Epidermal growth factor receptor (EGFR) inhibitors are valuable therapeutics in metastatic colorectal cancer (mCRC). Anti-EGFR monoclonal antibodies (MoAbs), such as cetuximab or panitumumab, in ...combination with chemotherapy are effective treatment options for patients with RAS and BRAF wild-type mCRC. Nevertheless, several issues are still open concerning the optimal use of anti-EGFR drugs in the continuum of care of mCRC. Novel approaches for increasing the efficacy of anti-EGFR therapies include better molecular selection of EGFR-dependent mCRC, intensification of chemotherapy, combination of anti-EGFR MoAbs and immune checkpoint inhibitors, and reintroduction of EGFR blockade or ‘rechallenge’ in selected patients who have previously responded to anti-EGFR MoAb therapy. An extensive translational research program was conducted in the Cetuximab After Progression in KRAS wIld-type colorectal cancer patients-Gruppo Oncologico dell' Italia Meridionale (CAPRI-GOIM) study with the aims of determining which subgroups of patients could benefit from the continuous inhibition of EGFR, from evaluating the role of liquid biopsy-based and its concordance with tissue-based molecular testing, and from investigating novel potential mechanisms of resistance to anti-EGFR therapies. In this review, we summarize the translational and clinical findings of the CAPRI-GOIM program in the context of the current knowledge of therapeutic strategies and of ongoing research on more appropriate uses of anti-EGFR therapies in RAS and BRAF wild-type mCRC patients.
•The epidermal growth factor (EGFR) is a therapeutic option for patients with all RAS WT metastatic colorectal cancer (mCRC).•A better knowledge of the mechanism of primary or acquired resistance to EGFR-therapies can improve patient's selection.•Despite disease progression a subset of mCRC are still sensitive to EGFR inhibition.•Rechallenge strategies with anti-EGFR might represent a promising therapeutic option.
Mechanisms of acquired resistance to trastuzumab‐based treatment in gastric cancer are largely unknown. In this study, we analyzed 22 pairs of tumor samples taken at baseline and post‐progression in ...patients receiving chemotherapy and trastuzumab for advanced HER2‐positive immunohistochemistry (IHC) 3+ or 2+ with in‐situ hybridization (ISH) amplification gastric or gastroesophageal cancers. Strict clinical criteria for defining acquired trastuzumab resistance were adopted. Loss of HER2 positivity and loss of HER2 over‐expression were defined as post‐trastuzumab IHC score <3+ and absence of ISH amplification, and IHC “downscoring” from 2+/3+ to 0/1+, respectively. HER2 IHC was always performed, while ISH was missing in 3 post‐progression samples. Patients with initial HER2 IHC score 3+ and 2+ were 14 (64%) and 8 (36%), respectively. Loss of HER2 positivity and HER2 over‐expression was observed in 32 and 32% samples, respectively. The chance of HER2 loss was not associated with any of the baseline clinicopathological variables. The only exception was in patients with initial IHC score 2+ versus 3+, for both endpoints of HER2 positivity (80 vs. 14%; p = 0.008) and HER2 over‐expression (63 vs. 14%; p = 0.025). As already shown in breast cancer, loss of HER2 may be observed also in gastric cancers patients treated with trastuzumab‐based chemotherapy in the clinical practice. This phenomenon may be one of the biological reasons explaining the failure of anti‐HER2 second‐line strategies in initially HER2‐positive disease.
What's new?
Patients with cancers positive for human epidermal growth factor receptor 2 (HER2) generally fail to respond to second‐line treatments, particularly when first‐line therapy included use of the HER2‐targeted agent trastuzumab. Post‐progression changes in HER2 expression, however, have not been studied extensively, and as a consequence, their therapeutic relevance is unclear. In this study, HER2 loss was associated with acquired resistance to trastuzumab in almost one‐third of patients with gastric or gastroesophageal cancers that initially were HER2‐positive. The findings suggest that after failure of trastuzumab, HER2 status should be reassessed prior to inclusion in clinical trials with targeted agents.
The epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase receptor involved in the proliferation and survival of cancer cells. EGFR is the first molecular target against which ...monoclonal antibodies (mAb) have been developed for cancer therapy. Here we review the mechanisms underlying the effects of EGFR-specific mAb in cancer therapy. The efficacy of EGFR-specific mAb in cancer occurs thanks to inhibition of EGFR-generated signalling; furthermore, the effects of antibodies on the immune system seem to play an important role in determining the overall anti-tumour response. In this review, attention is focused on cetuximab and panitumumab, two mAb introduced recently into clinical practice for treatment of metastatic colorectal and head and neck cancer which target the external part of EGFR.
