Right- vs. left-sided metastatic colorectal cancer: Differences in tumor biology and bevacizumab efficacy

There is evidence of a different response to treatment with regard to the primary tumor localization (right-sided or left-sided) in patients with metastatic colorectal cancer (mCRC). We analyzed the different outcomes and biomolecular characteristics in relation to tumor localization in 122 of the 370 patients with metastatic colorectal cancer enrolled onto the phase III prospective multicenter “Italian Trial in Advanced Colorectal Cancer (ITACa)”, randomized to receive first-line chemotherapy (CT) or CT plus bevacizumab (CT + B). RAS and BRAF mutations; baseline expression levels of circulating vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), cyclooxygenase-2 (COX2), ephrin type-B receptor 4 (EPHB4), hypoxia-inducible factor 1-alpha (HIF-1α), lactate dehydrogenase (LDH), and high-sensitivity C reactive protein (hs-CRP); and inflammatory indexes such as the neutrophil-to-lymphocyte ratio, platelet-lymphocyte rate and systemic immune-inflammation index were evaluated. Patients with right-sided tumors showed a longer median progression-free survival in the CT + B arm than in the CT group (12.6 vs. 9.0 months, respectively, p = 0.017). Baseline inflammatory indexes were significantly higher in left-sided tumors, whereas eNOS and EPHB4 expression was significantly higher and BRAF mutation more frequent in right-sided tumors. Our data suggest a greater efficacy of the CT + B combination in right-sided mCRC, which might be attributable to the lower inflammatory status and higher expression of pro-angiogenic factors that appear to characterize these tumors

HRAS overexpression predicts response to Lenvatinib treatment in gastroenteropancreatic neuroendocrine tumors

IntroductionNeuroendocrine neoplasms (NENs) are a rare group of tumors exceptionally heterogeneous, with clinical presentation ranging from well differentiated more indolent tumors to poorly differentiated very aggressive forms. Both are often diagnosed after the metastatic spread and require appropriate medical treatment. A high priority need in the management of this disease is the identification of effective therapeutic strategies for advanced and metastatic patients. The recent TALENT trial demonstrated the efficacy of lenvatinib, a multi-tyrosine kinase inhibitor, in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) with no other treatment indication. Further development of this drug in advanced NETs is warranted.MethodsWe investigated potential clinical and molecular determinants of lenvatinib response in human primary cultures derived from patients with GEP-NET of different grades and sites of origin. We correlated response to treatment with patient clinical characteristics, with the mutational status of 161-cancer associated genes and with the expression levels of MKI-related genes.ResultsLenvatinib exerted a significant antitumor activity in primary GEP-NET cells, with median survival inhibitions similar or higher than those of standard frontline treatments. Of the 11 primary cultures analyzed in our case series, 6 were classified as responder showing a significant survival inhibition, and 5 as non-responder. We observed that the overexpression of HRAS in the original tumor tissue compared to the matched healthy tissue significantly correlated with responsiveness of primary cells to lenvatinib (p=.048). All 5 non-responder cultures showed normal HRAS expression, while of the 6 responder cultures, 4 had HRAS overexpression. Overexpression of HRAS was not associated with gene mutation. None of the other evaluated clinical variables (grade, Ki67, site of origin and syndromic disease) or molecular markers correlated with response.DiscussionLenvatinib appears to be a highly effective drug for the treatment of NETs. The evaluation of HRAS expression in the tumor tissue might improve patient selection and optimize therapeutic outcome

Ultralight vector dark matter search using data from the KAGRA O3GK run

Among the various candidates for dark matter (DM), ultralight vector DM can be probed by laser interferometric gravitational wave detectors through the measurement of oscillating length changes in the arm cavities. In this context, KAGRA has a unique feature due to differing compositions of its mirrors, enhancing the signal of vector DM in the length change in the auxiliary channels. Here we present the result of a search for U(1)B−L gauge boson DM using the KAGRA data from auxiliary length channels during the first joint observation run together with GEO600. By applying our search pipeline, which takes into account the stochastic nature of ultralight DM, upper bounds on the coupling strength between the U(1)B−L gauge boson and ordinary matter are obtained for a range of DM masses. While our constraints are less stringent than those derived from previous experiments, this study demonstrates the applicability of our method to the lower-mass vector DM search, which is made difficult in this measurement by the short observation time compared to the auto-correlation time scale of DM

Search for gravitational-lensing signatures in the full third observing run of the LIGO-Virgo network

Gravitational lensing by massive objects along the line of sight to the source causes distortions of gravitational wave-signals; such distortions may reveal information about fundamental physics, cosmology and astrophysics. In this work, we have extended the search for lensing signatures to all binary black hole events from the third observing run of the LIGO--Virgo network. We search for repeated signals from strong lensing by 1) performing targeted searches for subthreshold signals, 2) calculating the degree of overlap amongst the intrinsic parameters and sky location of pairs of signals, 3) comparing the similarities of the spectrograms amongst pairs of signals, and 4) performing dual-signal Bayesian analysis that takes into account selection effects and astrophysical knowledge. We also search for distortions to the gravitational waveform caused by 1) frequency-independent phase shifts in strongly lensed images, and 2) frequency-dependent modulation of the amplitude and phase due to point masses. None of these searches yields significant evidence for lensing. Finally, we use the non-detection of gravitational-wave lensing to constrain the lensing rate based on the latest merger-rate estimates and the fraction of dark matter composed of compact objects

Search for eccentric black hole coalescences during the third observing run of LIGO and Virgo

