Prospective study of a molecular selection profile for RAS wild type colorectal cancer patients receiving irinotecan-cetuximab

Background: The aim of our study was to evaluate whether a panel of biomarkers, prospectively analysed might be able to predict patients' clinical outcome more accurately than RAS status alone. Methods: K-RAS (exons 2, 3, 4) wild type colorectal cancer patients, candidates to second/third-line cetuximab with chemotherapy were prospectively allocated into 2 groups on the basis of their profile: favourable (BRAF and PIK3CA exon 20 wild type, EGFR GCN ≥ 2.6, HER-3 Rajkumar score ≤ 8, IGF-1 immunostaining < 2) or unfavourable (any of the previous markers altered or mutated). After the introduction of N-RAS status (exons 2, 3, 4) only RAS wild type patients were considered eligible. Results: Forty-six patients were enrolled. Seventeen patients (37%) were allocated to the favourable and 29 patients (63%) to the unfavourable profile. RR in the favourable and unfavourable group was 11/17 (65%) and 2/29 (7%) (p = 0.007) respectively. The favourable group also showed an improved PFS (8months vs. 3months, p < 0.0001) and OS (15months vs. 6months, p < 0.0001). Conclusions: Our results suggest that prospective selection of optimal candidates for cetuximab treatment is feasible and may be able to improve clinical outcom

Epidermal growth factor receptor (EGFR) downstream signalling pathway in primary colorectal tumours and related metastatic sites: optimising EGFR-targeted treatment options

We analysed the expression of activated (phosphorylated) Akt and MAPK in 98 cases of paired primary colorectal tumours and metastases with the aim to define better the epidermal growth factor receptor (EGFR)-related molecular profile of colorectal cancer as a tool for treatment selection. Among 47 (48%) EGFR-negative primary tumours, 35 cases (74%) were positive for phosphorylated Akt and MAPK. Among 51 (52%) EGFR-positive primary colorectal cancers, 13 (25%) cases were negative for phosphorylated Akt and 15 (29%) were negative for phosphorylated MAPK. In EGFR-negative metastases (56 cases, 55%), phosphorylated Akt was expressed in 41 (73%) and phosphorylated MAPK was expressed in 36 (64%) samples, whereas in EGFR-positive metastases, phosphorylated Akt and MAPK were negative in 14 (31%) and in 10 (22%) cases, respectively. Phosphorylated Akt expression in primary colorectal tumours changed from positive to negative in 16 (16%) paired metastases and from negative to positive in 13 (13%) related metastatic sites. Phosphorylated MAPK expression in primary tumours changed from positive to negative in 13 (13%) paired metastases and from negative to positive in 12 (12%) related metastatic sites. Our findings suggest that phosphorylated Akt and MAPK status in primary tumours does not correlate with Akt and MAPK status in corresponding metastases. EGFR downstream signalling pathway can be overactivated even in the absence of EGFR expression in a considerable proportion of patients

Prognostic value for incidental antihypertensive therapy with β-blockers in metastatic colorectal cancer

Previous studies suggested that the incidental use of β-blockers might influence clinical outcome in solid tumors. We assessed the correlation between the incidental use of β-blockers and clinical outcome in colorectal cancer patients treated with first-line chemotherapy alone or in combination with bevacizumab in metastatic colorectal cancer patients. We collected data from 235 metastatic colorectal cancer patients treated with first-line chemotherapy alone (128 patients) or with bevacizumab (107 patients). Patients were stratified for clinical factors such as β-blockers use, age, sex, and site of metastases, previous adjuvant chemotherapy and ECOG performance status. In the chemotherapy alone group patients receiving β-blockers showed an improved overall survival (median OS 41.3 vs 25.7 months, P = 0.03, HR: 2.26, 95% CI: 1.05-3.24). A significant relationship with improved response rate was also evident for B-blocker users (P = 0.044). On the contrary in the β-blockers users group treated with chemotherapy in combination with bevacizumab we observed a trend toward a worse overall survival although nonstatistically significant (median OS 18.5 vs 23.6 months, HR: 0. 89, 95% CI: 0.38-2.03, P = 0.77). Our analysis confirmed a potential prognostic role for the use of β-blockers in colorectal cancer patients treated with chemotherapy. Our findings also suggest a potential worse outcome for patients on β-blockers receiving bevacizumab. Future prospective studies should include the incidental use of β-blockers as stratification factor for clinical outcome

Identifying a brain network for musical rhythm: A functional neuroimaging meta-analysis and systematic review

We conducted a systematic review and meta-analysis of 30 functional magnetic resonance imaging studies investigating processing of musical rhythms in neurotypical adults. First, we identified a general network for musical rhythm, encompassing all relevant sensory and motor processes (Beat-based, rest baseline, 12 contrasts) which revealed a large network involving auditory and motor regions. This network included the bilateral superior temporal cortices, supplementary motor area (SMA), putamen, and cerebellum. Second, we identified more precise loci for beat-based musical rhythms (Beat-based, audio-motor control, 8 contrasts) in the bilateral putamen. Third, we identified regions modulated by beat based rhythmic complexity (Complexity, 16 contrasts) which included the bilateral SMA-proper/pre-SMA, cerebellum, inferior parietal regions, and right temporal areas. This meta-analysis suggests that musical rhythm is largely represented in a bilateral cortico-subcortical network. Our findings align with existing theoretical frameworks about auditory-motor coupling to a musical beat and provide a foundation for studying how the neural bases of musical rhythm may overlap with other cognitive domains