Elastoviscoplastic flows in porous media De Vita, F.; Rosti, M.E.; Izbassarov, D. ...
Journal of non-Newtonian fluid mechanics,
08/2018, Volume:
258
Journal Article
Peer reviewed
Open access
We investigate the elastoviscoplastic flow through porous media by numerical simulations. We solve the Navier–Stokes equations combined with the elastoviscoplastic model proposed by Saramito for the ...stress tensor evolution 1. In this model, the material behaves as a viscoelastic solid when unyielded, and as a viscoelastic Oldroyd-B fluid for stresses higher than the yield stress. The porous media is made of a symmetric array of cylinders, and we solve the flow in one periodic cell. We find that the solution is time-dependent even at low Reynolds numbers as we observe oscillations in time of the unyielded region especially at high Bingham numbers. The volume of the unyielded region slightly decreases with the Reynolds number and strongly increases with the Bingham number; up to 70% of the total volume is unyielded for the highest Bingham numbers considered here. The flow is mainly shear dominated in the yielded region, while shear and elongational flow are equally distributed in the unyielded region. We compute the relation between the pressure drop and the flow rate in the porous medium and present an empirical closure as function of the Bingham and Reynolds numbers. The apparent permeability, normalized with the case of Newtonian fluids, is shown to be greater than 1 at low Bingham numbers, corresponding to lower pressure drops due to the flow elasticity, and smaller than 1 for high Bingham numbers, indicating larger dissipation in the flow owing to the presence of the yielded regions. Finally we investigate the effect of the Weissenberg number on the distribution of the unyielded regions and on the pressure gradient.
Treatment with antiepidermal growth factor receptor (anti-EGFR) monoclonal antibodies has been restricted to metastatic colorectal cancer (mCRC) patients with RAS wild-type tumors. Next-generation ...sequencing (NGS) allows the assessment in a single analysis of a large number of gene alterations and might provide important predictive and prognostic information.
In the CAPRI-GOIM trial, 340 KRAS exon 2 wild-type mCRC patients received first-line FOLFIRI plus cetuximab. Tumor samples (182/340, 53.5%) were assessed by NGS to search for mutations in 22 genes involved in colon cancer.
Objective responses in the NGS cohort were observed in 104/182 patients overall response rate (ORR) 57.1%; 95% confidence interval (95% CI) 52% to 66.4% with a median progression-free survival (mPFS) of 9.8 (95% CI 8.7–11.5) months. NGS analysis was successfully completed in all 182 samples. One or more gene mutations (up to five) were detected in 124/182 (68.1%) tumors within 14/22 genes for a total of 206 mutations. KRAS exon 2 mutations were identified in 29/182 (15.9%) samples, defined as wild type by local laboratory assessment. Frequently mutated genes were: TP53 (39.6%), KRAS exons 3/4 (8.8%), NRAS exons 2/3 (7.1%), PIK3CA exons 9/20 (13.2%), BRAF (8.2%). FOLFIRI plus cetuximab treatment determined ORR of 62.0% (95% CI 55.5% to 74.6%) with mPFS of 11.1 (95% CI 9.2–12.8) months in patients with KRAS and NRAS wild-type tumors. Conversely, ORR was 46.6% (95% CI 39.9–57.5%) with mPFS of 8.9 (95% CI 7.4–9.6) months in patients with KRAS or NRAS mutations. Similarly, the subgroup of patients carrying KRAS, NRAS, BRAF, or PIK3CA mutations showed a worse outcome, although this might be due to a prognostic effect.
This study demonstrates that NGS analysis in mCRC is feasible, reveals high level of intra and intertumor heterogeneity, and identifies patients that might benefit of FOLFIRI plus cetuximab treatment.
