5.0 months, P = 0.028), and for left-colon tumours (7.0 vs 3.0 months, P = 0.044). RAS-mutant status, first-line treatment and primary tumour surgery did not impact PFS. The disease control rate was 70.5%. The most common grade 3/4 toxicities were neutropenia (15.3%), asthenia (10.3%), diarrhea and mucositis (6.4% each). Dysphonia was reported in 39.7% of patients, and grade 3 hypertension in 3.8%. Development of hypertension (any grade) was significantly associated with a reduced risk of progression by multivariate analysis (HR = 2.7; 95%CI 1.3-5.4; P = 0.001). CONCLUSIONS: Efficacy with FOLFIRI-aflibercept in a real-life population was in line with results from the pivotal trial and toxicity was manageable with treatment adaptation. Survival outcomes were not impacted by primary tumour location, RAS-mutant status, first-line treatment or primary tumour surgery. Hypertension may be a surrogate marker of efficacy in this patient population.

Clinical Impact of Circulating Tumor RAS and BRAF Mutation Dynamics in Patients With Metastatic Colorectal Cancer Treated With First-Line Chemotherapy Plus Anti-Epidermal Growth Factor Receptor Therapy.

PURPOSE: RAS and BRAF mutations can be detected as a mechanism of acquired resistance in circulating tumor (ct) DNA in patients with metastatic colorectal cancer treated with anti-epidermal growth factor receptor therapy. METHODS: RAS and BRAF mutational status was assessed in ctDNA in a baseline plasma sample and a serum sample collected at the time of the last available determination (named secondary extraction) from patients with KRAS exon 2 wild-type metastatic colorectal cancer treated in two first-line prospective biomarker-designed clinical trials (PULSE, ClinicalTrials.gov identifier: NCT01288339; and POSIBA, ClincialTrials.gov identifier: NCT01276379). RESULTS: Analysis of extended RAS and BRAF in tissue and plasma from 178 patients with KRAS exon 2 wild-type metastatic colorectal cancer showed a sensitivity of 64.1% and a specificity of 90%. The median overall survival (OS) of baseline patients with RAS and BRAF mutations in ctDNA was 22.3 months (95% CI, 15.6 to 29 months) and 8.9 months (95% CI, 6.3 to 11.4 months), respectively, which was significantly inferior to the median OS of 40.4 months (95% CI, 35.9 to 44.9 months) in two patients with wild-type disease (P < .001). Acquisition of RAS/BRAF mutations occurred in nine of 63 patients (14%) with progressive disease (PD; ie, blood draw within 1 month before PD or after PD) compared with six of 73 patients (8%) with no PD or blood extraction for ctDNA analysis before 1 month of PD (P = .47). Median OS in patients with RAS/BRAF acquisition was 23.9 months (95% CI, 19.7 to 27.9 months) compared with 40.6 months (95% CI, not reached to not reached) in patients who remained free of mutations (P = .016). CONCLUSION: Our results confirm that baseline RAS and BRAF testing in ctDNA discriminates survival. The emergence of RAS/BRAF mutations has limited relevance for the time to progression to anti-epidermal growth factor receptor therapy.

Coexpression of p-IGF-1R and MMP-7 Modulates Panitumumab and Cetuximab Efficacy in RAS Wild-Type Metastatic Colorectal Cancer Patients.

INTRODUCTION: The coexpression of pIGF-1R and MMP-7 (double-positive phenotype, DP) correlates with poor overall survival (OS) in KRAS wild-type (WT) (exon 2) metastatic colorectal cancer (mCRC) patients treated with irinotecan-cetuximab in second/third line. METHODS: We analyzed two prospective biomarker design trials of newly diagnosed RAS-WT mCRC patients treated with panitumumab-FOLFOX6 (PULSE trial; NCT01288339) or cetuximab plus either FOLFOX6/FOLFIRI (POSIBA trial; NCT01276379). The main exposure was DP phenotype (DP/non-DP), as assessed by two independent pathologists. DP cases were defined by immunohistochemistry as >70% expression of moderate or strong intensity for both MMP-7 and pIGF-1R. Primary endpoint: progression-free survival (PFS); secondary endpoints: OS and response rate. PFS and OS were adjusted by baseline characteristics using multivariate Cox models. RESULTS: We analyzed 67 patients (30 non-DP, 37 DP) in the PULSE trial and 181 patients in the POSIBA trial (158 non-DP, 23 DP). Response rates and PFS were similar between groups in both studies. DP was associated with prolonged OS in PULSE (adjusted HR: 0.23; 95%CI: 0.11-0.52; P=.0004) and with shorter OS in POSIBA (adjusted HR: 1.67; 95%CI: 0.96-2.90; P=.07). CONCLUSION: A differential effect of anti-EGFRs on survival by DP phenotype was observed. Panitumumab might be more beneficial for RAS-WT mCRC patients with DP phenotype, whereas cetuximab might improve OS in non-DP.

Mechanical thrombectomy for basilar artery thrombosis: a comparison of outcomes with anterior circulation occlusions.

BACKGROUND AND PURPOSE: The benefits of mechanical thrombectomy (MT) in basilar artery occlusions (BAO) have not been explored in recent clinical trials. We compared outcomes and procedural complications of MT in BAO with anterior circulation occlusions. METHODS: Data from the Madrid Stroke Network multicenter prospective registry were analyzed, including baseline characteristics, procedure times, procedural complications, symptomatic intracranial hemorrhage (SICH), modified Rankin Scale (mRS), and mortality at 3 months. RESULTS: Of 479 patients treated with MT, 52 (11%) had BAO. The onset to reperfusion time lapse was longer in patients with BAO (median (IQR) 385 min (320-540) vs 315 min (240-415), p<0.001), as was the duration of the procedures (100 min (40-130) vs 60 min (39-90), p=0.006). Moreover, the recanalization rate was lower (75% vs 84%, p=0.01). A trend toward more procedural complications was observed in patients with BAO (32% vs 21%, p=0.075). The frequency of SICH was 2% vs 5% (p=0.25). At 3 months, patients with BAO had a lower rate of independence (mRS 0-2) (40% vs 58%, p=0.016) and higher mortality (33% vs 12%, p<0.001). The rate of futile recanalization was 50% in BAO versus 35% in anterior circulation occlusions (p=0.05). Age and duration of the procedure were significant predictors of futile recanalization in BAO. CONCLUSIONS: MT is more laborious and shows more procedural complications in BAO than in anterior circulation strokes. The likelihood of futile recanalization is higher in BAO and is associated with greater age and longer procedure duration. A refinement of endovascular procedures for BAO might help optimize the results.

Acute ischemic stroke in a 12-year-old successfully treated with mechanical thrombectomy.

We report the case of a healthy 12-year-old girl with an acute ischemic stroke successfully treated with mechanical thrombectomy. The child was referred to our hospital 6 hours after sudden onset of severe headache and left hemiparesis. Cerebral angiography findings were consistent with right distal internal carotid artery occlusion in addition to ipsilateral middle cerebral artery occlusion. Subsequent mechanical thrombectomy with Solitaire AB device resulted in complete vessel recanalization. The patient experienced progressive neurologic improvement with good clinical recovery at the 3-month follow-up. To our knowledge, only 3 cases of primary mechanical thrombectomy in children have been previously reported in the literature. Safety and efficacy data for endovascular therapies in pediatric acute ischemic stroke are lacking. We propose mechanical thrombectomy as an option in children with significant neurologic deficits and proven arterial occlusion, especially when the therapeutic window for intravenous thrombolysis has been exceeded.