Despite the growing number of confident binary black hole coalescences observed through gravitational waves so far, the astrophysical origin of these binaries remains uncertain. Orbital eccentricity is one of the clearest tracers of binary formation channels. Identifying binary eccentricity, however, remains challenging due to the limited availability of gravitational waveforms that include effects of eccentricity. Here, we present observational results for a waveform-independent search sensitive to eccentric black hole coalescences, covering the third observing run (O3) of the LIGO and Virgo detectors. We identified no new high-significance candidates beyond those that were already identified with searches focusing on quasi-circular binaries. We determine the sensitivity of our search to high-mass (total mass M>70 M⊙) binaries covering eccentricities up to 0.3 at 15 Hz orbital frequency, and use this to compare model predictions to search results. Assuming all detections are indeed quasi-circular, for our fiducial population model, we place an upper limit for the merger rate density of high-mass binaries with eccentricities 0<e≤0.3 at 0.33 Gpc−3 yr−1 at 90\% confidence level

<i>EGFR</i>and<i>K-ras</i>mutations in cytologic samples from fine-needle aspirates in NSCLC patients: Table 1–

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Analysis of Genetic Alterations in Tunisian Patients with Lung Adenocarcinoma

The identification of the mutations that drive lung cancer have furnished new targets for the treatment of non-small cell lung cancer (NSCLC) and led to the development of targeted therapies such as tyrosine kinase inhibitors that are used to combat the molecular changes promoting cancer progression. Furthermore, biomarkers identified from gene analysis can be used to detect early lung cancer, determine patient prognosis, and monitor response to therapy. In the present study we analyzed the molecular profile of seventy-three Tunisian patients with lung adenocarcinoma (LAD). Mutational analyses for EGFR and KRAS were performed using direct sequencing, immunohistochemistry or MassARRAY. Anaplastic lymphoma kinase (ALK) rearrangement was evaluated by immunohistochemistry using the D5F3 clone, and p53 expression was also assessed. The median age of patients at diagnosis was 61 years (range 23&#8722;82 years). Using different methodologies, EGFR mutations were found in 5.47% of patients and only exon 19 deletions &#8220;E746-A750 del&#8221; were detected. KRAS mutations were present in 9.58% of cases, while only one patient was ALK-positive. Moreover, abnormal immunostaining of p53 was detected in 56.16% of patients. In conclusion, the detected rates of EGFR and KRAS mutation and ALK rearrangement were lower than those found in European and Asian countries, whereas, abnormal p53 expression was slightly more frequent. Furthermore, given the small sample size of this study, a more comprehensive analysis of this patient set is warranted

Efficacy of sorafenib in BRAF-mutated nonsmall- cell lung cancer (NSCLC) and no response in synchronous BRAF wild typehepatocellular carcinoma: A case report

Background: Sorafenib is a multi-targeted kinase inhibitor with a demonstrated activity in renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC), and it is currently used for the treatment of these pathologies. Ongoing clinical trials are studying its activity in other malignancies, such as non-small-cell lung cancer (NSCLC). However, no biological marker is known to define either the sensitivity or resistance to the drug. Case presentation: Here we report a case of a patient with two synchronous tumors, HCC and NSCLC, with metastases in the contralateral lung and bone. The patient was treated with gemcitabine as first line, with a resulting progressive disease after two months, and then with sorafenib at standard dosage in the second line setting. After 6 months of treatment CT scan showed a partial response in the primary lesion of the lung, complete response of the metastasis in the contralateral lung, and stability of HCC. The patient had progression in the lung, liver and bone after 13 months of therapy. A molecular characterization of NSCLC and HCC lesions was performed, revealing a BRAF exon 11 mutation (G469V) only in NSCLC. We hypothesize that the response observed in NSCLC lesions could be due to the presence of BRAF mutation, and that this alteration could be responsible in determining sorafenib sensitivity. Conclusions: Results observed in this case encourage further research on the activity of sorafenib in both HCC and NSCLC, based on the presence of BRAF mutation. This could lead to a selection of HCC patients to be treated with this drug, and could help identify a novel treatment strategy for BRAF-mutated NSCLC patients

Clinicopathological Features of Non-Small Cell Lung Carcinoma with BRAF Mutation

(1) Background: BRAF mutations affect 4–5% of lung adenocarcinomas. This study aimed to analyze the clinicopathological features of lung carcinomas with BRAF mutations, focusing on V600E vs. non-V600E and the presence of co-mutations. (2) Methods: All BRAF-mutated lung carcinomas were retrieved from a molecular diagnostic unit (the reference unit for four different hospitals). The samples were analyzed using next-generation sequencing. Statistical analyses included log-rank tests for overall survival (OS) and progression-free survival (PFS). (3) Results: In total, 60 BRAF-mutated lung carcinomas were retrieved: 24 (40.0%) with V600E and 36 (60.0%) with non-V600E mutations, and 21 (35.0%) with other co-mutations and 39 (65.0%) with only BRAF mutations. Survival data were available for 54/60 (90.0%) cases. Targeted therapy was documented in 11 cases. Patients with V600E mutations exhibited a better prognosis than patients with non-V600E mutations (p = 0.008 for OS, p = 0.018 for PFS); this was confirmed in PFS (p = 0.036) when considering only patients who received no targeted therapy. Patients with co-mutations displayed no prognostic difference compared to patients carrying only BRAF mutations (p = 0.590 for OS, p = 0.938 for PFS). (4) Conclusions: BRAF-mutated lung carcinomas with V600E (40.0%) had a better prognosis than those without V600E. Concomitant co-mutations (35.0%) did not affect the prognosis