The prognosis of patients with pancreatic cancer is extremely poor, and current systemic therapies provide marginal survival benefits for treated patients. The era of targeted therapies has offered a ...new avenue to search for potentially more effective strategies. Epidermal growth factor receptor (EGFR) is a member of the erbB/human epidermal growth factor receptor family of tyrosine kinases, which includes erbB2/HER2, erbB3/HER3 and erbB4/HER4. Epidermal growth factor receptor overexpression may be detected in up to 90% of pancreatic tumors. Two pharmacologic approaches have been successfully used to inhibit epidermal growth factor receptor function in cancer treatment: neutralizing monoclonal antibodies and small molecule tyrosine inhibitors. The randomized trials studying the addition of EGFR targeted agents to gemcitabine compared with gemcitabine alone have been disappointing, although results with the EGFR tyrosine kinase inhibitor erlotinib were statistically significant but clinically of marginal benefit. In this article, we review the epidermal growth factor receptor signaling network in pancreatic cancer, the strategies to increase the effectiveness of epidermal growth factor receptor inhibitors, and the clinical trials of these inhibitors in pancreatic cancer.
The recent successful development of monoclonal antibodies that target key components of biological pathways has expanded the armamentarium of treatment options for patients with colorectal cancer ...(CRC). In particular, the epidermal growth factor receptor (EGFR), a tyrosine kinase growth factor receptor involved in CRC development and progression, is exploited by the newest monoclonal antibody that is available for use in CRC patients. Cetuximab, the first chimeric monoclonal antibody, which has been generated against the EGFR, is currently registered in USA, Europe and worldwide, in combination with irinotecan in the treatment of metastatic CRC patients who have progressed on irinotecan containing chemotherapy. Cetuximab is well tolerated and does not exacerbate the toxicity of concomitant chemotherapy. Furthermore, a series of phase III clinical trials are currently evaluating the combination of cetuximab with standard chemotherapy regimens in the first-line treatment chemotherapy-naïve patients with metastatic CRC.
Sorafenib is considered the standard systemic therapy for hepatocellular carcinoma (HCC), in patients with well-preserved liver function (Child-Pugh A class) and advanced-stage HCC (BCLC-C) or in ...patients with HCC progressing after locoregional therapies, with a high grade of recommendation. The approval of sorafenib for this indication was grounded on the efficacy and the safety results reported by two international randomized, controlled trials, the SHARP and the Asia-Pacific studies. In addition, the efficacy and the safety of sorafenib in clinical practice are addressed by several field-practice experiences, including the multinational GIDEON study and the SOFIA study. Finally, further research on sorafenib is ongoing to optimize the use of this molecule. This review aims to provide an overview of the most relevant clinical data on the efficacy and the safety of sorafenib in patients with HCC.
SUMMARY Surgery is the only curative therapy for gastric cancer. In the metastatic setting the objective of treatment is to manage symptoms, improve quality of life and prolong survival, but current ...treatment options have limited efficacy and some of them exhibit unfavourable toxicity profiles. Fluoropyrimidine, taxanes and platinum-based regimens are used most frequently and offer a response rate of 30–50% with a median overall survival of =1 year. These discouraging data support the need for new therapeutic strategies based on targeted drugs. Trastuzumab, a monoclonal antibody against HER2, has shown survival benefits when given with chemotherapy in all setting of HER2-positive breast cancer patients. The ToGA trial, the first study evaluating the efficacy and safety of adding trastuzumab to chemotherapy in HER-2 positive advanced gastric cancer, showed a significant superiority of combination over chemotherapy alone. Based on these results trastuzumab combined with a cisplatin and fluoropyrimidine regimen appear the new reference treatment for HER-2 positive metastatic gastric cancer.
This work focuses on the comparison between Newtonian and non-Newtonian blood flows through a bileaflet mechanical heart valve in the aortic root. The blood, in fact, is a concentrated suspension of ...cells, mainly red blood cells, in a Newtonian matrix, the plasma, and consequently its overall behavior is that of a non-Newtonian fluid owing to the action of the cells’ membrane on the fluid part. The common practice, however, assumes the blood in large vessels as a Newtonian fluid since the shear rate is generally high and the effective viscosity becomes independent of the former. In this paper, we show that this is not always the case even in the aorta, the largest artery of the systemic circulation, owing to the pulsatile and transitional nature of the flow. Unexpectedly, for most of the pulsating cycle and in a large part of the fluid volume, the shear rate is smaller than the threshold level for the blood to display a constant effective viscosity and its shear thinning character might affect the system dynamics. A direct inspection of the various flow features has shown that the valve dynamics, the transvalvular pressure drop and the large-scale features of the flow are very similar for the Newtonian and non-Newtonian fluid models. On the other hand, the mechanical damage of the red blood cells (hemolysis), induced by the altered stress values in the flow, is larger for the non-Newtonian fluid model than for the Newtonian one.
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