Linking the genomic signatures of human beat synchronization and learned song in birds

The development of rhythmicity is foundational to communicative and social behaviours in humans and many other species, and mechanisms of synchrony could be conserved across species. The goal of the current paper is to explore evolutionary hypotheses linking vocal learning and beat synchronization through genomic approaches, testing the prediction that genetic underpinnings of birdsong also contribute to the aetiology of human interactions with musical beat structure. We combined state-of-the-art-genomic datasets that account for underlying polygenicity of these traits: birdsong genome-wide transcriptomics linked to singing in zebra finches, and a human genome-wide association study of beat synchronization. Results of competitive gene set analysis revealed that the genetic architecture of human beat synchronization is significantly enriched for birdsong genes expressed in songbird Area X (a key nucleus for vocal learning, and homologous to human basal ganglia). These findings complement ethological and neural evidence of the relationship between vocal learning and beat synchronization, supporting a framework of some degree of common genomic substrates underlying rhythm-related behaviours in two clades, humans and songbirds (the largest evolutionary radiation of vocal learners). Future cross-species approaches investigating the genetic underpinnings of beat synchronization in a broad evolutionary context are discussed

Lactate dehydrogenase in hepatocellular carcinoma: something old, something new

Hepatocellular carcinoma (HCC) is the most common primary liver tumour (80-90%) and represents more than 5.7% of all cancers. Although in recent years the therapeutic options for these patients have increased, clinical results are yet unsatisfactory and the prognosis remains dismal. Clinical or molecular criteria allowing a more accurate selection of patients are in fact largely lacking. Lactic dehydrogenase (LDH) is a glycolytic key enzyme in the conversion of pyruvate to lactate under anaerobic conditions. In preclinical models, upregulation of LDH has been suggested to ensure both an efficient anaerobic/glycolytic metabolism and a reduced dependence on oxygen under hypoxic conditions in tumour cells. Data from several analyses on different tumour types seem to suggest that LDH levels may be a significant prognostic factor. The role of LDH in HCC has been investigated by different authors in heterogeneous populations of patients. It has been tested as a potential biomarker in retrospective, small, and nonfocused studies in patients undergoing surgery, transarterial chemoembolization (TACE), and systemic therapy. In the major part of these studies, high LDH serum levels seem to predict a poorer outcome. We have reviewed literature in this setting trying to resume basis for future studies validating the role of LDH in this diseas

Angiogenesis genotyping in the selection of first-line treatment with either sunitinib or pazopanib for advanced renal cell carcinoma

Recent data from the COMPARZ study seem to suggest a noninferiority of pazopanib confronted with sunitinib in PFS and OS. We previously reported how VEGF and VEGFR polymorphisms might have a predictive role in patients treated with first-line sunitinib. Aim of our study was to investigate whether tumour angiogenesis genotyping could influence clinical outcome in RCC patients treated with either sunitinib or pazopanib, in order to help clinicians select the appropriate treatment for each patient. Results: 19 patients were treated with pazopanib while 78 received sunitinib. VEGF A rs833061 resulted significant in PFS in sunitinib vs pazopanib patients (CC+CT > TT in sunitinib, TT > CC+CT in pazopanib; p CC in sunitinib, CC > GG+CG in pazopanib; p CC in sunitinib, CC > AA+AC in pazopanib; p < 0,0001). OS showed no statistically significant difference. Conclusions: In our analysis patients with opposite polymorphisms of rs833061, rs2010963, rs699947 of VEGF A seems to have a better PFS if treated with either sunitinib or pazopanib. Our data seem to suggest that biology could have a role choosing first line treatment for mRCC patients. Methods: A retrospective analysis on 97 histologic samples of mRCC patients was conducted for VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs

Emerging treatment evolutions and integrated molecular characteristics of biliary tract cancers

Biliary tract cancers&nbsp;(BTCs) consist of a group of highly heterogeneous malignancies that&nbsp;are&nbsp;characterized by&nbsp;genomic differences among tumors from different anatomic sites. The current&nbsp;treatment&nbsp;for&nbsp;BTC&nbsp;includes surgery,&nbsp;chemotherapy, target therapy, and immunotherapy. Although surgery remains the primary option for localized disease, representing the only potential curative treatment, a high risk of recurrence cannot be neglected.&nbsp;Chemotherapy has been considered&nbsp;the standard of care for both advanced and metastatic disease and in adjuvant settings. However, drug resistance is a major obstacle associated with chemotherapy. The development of genetic testing technologies, including next-generation sequencing, has opened the door for the identification of drug targets and candidate molecules.&nbsp;A series of preclinical studies has demonstrated the role of gene mutations, abnormal signaling pathways, and immunosuppression in the pathogenesis of BTC, laying the foundation for the application of targeted therapy and immunotherapy. A variety of molecularly targeted agents, including pemigatinib, have shown promising survival benefits in patients with advanced disease. The rapidly evolving role of multimodal therapy represents the subject of this review